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In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort
Abstract
Arsenic has wide-ranging effects on human health and there is evidence that it alters the immune response by influencing CD4 +/CD8 + T cell ratios, IL-2 cytokine levels, and the expression of immune-response genes. We investigated the impact of in utero environmental arsenic exposure on immune development and function in newborns participating in a pregnancy cohort in New Hampshire, U.S., where arsenic levels have exceeded the current EPA maximum contaminant level of 10 μg/L. Our results showed that maternal urinary arsenic concentrations were inversely related to absolute total CD45RA + CD4 + cord blood CD69 + T cell counts (N = 116, p = 0.04) and positively associated with CD45RA + CD69- CD294 + cell counts (p = 0.01). In placental samples (N = 70), higher in utero urinary arsenic concentrations were positively associated with expression of IL1β (p = 0.03). These data provide evidence that relatively low-level arsenic exposure in utero may alter the fetal immune system and lead to immune dysregulation.
... Nygaard et al. found that maternal As exposure was inversely associated with levels of memory T cells in the umbilical cord blood T cell subset in all children (β = −21 %, 95%CI: −36 %, −3 %) and with levels of activated memory T cells in male children (β = −26 %, 95%CI: −43 %, −3 %) (Nygaard et al., 2017). Nadeau et al. found that maternal urinary As concentrations were negatively correlated with absolute counts of naive activated T cells (CD69 + ) in cord blood and positively correlated with absolute naive non-activated CD294 + T cell (a surrogate Th2 cell surface phenotype) counts, suggesting that As is toxic to naive T cells and promotes Th2-type responses (Nadeau et al., 2014). Results from a birth cohort study suggest that prenatal and childhood exposure to As leads to reduced production of naive T cells (Mannan et al., 2018), which may contribute to immunosenescence and immunodeficiency. ...
... As a growth factor for keratinocytes, GM-CSF has an enhancing effect on inflammatory cell influx, and the association of increased GM-CSF secretion with increased urinary As concentrations suggest the proinflammatory properties of As. Similarly, Nadeau et al. found that As exposure in utero was associated with increased expression of the proinflammatory cytokine IL-1β in the placenta (Nadeau et al., 2014). Zhang et al. found that the anti-inflammatory cytokine IL-1RA concentration in children was inversely correlated with blood As concentration (β = −0.173, ...
... The above results suggest that both prenatal and childhood As exposure lead to decreased levels of childhood T lymphocytes and their subsets, K. Zheng et al. Science of the Total Environment 868 (2023) 161691 especially naive T cells, which would impair T cell-mediated cellular immune responses (Ahmed et al., 2011;Kile et al., 2014;Mannan et al., 2018;Nadeau et al., 2014;Nygaard et al., 2017;Soto-Peña et al., 2006). As exposure also acts on children's innate immune cells, attenuates macrophage-mediated pathogen killing, and increases the risk of childhood respiratory disease (Parvez et al., 2019). ...
Heavy metals exist widely in daily life, and exposure to heavy metals caused by environmental pollution has become a serious public health problem worldwide. Due to children's age-specific behavioral characteristics and imperfect physical function, the adverse health effects of heavy metals on children are much higher than in adults. Studies have found that heavy metal exposure is associated with low immune function in children. Although there are reviews describing the evidence for the adverse effects of heavy metal exposure on the immune system in children, the summary of evidence from epidemiological studies involving the level of immune molecules is not comprehensive. Therefore, this review summarizes the current epidemiological study on the effect of heavy metal exposure on childhood immune function from multiple perspectives, emphasizing its risks to the health of children's immune systems. It focuses on the effects of six heavy metals (lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), nickel (Ni), and manganese (Mn)) on children's innate immune cells, lymphocytes and their subpopulations, cytokines, total and specific immunoglobulins, and explores the immunotoxicological effects of heavy metals. The review finds that exposure to heavy metals, particularly Pb, Cd, As, and Hg, not only reduced lymphocyte numbers and suppressed adaptive immune responses in children, but also altered the innate immune response to impair the body's ability to fight pathogens. Epidemiological evidence suggests that heavy metal exposure alters cytokine levels and is associated with the development of inflammatory responses in children. Pb, As, and Hg exposure was associated with vaccination failure and decreased antibody titers, and increased risk of immune-related diseases in children by altering specific immunoglobulin levels. Cd, Ni and Mn showed activation effects on the immune response to childhood vaccination. Exposure age, sex, nutritional status, and co-exposure may influence the effects of heavy metals on immune function in children.
... Finally, 57 research articles were included . The main evaluated outcomes were telomere length (TL) [24][25][26][27][28][29][30], DNA damage [31][32][33][34], mitochondrial DNA (mtDNA) content [35][36][37][38][39][40], gene expression [41][42][43][44][45][46][47][48], protein expression [49], metabolomics [50], and epigenetic modifications [48,. Only one study evaluated metal concentrations in the early postnatal period [55]. ...
... Regarding gene expression, eight articles with high quality (Table 4) reported adverse effects on the expression of some genes due to prenatal exposure to PTMs [41][42][43][44][45][46][47][48]. Al, As, Cd, and magnesium (Mg) were associated with altered gene expression. ...
... As concentrations in the maternal urine and umbilical cord blood were positively associated with alterations in the expression of genes involved in inflammation, such as interleukin 1 beta (IL-1β) in the placenta [46], the regulation of angiogenesis, and the development of embryonic vasculature, such as fms-related receptor tyrosine kinase 1 (sFLT1) [47]. On the other hand, Deyssenroth et al. [43] observed an inverse association between As concentrations and a 201gene module independent of the concentration of the other PTMs or the essential metals evaluated. ...
In recent years, the background level of environmental pollutants, including metals, has increased. Pollutant exposure during the earliest stages of life may determine chronic disease susceptibility in adulthood because of genetic or epigenetic changes. The objective of this review was to identify the association between prenatal and early postnatal exposure to potentially toxic metals (PTMs) and their adverse effects on the genetic material of offspring. A systematic review was carried out following the Cochrane methodology in four databases: PubMed, Scopus, Web of Science, and the Cochrane Library. Eligible papers were those conducted in humans and published in English between 2010/01/01 and 2021/04/30. A total of 57 articles were included, most of which evaluated prenatal exposure. Most commonly evaluated PTMs were As, Cd, and Pb. Main adverse effects on the genetic material of newborns associated with PTM prenatal exposure were alterations in telomere length, gene or protein expression, mitochondrial DNA content, metabolomics, DNA damage, and epigenetic modifications. Many of these effects were sex-specific, being predominant in boys. One article reported a synergistic interaction between As and Hg, and two articles observed antagonistic interactions between PTMs and essential metals, such as Cu, Se, and Zn. The findings in this review highlight that the problem of PTM exposure persists, affecting the most susceptible populations, such as newborns. Some of these associations were observed at low concentrations of PTMs. Most of the studies have focused on single exposures; however, three interactions between essential and nonessential metals were observed, highlighting that metal mixtures need more attention.
... Diverse epidemiological studies have examined the effects of prenatal exposure to toxic metals on immune system biomarkers in cord blood of neonates [136,[140][141][142][143] (Table 6). Changes in cord blood lymphocytes include a decreased number of activated T naïve cells, decreased percentages of Th, Th memory and activated cells, and increased number of Th2-related T cells in newborns exposed to mercury [125], arsenic [141,142] and cadmium [142]. ...
... Diverse epidemiological studies have examined the effects of prenatal exposure to toxic metals on immune system biomarkers in cord blood of neonates [136,[140][141][142][143] (Table 6). Changes in cord blood lymphocytes include a decreased number of activated T naïve cells, decreased percentages of Th, Th memory and activated cells, and increased number of Th2-related T cells in newborns exposed to mercury [125], arsenic [141,142] and cadmium [142]. Moreover, prenatal exposure to arsenic has been associated with an increased T cell proliferation and a decreased Treg suppressor function [141]. ...
... Changes in cord blood lymphocytes include a decreased number of activated T naïve cells, decreased percentages of Th, Th memory and activated cells, and increased number of Th2-related T cells in newborns exposed to mercury [125], arsenic [141,142] and cadmium [142]. Moreover, prenatal exposure to arsenic has been associated with an increased T cell proliferation and a decreased Treg suppressor function [141]. Furthermore, Belles-Isles et al. found negative correlations between mercury and cord blood IgM levels but positive correlations between lead and IgG cord blood levels [125]. ...
It is suggested that programming of the immune system starts before birth and is shaped by environmental influences acting during critical windows of susceptibility for human development. Prenatal and perinatal exposure to physiological, biological, physical, or chemical factors can trigger permanent, irreversible changes to the developing immune system, which may be reflected in cord blood of neonates. The aim of this narrative review is to summarize the evidence on the role of the prenatal and perinatal environment, including season of birth, mode of delivery, exposure to common allergens, a farming environment, pet ownership, and exposure to tobacco smoking and pollutants, in shaping the immune cell populations and cytokines at birth in humans. We also discuss how reported disruptions in the immune system at birth might contribute to the development of asthma and related allergic manifestations later in life.
... Maternal urinary arsenic concentrations are related to impaired function of T-cell in cord blood; in placental samples, higher in utero urinary arsenic concentrations are positively associated with IL1β2 expression Nadeau et al. (2014) in male C57BL/6 mice chronically exposed to arsenite or methylarsonous acid in drinking water confirmed that arsenite could induce impaired glucose tolerance in mice, but only at a higher concentration (50 mg/L) than that in humans (Paul et al. 2008). This may because of the higher rate of iAs metabolism and clearance in mice compared to humans. ...
... Expression of inflammatory genes IL1B and IL6 were elevated in association with arsenic exposure in human subjects (Wu et al. 2003). In a US pregnancy cohort in New Hampshire, where arsenic levels exceeded the current EPA maximum contaminant level of 10 μg/L, in utero arsenic exposure has shown greater IL1β expression in the placenta and changes of T cell phenotypes and T cell function in cord blood, which may alter fetal immune system development and lead to immune dysregulation (Nadeau et al. 2014). Another study in Bangladesh showed that maternal exposure to iAs during pregnancy increased oxidative stress and proinflammatory cytokines (IL1β, TNF-α, and IFNγ ) in the placenta and altered cord blood cytokines (IL1β, IL8, IFNγ , TNF-α) (Ahmed et al. 2011). ...
Diabetes mellitus (DM) is an enormous public health issue worldwide. Recent data suggest that chronic arsenic exposure is linked to the risk of developing type 1 and type 2 DM, albeit the underlying mechanisms are unclear. This review discusses the role of the immune system as a link to possibly explain some of the mechanisms of developing T1DM or T2DM associated with arsenic exposure in humans, animal models, and in vitro studies. The rationale for the hypothesis includes: (1) Arsenic is a well-recognized modulator of the immune system; (2) arsenic exposures are associated with increased risk of DM; and (3) dysregulation of the immune system is one of the hallmarks in the pathogenesis of both T1DM and T2DM. A better understanding of DM in association with immune dysregulation and arsenic exposures may help to understand how environmental exposures modulate the immune system and how these effects may impact the manifestation of disease.
... This may be because the sample size was limited and because our study only followed the child up to 5 years of age; according to Liu et al., it is between 8 and 11 years when the highest peak of CB-tIgE (cord blood total IgE) is identified, and these levels are associated with atopic diseases including AD [30]. However, it is important to mention that concentrations of total urinary arsenic obtained from the mothers showed levels higher than those reported by the US Environmental Protection Agency during the period from 2003 to 2016, in its National Report on Human Exposure to Environmental Chemicals [32]. Geometric mean arsenic levels for our study was 28.9 µg/L; this value is relevant because the total As concentration in the mother's urine is an exposure marker for the minimum amount of As that fetus is exposed; if a greater amount of total As than 0.010 mg/L is detected in the mother's urine, it means that the fetus has been exposed to at least that concentration of arsenic as well. ...
... alterations in the immune systems of pregnant women exposed to high levels of arsenic (even with a relatively low intrauterine exposure) and consequently an immune fetal dysregulation. As a result, children experienced a predominance of Th2 immunity and increased activation of the immune response, increasing the risk of exacerbated allergic reactions [32]. ...
Childhood atopic dermatitis (AD) is a chronic and recurrent health problem that involves multiple factors, particularly immunological and environmental. We evaluated the impact of docosahexaenoic acid (DHA) supplementation on prenatal arsenic exposure on the risk of atopic dermatitis in preschool children as part of the POSGRAD (Prenatal Omega-3 fatty acid Supplements, GRowth, And Development) clinical trial study in the city of Morelos, Mexico. Our study population included 300 healthy mother–child pairs. Of these, 146 were in the placebo group and 154 in the supplement group. Information on family history, health, and other variables was obtained through standardized questionnaires used during follow-up. Prenatal exposure to arsenic concentrations, which appear in maternal urine, was measured by inductively coupled plasma optical emission spectrometry. To assess the effect of prenatal arsenic exposure on AD risk, we ran a generalized estimating equation model for longitudinal data, adjusting for potential confounders, and testing for interaction by omega-3 fatty acid supplementation during pregnancy. The mean and SD (standard deviation) of arsenic concentration during pregnancy was 0.06 mg/L, SD (0.04 mg/L). We found a marginally significant association between prenatal arsenic exposure and AD (OR = 1.12, 95% CI: 0.99, 1.26); however, DHA supplementation during pregnancy modified the effect of arsenic on AD risk (p < 0.05). The results of this study strengthen the evidence that arsenic exposure during pregnancy increases the risk of atopic dermatitis early in life. However, supplementation with omega-e fatty acids during pregnancy could modify this association.
... We incorporated covariates into the model based on statistical results that the variable showed a correlation with at least one target indicator of children immune responses with a P-value less than 0.1 in univariate analysis, and we also included gender in the adjusted model. The following confounding variables were included in the final multivariable prenatal exposure model: maternal age (years) as continuous variables; parity (nulliparous and multiparous), children's gender (boys and girls), passive smoke during pregnancy (yes and no) as dichotomous variables, education (categorized as less than high school and more than high school) as an ordinal variable (Nadeau et al., 2014). The following confounding variables were included in the final multivariable childhood exposure model: children's age (months) as continuous variables, children's gender (boys and girls) and breast feeding status (categorized as < 12 months and ≥ 12 months) as dichotomous variables . ...
... Second, simultaneously measurements of blood lead exposure and immune response indicators in children resulted in a crosssectional study that appears suggested the possibility of false positives between lead exposure and immune indicators in children. Finally, we did not include more confounders, such as exposure to arsenic, cadmium, and iron that were reported to affected immune functions (Hanson et al., 2012;Nadeau, 2014;Nairz, 2018), which should be considered in the future research. ...
Studies have shown that lead exposure affected the immune function, but few studies have examined the relationships between in utero lead exposure, a sensitive period that is important for immune development, and later immune responses. To investigate the effects of prenatal and childhood lead exposure on the preschool-aged children’s immune responses, a prospective birth cohort study was established in Wuhan, China, in which lead concentrations were analyzed in maternal urine during the third trimester and in plasma samples from children aged about 3 years. We assessed immune responses by measuring immune cytokines in the children's plasma (n = 326) and peripheral blood T lymphocyte subsets (n = 394) at 3 years of age. Each unit increase in maternal urinary lead concentration (μg/g creatinine) was associated with reduced IL-10 (β = −5.93%, 95%CI: −11.82%, −0.03%) and reduced IL-4 levels (β = −5.62%, 95%CI: −10.44%, −0.80%). Lead in children’s plasma (μg/L) was associated with significant increase in TNF-α (β = 10.78%, 95%CI: 3.97%, 17.59%). No statistically significant relationship of childhood lead exposure with T lymphocyte subsets was observed. The study suggested prenatal and childhood lead exposure was associated with changes in preschool children’s plasma cytokine levels.
... In a pregnancy cohort study in the United States, prenatal exposure to low-level arsenic was found to be associated with the presence of specific immunophenotypes of cord blood cells and impaired function of the T cell subsets (CD45RA+ CD69+ T cells and CD45RA+ CD69− CD294+ T cells). This effect leads to immune dysregulation and delays in normal T cell polarization from the fetal Th2 predominant toward the postnatal Th1 stage (Nadeau et al., 2014). Evidence has shown that newborns with a Th2-skewed immune system have enhanced responses to common environmental allergens, which contribute to exacerbated allergic conditions later in life (Martino and Prescott, 2010). ...
... In an experimental study on human bronchial epithelial cells, chronic lowdose arsenic exposure compromised airway epithelial wound repair, and altered intracellular signaling critical to normal airway innate immunity (Sherwood et al., 2013). Prenatal arsenic exposure has also been shown to have the potential to alter the fetal immune system probably through DNA methylation (Nadeau et al., 2014;Strickland and Richardson, 2008). In our study, postnatal arsenic exposure had no association with asthma. ...
Background
The prevalence of allergic diseases in children has increased globally. Early-life exposure to inorganic arsenic has been found to be associated with impaired immune function and decreased lung function in children; however, the results are inconsistent. We aimed to evaluate the effect of prenatal and childhood exposure to inorganic arsenic on allergic diseases in children, through a 15-year follow-up birth cohort study, conducted in central Taiwan.
Methods
Children born to women enrolled in the Taiwan Maternal and Infant Cohort Study (TMICS-pilot) from December 2000 to November 2001 were recruited and followed every 2–3 years until the age of 14 years. Urinary specimens were collected in the pregnant women during the 3rd trimester and the followed children. Diagnoses of allergic diseases were based on physician diagnoses using the International Study of Asthma and Allergies in Childhood questionnaire. Urinary arsenic speciation was performed using high-performance liquid chromatography and inductively coupled plasma dynamic reaction cell mass spectrophotometry.
Results
Of the 261 children from 358 mother-infant pairs for this study, those with asthma and allergic rhinitis reported a higher prevalence of maternal allergy (49.47%) than did non-allergic children (29.81%). In the fully adjusted model, levels of maternal urine (iAs + MMA + DMA) greater than the median were found to be significantly associated with an increased risk of asthma (OR = 4.28; 95% CI 1.32, 13.85). Levels of urinary (iAs + MMA + DMA) in children higher than the median were associated with an increased risk of allergic rhinitis (OR = 2.26; 95% CI 1.20, 4.26).
Conclusion
Prenatal and childhood exposure to inorganic arsenic were found to be significantly associated with the occurrence of asthma and allergic rhinitis in children, respectively. Further large cohort follow-up studies are important to validate the association between inorganic arsenic exposure and allergic diseases in children.
... Participants in the study are pregnant women who use an unregulated private water supply in a US region with low to moderate groundwater arsenic levels. Analyses of the NHBCS have already revealed associations of arsenic exposure with fetal growth measures including birth weight [4]; childhood infections [5]; and various physiological and molecular changes in both the cord blood and placenta [6][7][8][9][10]. ...
... Our results appear to suggest that, in male fetal placenta, arsenic exposure increases this anti-inflammatory bias. This finding aligns with a previous study of the NHBCS, which found increased numbers of Th2-type cells in cord blood at high arsenic exposure, although sex differences were not observed [10]. Studies of adults chronically exposed to arsenic have also shown immune effects, including reduced expression of IFNG [45]. ...
Abstract Background Increasing evidence suggests that prenatal exposure to arsenic, even at common environmental levels, adversely affects child health. These adverse effects include impaired fetal growth, which can carry serious health implications lifelong. However, the mechanisms by which arsenic affects fetal health and development remain unclear. Methods We addressed this question using a group of 46 pregnant women selected from the New Hampshire Birth Cohort Study (NHBCS), a US cohort exposed to low-to-moderate arsenic levels in drinking water through the use of unregulated private wells. Prenatal arsenic exposure was assessed using maternal urine samples taken at mid-gestation. Samples of the fetal portion of the placenta were taken from the base of the umbilical cord insertion at the time of delivery, stored in RNAlater and frozen. We used RNA sequencing to analyze changes in global gene expression in the fetal placenta associated with in utero arsenic exposure, adjusting for maternal age. Gene set enrichment analysis and enrichment mapping were then used to identify biological processes represented by the differentially expressed genes. Since our previous analyses have identified considerable sex differences in placental gene expression associated with arsenic exposure, we analyzed male and female samples separately. Results At FDR
... Hampshire, fetal immune deregulation was reported in the cases of mothers exposed to low As (mean 5.7 μg/L) (Nadeau et al., 2014). ...
... of T-cell subsets including CD45RA + CD69 + T cells and CD45RA + CD69 − CD294 + cells (Nadeau et al., 2014). However, an Expanded ...
Groundwater arsenic (As) contamination is a global public health concern. The high level of As exposure (100‐1000 μg/L or even higher) through groundwater has been frequently associated with serious public health hazards, e.g., skin disorders, cardiovascular diseases, respiratory problems, complications of gastrointestinal tract, liver and splenic ailments, kidney and bladder disorders, reproductive failure, neurotoxicity and cancer. However, reviews on low‐level As exposure and the imperative health effects are far less documented. The World Health Organization (WHO) and the United States Environmental Protection Agency (USEPA) has set the permissible standard of As in drinking water at 10 μg/L. Considering the WHO and USEPA guidelines, most of the developed countries have established standards at or below this guideline. Worldwide many countries including India have millions of aquifers with low‐level As contamination (≤50 μg/L). The exposed population of these areas might not show any As‐related skin lesions (hallmark of As toxicity particularly in a population consuming As contaminated groundwater >300 μg/L) but might be subclinically affected. This review has attempted to encompass the wide range of health effects associated with chronic low‐level As exposure ≤50 μg/L and the probable mechanisms that might provide a better insight regarding the underlying cause of these clinical manifestations. Therefore, there is an urgent need to create mass awareness about the health effects of chronic low‐level As exposure and planning of proper mitigation strategies. The current review is an attempt to compile the huge arena of health effects due to chronic low‐level As exposure as well as to throw an insight into the probable mechanisms involved with the myriad of clinical manifestations. The objective is to bring the deleterious health effects of As exposure, even at low levels, to the attention of people from both the scientific and the non‐scientific community.
... The study included women who had been exposed to low to moderate quantities of arsenic through the use of private wells as well as dietary sources. Analyses of NHBCS data have indicated links between prenatal arsenic exposure and fetal and neonatal development (12,13), infant infection rates (14), immunological profiles, inflammatory markers, and leptin levels in cord blood (15)(16)(17), and gene expression and DNA methylation in the fetal placenta (18)(19)(20)(21)(22). As a result, it is becoming increasingly clear that even low-to-moderate amounts of arsenic have various impacts on the developing fetus and result in poor infant health outcomes. ...
Arsenic (As) exposure is progressively associated with chronic kidney disease (CKD), a leading public health concern present worldwide. The adverse effect of As exposure on the kidneys of people living in As endemic areas have not been extensively studied. Furthermore, the impact of only prenatal exposure to As on the progression of CKD also has not been fully characterized. In the present study, we examined the effect of prenatal exposure to low doses of As 0.04 and 0.4 mg/kg body weight (0.04 and 0.4 ppm, respectively) on the progression of CKD in male offspring using a Wistar rat model. Interestingly, only prenatal As exposure was sufficient to elevate the expression of profibrotic (TGF-β1) and proinflammatory (IL-1α, MIP-2α, RANTES, and TNF-α) cytokines at 2-day, 12- and 38-week time points in the exposed progeny. Further, alteration in adipogenic factors (ghrelin, leptin, and glucagon) was also observed in 12- and 38-week old male offspring prenatally exposed to As. An altered level of these factors coincides with impaired glucose metabolism and homeostasis accompanied by progressive kidney damage. We observed a significant increase in the deposition of extracellular matrix components and glomerular and tubular damage in the kidneys of 38-week-old male offspring prenatally exposed to As. Furthermore, the overexpression of TGF-β1 in kidneys corresponds with hypermethylation of the TGF-β1 gene-body, indicating a possible involvement of prenatal As exposure-driven epigenetic modulations of TGF-β1 expression. Our study provides evidence that prenatal As exposure to males can adversely affect the immunometabolism of offspring which can promote kidney damage later in life.
... Proliferation of effector T cells was higher and placental IL1b was higher with higher maternal As exposure. 27 Diarrhea and lower respiratory tract infections Maternal urinary inorganic As at 8 & 30 weeks gestation was related to higher risk of lower respiratory tract infection and diarrhea among infants under 12 months in a highly-exposed cohort. 28 Respiratory infections requiring prescription medication Maternal urinary inorganic As in mid-pregnancy was associated with higher risk of any lower and any upper respiratory tract infections requiring treatment with prescription medication in a cohort with low As exposure. ...
Concerns are growing regarding the presence of toxic elements such as arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) in the ingredients and prepared foods for infants and young children. There are few clear, evidence-based, guidelines on the maximum tolerable limits of toxicants in foods and little understanding of toxicant exposure or adverse health effects attributable to dietary exposure. Caregivers are faced with the burden of making decisions about which foods to select, how often to feed them to their children, and what foods to limit. This article reviews the current literature and existing recommendations on dietary exposure to toxic elements in children under 2 years of age, and their health effects in early childhood-focusing on growth, neurodevelopment, and immune function. The article also outlines best practices for healthcare providers to address the concerns of toxic element exposure through the diet in young children. Several foods consistently appear in the literature as potential sources of toxic element exposure. Contaminated drinking and cooking water, including water used to prepare infant formula, could also be a major exposure source. In the absence of stronger evidence on effects of dietary modification, exclusive breastfeeding until six months of age, followed by a diverse diet are some strategies to reduce dietary toxic element exposure while ensuring an adequate and balanced nutrient intake. Healthcare providers can support families by sharing information and encouraging blood Pb testing, the only element for which such testing is currently recommended.
... Inorganic arsenic accumulates in the lungs, kidney, and liver [65][66][67] and could cause damage in lung tissue by inducing inflammation [3,39,68], and generate oxidative stress [69][70][71]. IgE production is a marker of allergic response generated by Th2 cells, which have been related to increased urinary arsenic concentrations [72,73]. Increased urinary arsenic concentrations have also been associated with reduced percentages of CD4 T cells and interleukin (IL)-2 secretion levels [74] and T-cell proliferation and cytokine secretion that could cause immunosuppression [75]. ...
Ingested inorganic arsenic (iAs) is a human carcinogen that is also linked to other adverse health effects, such as respiratory outcomes. Yet, among populations consuming low-arsenic drinking water, the impact of iAs exposure on childhood respiratory health is still uncertain. For a Spanish child study cohort (INfancia y Medio Ambiente—INMA), low-arsenic drinking water is usually available and ingestion of iAs from food is considered the major source of exposure. Here, we explored the association between iAs exposure and children’s respiratory outcomes assessed at 4 and 7 years of age ( n = 400). The summation of 4-year-old children’s urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) was used as a biomarker of iAs exposure (∑As) (median of 4.92 μg/L). Children’s occurrence of asthma, eczema, sneeze, wheeze, and medication for asthma and wheeze at each assessment time point (i.e., 4- and 7-year) was assessed with maternal interviewer-led questionnaires. Crude and adjusted Poisson regression models using Generalized Estimating Equation (GEE) were performed to account for the association between natural logarithm transformed (ln) urinary ∑As in μg/L at 4 years and repeated assessments of respiratory symptoms at 4 and 7 years of age. The covariates included in the models were child sex, maternal smoking status, maternal level of education, sub-cohort, and children’s consumption of vegetables, fruits, and fish/seafood. The GEE—splines function using Poisson regression showed an increased trend of the overall expected counts of respiratory symptoms with high urinary ∑As. The adjusted expected counts (95% confidence intervals) at ln-transformed urinary ∑As 1.57 (average concentration) and 4.00 (99 th percentile concentration) were 0.63 (0.36, 1.10) and 1.33 (0.61, 2.89), respectively. These exploratory findings suggest that even relatively low-iAs exposure levels, relevant to the Spanish and other populations, may relate to an increased number of respiratory symptoms during childhood.
... Exposure to non-essential elements such as arsenic (As), lead (Pb), mercury (Hg), and cadmium (Cd) has become a significant global health issue owing to their frequency and toxic effects on human health (ATSDR 2019a). This concern is particularly relevant for infants and young children for whom non-essential element exposures, even at the low levels common in the United States of America (US) and elsewhere, may have health consequences (Farzan et al. 2016;Nadeau et al. 2014;Vahter et al. 2020;Wasserman et al. 2014). ...
Unlabelled:
Even the low levels of non-essential elements exposure common in the US may have health consequences especially early in life. However, little is known about the infant's dynamic exposure to essential and non-essential elements. This study aims to evaluate exposure to essential and non-essential elements during infants' first year of life and to explore the association between the exposure and rice consumption. Paired urine samples from infants enrolled in the New Hampshire Birth Cohort Study (NHBCS) were collected at approximately 6 weeks (exclusively breastfed) and at 1 year of age after weaning (n = 187). A further independent subgroup of NHBCS infants with details about rice consumption at 1 year of age also was included (n = 147). Urinary concentrations of 8 essential (Co, Cr, Cu, Fe, Mn, Mo, Ni, and Se) and 9 non-essential (Al, As, Cd, Hg, Pb, Sb, Sn, V, and U) elements were determined as a measure of exposure. Several essential (Co, Fe, Mo, Ni, and Se) and non-essential (Al, As, Cd, Hg, Pb, Sb, Sn, and V) elements had higher concentrations at 1 year than at 6 weeks of age. The highest increases were for urinary As and Mo with median concentrations of 0.20 and 1.02 µg/L at 6 weeks and 2.31 and 45.36 µg/L at 1 year of age, respectively. At 1 year of age, As and Mo urine concentrations were related to rice consumption. Further efforts are necessary to minimize exposure to non-essential elements while retaining essential elements to protect and promote children's health.
Supplementary information:
The online version contains supplementary material available at 10.1007/s12403-022-00489-x.
... Chronic iAs exposure leads to placental insufficiency complications including preterm delivery and intrauterine growth retardation (IUGR) [154]. During pregnancy, As inorganic forms and their methylated metabolites cross the placenta and enter cord blood, leading to altered immune cell and gene expression in the cord blood of a highly exposed mother [167][168][169][170]. Moreover, other fetal complications also reported include slow fetal growth, low birth weight, and the effect of neuronal development in early life [89,171]. ...
Citation: Khan, M.I.; Ahmad, M.F.; Ahmad, I.; Ashfaq, F.; Wahab, S.; Alsayegh, A.A.; Kumar, S.; Hakeem, K.R. Arsenic Exposure through
... Chronic iAs exposure leads to placental insufficiency complications including preterm delivery and intrauterine growth retardation (IUGR) [154]. During pregnancy, As inorganic forms and their methylated metabolites cross the placenta and enter cord blood, leading to altered immune cell and gene expression in the cord blood of a highly exposed mother [167][168][169][170]. Moreover, other fetal complications also reported include slow fetal growth, low birth weight, and the effect of neuronal development in early life [89,171]. ...
Dietary arsenic (As) contamination is a major public health issue. In the Middle East, the food supply relies primarily on the import of food commodities. Among different age groups the main source of As exposure is grains and grain-based food products, particularly rice and rice-based dietary products. Rice and rice products are a rich source of core macronutrients and act as a chief energy source across the world. The rate of rice consumption ranges from 250 to 650 g per day per person in South East Asian countries. The source of carbohydrates through rice is one of the leading causes of human As exposure. The Gulf population consumes primarily rice and ready- to-eat cereals as a large proportion of their meals. Exposure to arsenic leads to an increased risk of non-communicable diseases such as dysbiosis, obesity, metabolic syndrome, diabetes, chronic kidney disease, chronic heart disease, cancer, and maternal and fetal complications. The impact of arsenic-containing food items and their exposure on health outcomes are different among different age groups. In the Middle East countries, neurological deficit disorder (NDD) and autism spectrum disorder (ASD) cases are alarming issues. Arsenic exposure might be a causative factor that should be assessed by screening the population and regulatory bodies rechecking the limits of As among all age groups. Our goals for this review are to outline the source and distribution of arsenic in various foods and water and summarize the health complications linked with arsenic toxicity along with identified modifiers that add heterogeneity in biological responses and suggest improvements for multi-disciplinary interventions to minimize the global influence of arsenic. The development and validation of diverse analytical techniques to evaluate the toxic levels of different As contaminants in our food products is the need of the hour. Furthermore, standard parameters and guidelines for As-containing foods should be developed and implemented.
... Chronic iAs exposure leads to placental insufficiency complications including preterm delivery and intrauterine growth retardation (IUGR) [154]. During pregnancy, As inorganic forms and their methylated metabolites cross the placenta and enter cord blood, leading to altered immune cell and gene expression in the cord blood of a highly exposed mother [167][168][169][170]. Moreover, other fetal complications also reported include slow fetal growth, low birth weight, and the effect of neuronal development in early life [89,171]. ...
Citation: Khan, M.I.; Ahmad, M.F.; Ahmad, I.; Ashfaq, F.; Wahab, S.; Alsayegh, A.A.; Kumar, S.; Hakeem, K.R. Arsenic Exposure through
... Some beneficial effects of As have also been reported including treating acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (AML) [6][7][8]. However, human population studies have shown evidence of As toxicity in peripheral blood leukocytes obtained from adults and children exposed to As [9,10], as well as from cord blood [11,12]. ...
There is limited evidence on the effects of environmental exposure to arsenic (As) on the immune system in adults. In a population-based study, we have found that urinary As (UAs), and its metabolites [inorganic As (InAs), monomethylated arsenicals (MMA +3/+5 ), and dimethylated arsenicals (DMA +3/+5 )] modulate or influence the number of T-helper 17 (Th17) cells and IL-17A cytokine production. In non-smoking women, we observed that UAs and DMA +3/+5 were associated with changes in Th17 cell numbers in a nonlinear fashion. In smoking males, we found that UAs was associated with a significant decrease of Th17 cell numbers. Similar association was observed among non-smoking males. Likewise, UAs, DMA +3/+5 and MMA +3/+5 were associated with diminished production of IL-17A among non-smoking males. When stratified by Vitamin D levels defined as sufficient (≥20 ng/ml) and insufficient (<20 ng/ml), we found a substancial decrease in Th17 cell numbers among those with insufficient levels. Individuals with sufficient VitD levels demonstrated significant inhibition of IL-17A production in non-smoking males. Collectively, we find that exposure to As via drinking water is associated with alterations in Th17 numbers and IL-17A production, and that these associations may be modified by Vitamin D status. Our findings have significance for health outcomes associated with As exposure.
... In children, the T-helper type 1 (Th1) cytokine levels decreases however, the levels of IgG and IgE increases in the plasma upon arsenic exposure (Raqib et al., 2017). The New Hampshire Birth Cohort study (NHBSC) has showed that there is an associations of prenatal arsenic exposure with the measures of fetal immune profiles and inflammatory markers (Farzan et al., 2016;Nadeau et al., 2014). The analysis of twelve different population studies identified TNF-α as a key regulator, which was most significantly upregulated among the genes affected by prenatal exposure to arsenic (Laine and Fry, 2016). ...
Prenatal and postnatal life stress could be a potent programmer of phenotype or disease state of an individual in the later life. Prenatal arsenic exposure has been shown to promote developmental defects, low birth weight, immunotoxicity and is associated with various cancers including skin cancer in adulthood. To investigate the association between prenatal arsenic exposure and adult life skin carcinogenesis, we used a two-stage cutaneous carcinogenesis model in which BALB/c mice were prenatally exposed to 0.04 mg/kg and 0.4 mg/kg arsenic (As). Exposure to arsenic was sufficient to shorten the tumor latency period and promote epidermal hyperplasia in the offspring upon challenge with dimethylbenz[a]/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA). The levels of inflammatory and tissue microenvironment remodeling factors such as IL-1α and TNF-α were persistently elevated in the skin, and their inhibition through diacerein led to a significant decrease in the tumor response, suggesting their role in tumorigenesis. While there was overexpression of multiple epigenetic regulators at tissue level, we found decreased enrichment of Polycomb repressive complex 2 (PRC2) member EZH2 and H3K27me3 mark at the upstream of the affected inflammatory genes. The higher expression of the inflammatory genes suggests the gene specific selective nature of EZH2 repression which was also associated with increased binding of the activator KDM6a (demethylase). Further, arsenic conditioned basal keratinocytes cells (BKCs) showed increased migration and proliferation along with higher expression of tumor associated cytokines. Inhibition of EZH2 in the BKCs lead to their further upregulation suggesting that BKCs might be the potential cell type for the interaction of EZH2 and inflammatory cytokines. The present study provides new evidence for the role of PRC2 group regulators in inflammatory conditioning and development of skin cancer in offspring prenatally exposed to arsenic.
... arsenic exposure may influence the epigenome of the placenta 23 , immune cell profiles in newborn cord blood 24 , and the infant gut microbiome 25 . While epidemiologic data are lacking on allergy outcomes, maternal urinary arsenic concentrations during pregnancy were related to higher activated Th2 cells, which produce cytokines responsible for IgE production, a marker of allergic response [26][27][28][29] . In addition, there is evidence that early arsenic exposure influences childhood infections risk in highly exposed populations 30,31 . ...
Rice products marketed in the USA, including baby rice cereal, contain inorganic arsenic, a putative immunotoxin. We sought to determine whether the timing of introduction of rice cereal in the first year of life influences occurrence of infections, respiratory symptoms, and allergy. Among 572 infants from the New Hampshire Birth Cohort Study, we used generalized estimating equation, adjusted for maternal smoking during pregnancy, marital status, education attainment, pre-pregnancy body mass index, maternal age at enrollment, infant birth weight, and breastfeeding history. Among 572 infants, each month earlier of introduction to rice cereal was associated with increased risks of subsequent upper respiratory tract infections (relative risk, RR = 1.04; 95% CI: 1.00–1.09); lower respiratory tract infections (RR = 1.19; 95% CI: 1.02–1.39); acute respiratory symptoms including wheeze, difficulty breathing, and cough (RR = 1.10; 95% CI: 1.00–1.22); fever requiring a prescription medicine (RR = 1.22; 95% CI: 1.02–1.45) and allergy diagnosed by a physician (RR = 1.20; 95% CI: 1.06–1.36). No clear associations were observed with gastrointestinal symptoms. Our findings suggest that introduction of rice cereal earlier may influence infants’ susceptibility to respiratory infections and allergy.
... Animal studies have revealed that arsenic exposure affected CD4 + T cell numbers and CD4/CD8 ratios in the spleen and thymus [9,10]. An epidemiologic study found that the maternal urinary arsenic concentrations were negatively associated with CD45RA+ CD4 + cells in cord blood [11]. CD4+ T cells could differentiate into Th1, Th2, Th17, and Treg by a series of corresponding transcription factors and cytokines [12]. ...
Numerous studies on arsenic-induced hepatonephric toxicity including cancer have been reported. Given that chronic inflammatory response and immune imbalance are associated with oncogenesis, we investigated whether arsenic could influence the hepatic and nephritic expression of inflammatory factors and the differentiation of T cells. Mice were exposed to NaAsO2 (0, 25, and 50 mg/L) for 1 and 3 months. Our data showed the destruction of the structure and inflammatory infiltration in the liver. The arsenic markedly increased the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The myeloperoxidase (MPO) activities increased in the liver at 25 and 50 mg/L arsenic for 3 months as well as in the kidney at both 1 and 3 months. An increased expression of inflammatory indicators (IL-1β, IL-12, and TNF-α) at 25 and 50 mg/L arsenic for 1 and 3 months in the liver and kidney, as well as IL-1β in the liver for 3 months and in the kidney at 50 mg/L for 1 and 3 months were demonstrated in our experiments. Besides, a definite tendency toward Th1/Th17 cytokines in the liver while Th2/Th17 cytokines in kidney was also observed by arsenic. Moreover, arsenic enhanced the expression of MAPK/Nrf2/NF-κB signaling molecules. In conclusion, the results of the study suggested that arsenic induces continuous immune-inflammatory responses in the liver and kidney.
... The third example is a longitudinal analysis of 67 pregnant women to investigate arsenic exposure in pregnant women (environmental factor) impacts the health of their children (Farzan et al. 2013). In the third example, the mediation analysis was to examine whether maternal arsenic exposure (total in utero arsenic level) impacts treated cough effect of their children mediated by gut microbiome of infants (Nadeau et al. 2014). There is a presence of a large portion (54%) of zero values in this microbiome data. ...
Microbiome research has basically focused on three factors: environment, microbiome, and host. The interactions among these three factors are dynamic and complicated. Three general hypotheses have been developed to detect these interactions. Among these hypotheses, testing the mediated effects of environmental factors and host mediated by microbiome is the most often designed, because mediation analysis of the human microbiome in these dynamic and very complicated relationships could potentially provide insights into the role of the microbiome in health and the etiology of disease and, more importantly, lead to novel clinical interventions by modulating the microbiome.
... We applied our approach in the NHBCS study to examine the association between in utero arsenic exposure measured by maternal urinary arsenic concentrations ) during pregnancy and the infant gut microbiome. In our analysis, the natural log-transformed total in utero arsenic level (Nadeau et al. 2014) was the exposure variable X and gut microbiome of infants at 6 weeks of age was the outcome variable. Delivery mode (vaginal vs. C-section) and feeding type (breast fed vs. others) were adjusted as potential confounders in the model (i.e., W i in Equation (1)). ...
The target of inference in microbiome analyses is usually relative abundance (RA) because RA in a sample (e.g., stool) can be considered as an approximation of RA in an entire ecosystem (e.g., gut). However, inference on RA suffers from the fact that RA are calculated by dividing absolute abundances (AA) over the common denominator (CD), the summation of all AA (i.e., library size). Because of that, perturbation in one taxon will result in a change in the CD and thus cause false changes in RA of all other taxa, and those false changes could lead to false positive/negative findings. We propose a novel analysis approach (IFAA) to make robust inference on AA of an ecosystem that can circumvent the issues induced by the CD problem and compositional structure of RA. IFAA can also address the issues of overdispersion and handle zero-inflated data structures. IFAA identifies microbial taxa associated with the covariates in Phase one and estimates the association parameters by employing an independent reference taxon in Phase two. Two real data applications are presented and extensive simulations show that IFAA outperforms other established existing approaches by a big margin in the presence of unbalanced library size.
... Several studies have been conducted surrounding HEV in pregnant women, but few have studied the general population. In the US, in utero environmental arsenic exposure was shown to alter the fetal immune system and cause immune dysregulation through altered lymphocyte profiles in newborns [12]. In the general population, arsenic exposure has been linked to higher rates of other types of hepatitis including hepatitis A and B [13] [14]. ...
... For example, MADRES urinary levels of total As (no AsB) were very similar to those reported in the New Hampshire Birth Cohort Study (NHBCS) (mean 6.05 ± SD: 13.19), which includes women exposed to a wide range of environmental As via well water [47]. Studies from the NHBCS have observed associations between these low-tomoderate levels of As exposure and numerous maternal and newborn health effects, including gestational diabetes, elevated blood pressure, birth outcomes, and infant health [5,44,[71][72][73]. Mean total urinary As levels (including AsB) observed in MADRES were also similar to those of postpartum Mexican-American women living in Texas [48] and to women in their first trimester of pregnancy in the Seattle-Tacoma area Omega cohort [49]. ...
Arsenic (As) is a contaminant of top public health concern, due to its range of detrimental health effects. Arsenic exposure has not been well-characterized among the US Hispanic populations and has been particularly understudied in this population during pregnancy.
As part of the MADRES ongoing pregnancy cohort of predominantly lower-income, Hispanic women in Los Angeles, CA, we examined levels of maternal first trimester urinary As, including total As and As metabolites (inorganic (iAs), monomethylated (MMA) and dimethylated As (DMA)), in relation to participant demographics, lifestyle characteristics, and rice/seafood consumption, to identify factors that may influence As exposure and its metabolites during pregnancy (N = 241).
Total As concentrations ranged from low to high (0.8–506.2 μg/L, mean: 9.0 μg/L, SD: 32.9) in our study population. Foreign-born Hispanic women had 8.6% higher %DMA (95% CI: 3.3%, 13.9%) and −7.7% lower %iAs (95% CI: −12.6%, −2.9%) than non-Hispanic women. A similar trend was observed for US-born Hispanic women. In addition, maternal age was associated with 0.4% higher %iAs (95% CI: 0.1%, 0.6%) and 0.4% lower %DMA (95% CI: −0.7%, −0.1%) per year, which may indicate poor As methylation capacity.
Individual factors may predict As exposure and metabolism in pregnancy, and in turn, greater risk of adverse health effects.
... Surprisingly, there have been only a few population-based studies that have examined the effects of arsenic on the immune system of humans. These studies, all with relatively small sample sizes, have focused on PBMC obtained from adults and children [3,4], or on cord blood leukocytes [5,6]. The sole study on adults was conducted among individuals with arsenic induced skin lesions, an indirect measure of arsenic exposure [3]. ...
There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.
... For instance, immunosuppression due to prenatal As exposure was identified (i.e. poor cellular immune function reported among cord blood cells) in human cohorts (Nadeau et al. 2014). Impaired function of T-cell subsets has also shown to be associated with prenatal As exposure. ...
Arsenic (As) readily crosses the placenta and exposure of the fetus may cause adverse consequences later in life, including immunomodulation. In the current study, the question was asked how the immune repertoire might respond in postnatal life when there is no further As exposure. Here, pregnant mice (Balb/c [H-2d]) were exposed to arsenic trioxide (As2O3) through their drinking water from time of conception until parturition. Their offspring, 4-week-old mice who had not been exposed again to As, were used for functional analyses of innate, humoral and cellular immunity. Compared to cells from non-As-exposed dam offspring, isolated peritoneal macro-phages (Mϕ) displayed no differences in T-cell stimulating ability. Levels of circulating IgG2a but not IgG1 were decreased in As-exposed dam offspring as compared to control offspring counterparts. Mixed-leukocyte reactions (MLR) indicated that CD4⁺ T-cells from the prenatal As-exposed mice were significantly less responsive to allogenic stimulation as evidenced by decreases in interferon (IFN)-γ and IL-2 production and in expression of CD44 and CD69 (but not CD25) activation markers. Interestingly, the Mϕ from the prenatal As-exposed mice were capable of stimulating normal allogenic T-cells, indicating that T-cells from these mice were refractory to allogenic signals. There was also a significant decrease in absolute numbers of splenic CD4⁺ and CD8⁺ T-cells due to prenatal As exposure (as compared to control). Lastly, the impaired immune function of the prenatal As-exposed mice was correlated with a very strong susceptibility to Escherichia coli infection. Taken together, the data from this study clearly show that in utero As exposure may continue to perpetuate a dampening effect on the immune repertoire of offspring, even into the early stages of postnatal life.
... Results from retrospective studies of arsenic exposure in Chile have linked perinatal arsenic exposure with bronchiectasis, a disease characterized by chronic airway infection, inflammation, and significant morbidity resulting from progressive airway damage, in adulthood, decades after the cessation of arsenic exposure (Roh et al., 2018). Additional clinical correlates were observed in a study of a well-characterized U.S. cohort of 412 infants born to mothers drinking well water during pregnancy (Farzan et al., 2015(Farzan et al., , 2016Nadeau et al., 2014). In this study, maternal urinary arsenic concentrations were positively correlated with respiratory infections in infants requiring a physician visit (Farzan et al., 2016). ...
Arsenic exposure via drinking water is a serious environmental health concern. Epidemiological studies suggest a strong association between prenatal arsenic exposure and subsequent childhood respiratory infections, as well as morbidity from respiratory diseases in adulthood, long after systemic clearance of arsenic. We investigated the impact of exclusive prenatal arsenic exposure on the inflammatory immune response and respiratory health after an adult influenza A (IAV) lung infection. C57BL/6J mice were exposed to 100 ppb sodium arsenite in utero, and subsequently infected with IAV (H1N1) after maturation to adulthood. Assessment of lung tissue and bronchoalveolar lavage fluid (BALF) at various time points post IAV infection reveals greater lung damage and inflammation in arsenic exposed mice versus control mice. Single-cell RNA sequencing analysis of immune cells harvested from IAV infected lungs suggests that the enhanced inflammatory response is mediated by dysregulation of innate immune function of monocyte derived macrophages, neutrophils, NK cells, and alveolar macrophages. Our results suggest that prenatal arsenic exposure results in lasting effects on the adult host innate immune response to IAV infection, long after exposure to arsenic, leading to greater immunopathology. This study provides the first direct evidence that exclusive prenatal exposure to arsenic in drinking water causes predisposition to a hyperinflammatory response to IAV infection in adult mice, which is associated with significant lung damage.
... Long-term As exposure is known to result in lung, bladder, liver, skin and kidney cancers [9]. Concerning non-carcinogenic endpoints, while skin lesions are considered to be a primary marker of As toxicity [10], it has also been reported to be associated with different neurological problems [11], increased risk of immune problems in new-born [12], infant infections [13], some reproductive health problems in pregnant women [14] and, importantly, cardiovascular diseases (CVD). A prospective study conducted in Bangladesh found an increased risk of mortality from ischemic heart disease and cerebrovascular disease in populations exposed to high concentration of inorganic arsenic (iAs) in well water [15]. ...
To the best of our knowledge, a dose-response meta-analysis of the relationship between cardiovascular disease (CVD) and arsenic (As) exposure at drinking water As concentrations lower than the WHO provisional guideline value (10 µg/L) has not been published yet. We conducted a systematic review and meta-analyses to estimate the pooled association between the relative risk of each CVD endpoint and low-level As concentration in drinking water both linearly and non-linearly using a random effects dose-response model. In this study, a significant positive association was found between the risks of most CVD outcomes and drinking water As concentration for both linear and non-linear models (p-value for trend < 0.05). Using the preferred linear model, we found significant increased risks of coronary heart disease (CHD) mortality and CVD mortality as well as combined fatal and non-fatal CHD, CVD, carotid atherosclerosis disease and hypertension in those exposed to drinking water with an As concentration of 10 µg/L compared to the referent (drinking water As concentration of 1 µg/L) population. Notwithstanding limitations included, the observed significant increased risks of CVD endpoints arising from As concentrations in drinking water between 1 µg/L and the 10 µg/L suggests further lowering of this guideline value should be considered.
... The increased urinary Arsenic concentration is linked with fever and diarrhea during pregnancy [34]. The in-utero Arsenic exposure with the fetal immune repertoire [35] and infectious outcomes during early childhood [36,37] has been established. The understanding of the immunomodulatory properties of Arsenic that susceptibility to specific infections in humans is poorly understood. ...
... arsenic exposure may influence the epigenome of the placenta 23 , immune cell profiles in newborn cord blood 24 , and the infant gut microbiome 25 . While epidemiologic data are lacking on allergy outcomes, maternal urinary arsenic concentrations during pregnancy were related to higher activated Th2 cells, which produce cytokines responsible for IgE production, a marker of allergic response [26][27][28][29] . In addition, there is evidence that early arsenic exposure influences childhood infections risk in highly exposed populations 30,31 . ...
... We applied our approach in the NHBCS study to examine the association between in utero arsenic exposure measured by maternal urinary arsenic concentrations during pregnancy and the infant gut microbiome. In our analysis, the natural log-transformed total in utero arsenic level (Nadeau et al., 2014) was the exposure variable X and gut microbiome of infants at 6 weeks of age was the outcome variable. Delivery mode (vaginal VS. ...
The target of inference in microbiome analyses is usually relative abundance (RA) because RA in a sample (e.g., stool) can be considered as an approximation of RA in an entire ecosystem (e.g., gut). However, inference on RA suffers from the fact that RA are calculated by dividing absolute abundances (AA) over the common denominator (CD), the summation of all AA (i.e., library size). Because of that, perturbation in one taxon will result in a change in the CD and thus cause false changes in RA of all other taxa, and those false changes could lead to false positive/negative findings. We propose a novel analysis approach (IFAA) to make robust inference on AA of an ecosystem that can circumvent the issues induced by the CD problem and compositional structure of RA. IFAA can also address the confounding effect of library size and handle zero-inflated data structures. IFAA identifies microbial taxa associated with the covariates in Phase one and estimates the association parameters by employing an independent reference taxon in Phase two. Two real data applications are presented and extensive simulations show that IFAA outperforms other established existing approaches by a big margin in the presence of confounding effect of library size.
... Most of the studies focus on direct exposure to pregnant women, especially in relation to consumption through ingestion of water, and some are related to rice cultivated at contaminated areas with consequent ingestion and exposure of population (Hopenhayn-Rich et al. 2000;Smith et al. 2000;. These studies focus on the determination of the urine of pregnant women in which is a bioindicator of exposure to the pregnant women's As and indirectly of the fetus (Farzan et al. 2013;Nadeau et al. 2014; Firstly, it is important to understand the As-metabolism. The As 3+ enters in the body through mechanisms of simple diffusion. ...
Arsenic (As) is a toxic and ubiquitously present element. It is present in some places of the world in excessively high concentrations in water and soil that threaten public health. North America constitutes one of the hotspots of As contamination. In Canada and the USA, a number of reports show the contamination of As in a number of food items including rice, rice-based products, fruits, beverages, animal food items, etc. Further, As contamination of water sources is also known to occur in different states of both Canada and the USA. Thus, the problem of As contamination is widespread and needs attention. This chapter provides an overview of As contamination of water and food sources of North America.
... Most of the studies focus on direct exposure to pregnant women, especially in relation to consumption through ingestion of water, and some are related to rice cultivated at contaminated areas with consequent ingestion and exposure of population (Hopenhayn-Rich et al. 2000;Smith et al. 2000;Abedin et al. 2002;Meharg and Rahman 2003). These studies focus on the determination of the urine of pregnant women in which is a bioindicator of exposure to the pregnant women's As and indirectly of the fetus (Farzan et al. 2013;Nadeau et al. 2014;Davis et al. 2015;Liu et al. 2018) Firstly, it is important to understand the As-metabolism. The As 3+ enters in the body through mechanisms of simple diffusion. ...
Currently, there is a range of rice-based foods such as baby foods, crackers, porridge, and milk, among others. Children and celiac population highly consume these foods. Rice and rice-based food are essential for society due to their health benefits and historical cultivation. However, nowadays, rice is the focus of several studies not only for the benefits but also because it is a plant able to absorb about tenfold more arsenic (As) than other cereals. Arsenic is known by its genotoxic and carcinogenic capacity, mainly concerning inorganic As (i-As), about 100-fold more toxic than organic As. Several rice-based foods were above 200 μg kg⁻¹, the maximum limit recommended by Codex for i-As, such as husked rice flour with a concentration of 528 μg kg⁻¹. Other rice-based foods with lower concentrations of i-As, such as milk with 4.3 μg kg⁻¹, are also relevant to mention since there is no safe daily intake for As. In this regard, values for confidence limit lower than the reference dose (BMDL 0.1) of 0.3 to 8 μg kg⁻¹ body weight per day are used for assessment and characterization of the related health risks, such as bladder cancer. Thus, the determination of As concentrations in these foods is fundamental for a better risk assessment, especially concerning children, due to their physical and physiological condition, in which they may be more exposed to the damages caused by As when compared to adults in general.
... Several human cord blood studies also examined the effects of As on cell subsets. Nadeau et al [52] found that As, measured as UAs, increased T cell proliferation in cord blood samples, a finding similar to our previous work [19]. In cord blood Nygaard et al. [53] found a decrease in Th and Tmem cells that was somewhat more prevalent in females than in males. ...
Exposures to environmental arsenic (As) and polycyclic aromatic hydrocarbons (PAH) have been shown to independently cause dysregulation of immune function. Little data exists on the associations between combined exposures to As and PAH with immunotoxicity in humans. In this work we examined associations between As and PAH exposures with lymphoid cell populations in human peripheral blood mononuclear cells (PBMC), as well as alterations in differentiation and activation of B and T cells. Two hundred men, participating in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, were selected for the present study based on their exposure to As from drinking water and their cigarette smoking status. Blood and urine samples were collected from study participants. We utilized multiparameter flow cytometry in PBMC to identify immune cells (B, T, monocytes, NK) as well as the T-helper (Th) cell subsets (Th1, Th2, Th17, and Tregs) following ex vivo activation. We did not find evidence of interactions between As and PAH exposures. However, individual exposures (As or PAH) were associated with changes to immune cell populations, including Th cell subsets. Arsenic exposure was associated with an increase in the percentage of Th cells, and dose dependent changes in monocytes, NKT cells and a monocyte subset. Within the Th cell subset we found that Arsenic exposure was also associated with a significant increase in the percentage of circulating proinflammatory Th17 cells. PAH exposure was associated with changes in T cells, monocytes and T memory (Tmem) cells and with changes in Th, Th1, Th2 and Th17 subsets all of which were non-monotonic (dose dependent). Alterations of immune cell populations caused by environmental exposures to As and PAH may result in adverse health outcomes, such as changes in systemic inflammation, immune suppression, or autoimmunity.
... We applied our approach in the NHBCS study to examine the mediation effect of gut microbiome in the causal pathway from maternal arsenic exposure to infant's health outcomes during the first year of life. In our analysis, the total in-utero arsenic level [24] was the exposure variable X, gut microbiome of infants at 6 weeks of age was the mediator M and the outcome Y is cough treated with a prescribed medicine between 8 and 12 months of age. Here X is a continuous variable and Y is a binary variable coded as 1/0 indicating yes/no. ...
Zero-inflated data is commonly seen in biomedical research such as microbiome studies and single-cell sequencing studies where zero-valued sequencing reads arise due to technical and/or biological reasons. Mediation analysis approaches for analyzing zero-inflated mediators are still lacking largely because of challenges raised by the zero-inflated data structure: (a) disentangling the mediation effect induced by the point mass at zero is not straightforward; and (b) identifying the observed zero-valued data points that are actually not zero (i.e., false zeros) is difficult. Existing approaches for analyzing microbiome as a high-dimensional mediator can not handle the zero-inflated data structure. In this paper, we developed a novel mediation analysis method under the potential-outcomes framework to fill the research gap. We show that the mediation effect of a zero-inflated mediator can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions: the first component corresponds to the mediation effect attributable to a unit-change over its positive domain (often counts or continuous values) and the second component corresponds to the mediation effect attributable to discrete jump of the mediator from zero to a non-zero state. With probabilistic models to account for observing zeros, we can also address the challenge with false zeros. A comprehensive simulation study and the applications in two real microbiome studies demonstrate that our approach outperforms current standard mediation analysis approaches.
... The symptoms of chronic exposure to arsenic in drinking water include the progression of various malignant and nonmalignant skin lesions [66,98]; peripheral neuropathy [40,70] and cancers of liver, lung and urinary bladder [81,121,137,138]. It has also been established that arsenic acts to attenuate the immune system following chronic exposure, rendering the individual susceptible towards pathogenic invasion [39,90,107]. Arsenic induced toxicity have been very well documented and reviewed in animal systems by various research groups across the globe, resulting in strict quality control measures by authorities, which limited the maximum tolerable level of inorganic arsenic in drinking water to 10 parts per billion (10 μg/L) in the developed countries. ...
Environmental exposure to toxicants/heavy metals during critical periods of development can influence changes in embryo and germline of the offspring; and later on affect the disease susceptibility in adults. Exposures to toxic metals or endocrine disruptors are particularly harmful during fetal development. Arsenic, a well-known toxic metalloid and reproductive toxicant is one the major concern because of its adverse and delayed health effects. Considering the complex and numerous adverse health effects of prenatal arsenic exposure, it is very difficult to identify the one single mechanism for arsenic-induced toxicity. This is further complicated due to biphasic response reported where arsenic has very different effects at low and high doses particularly during early life exposure scenario. In this review, we are focusing on prenatal arsenic exposure and its lifelong adverse effects, and their association with endocrine disruption and epigenetic changes. We provide evidence that developmental arsenic exposure alters the functional fetal epigenome in a tissue-specific manner by alterations in DNA methylation patterns, histone modifications and changes in micro RNA. Arsenic as an endocrine disruptor also affects the reproductive potential of the organism. These adverse effects of arsenic could manifest directly through classical hormone imprinting or through irreversible epigenetic modulation. Thus, understanding the association of epigenetic changes and endocrine disruption by prenatal arsenic exposure may help unravel the crucial mechanism for the development of disease later in life.
... May 16, 2019 surveillance of cancer. There have been a few developmental immune system studies in children who received in utero exposures to arsenic [26,27,37,40,41]. These studies focused on T-cell development and responses to childhood immunizations, and generally found decreased responses to childhood MMR and BCG vaccines. ...
Arsenic and polycyclic aromatic hydrocarbons (PAH) are environmental pollutants to which people around the world are exposed through water, food and air. In mouse and in vitro studies of human cells, both of these chemicals have been shown to modulate the immune system. In some experimental studies, a synergistic disruption of immune function was observed by a combined exposure to arsenic and PAH. However, a joint effect of arsenic and PAH on immune function has not been studied in humans. We have conducted an epidemiological investigation to examine effects of chronic arsenic and PAH exposures on immune function. We assessed T-cell proliferation (TCP) and cytokine production of anti-CD3/anti-CD28 stimulated lymphocytes in human peripheral blood mononuclear cells (HPBMC) among 197 healthy men enrolled to the Health Effects of Arsenic Longitudinal (HEALS) cohort in Bangladesh. By design, approximately half were active smokers and the rest were never smokers. Our analyses demonstrated that IL-1b, IL-2, IL-4 and IL-6 were significantly stimulated as a function of urinary arsenic levels in models adjusted for age, body mass index (BMI), smoking status and PAH-DNA adducts. After correcting for false detection rate (FDR), only IL-1b remained statistically significant. We found a U-shaped dose response relationship between urinary arsenic and IL-1b. On the other hand, PAH-DNA adducts were associated with an inhibition of TCP and appeared as an inverted U-shape curve. Dose response curves were non-monotonic for PAH-DNA adduct exposures and suggested that cytokine secretion of IFNg, IL-1b, IL-2, IL-10 and IL17A followed a complex pattern. In the majority of donors, there was a trend towards a decrease in cytokine associated with PAH-DNA adducts. We did not observe any interaction between urinary arsenic and PAH-DNA adducts on immune parameters. Our results indicate that long-term exposures to arsenic and PAH have independent, non-monotonic associations with TCP and cytokine production.
... Women exposed to low to moderate levels of arsenic through the use of private wells, as well as through dietary sources, were enrolled in the study. Analyses of data from the NHBCS have revealed associations between prenatal arsenic exposure and measures of fetal and newborn growth [5,6]; rates of infant infections [7]; immune profiles, inflammatory markers, and leptin levels in cord blood [8][9][10]; and gene expression and DNA methylation in fetal placenta [11][12][13][14][15]. Thus, it is increasingly evident that even low-to-moderate levels of arsenic have multiple effects on the developing fetus and lead to adverse infant health outcomes. However, the mechanisms that link arsenic's molecular effects with its impacts on infant health are still being determined. ...
Background
Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in gene expression. Several studies have demonstrated effects of prenatal arsenic exposure on DNA methylation; however the impact of arsenic on the generation and decoding of post-translational histone modifications (PTHMs) is less well characterized, and has not been studied in the context of prenatal human exposures.
Methods
In the current study, we examined the effect of exposure to low-to-moderate levels of arsenic in a US birth cohort, on the expression of 138 genes encoding key epigenetic regulators in the fetal portion of the placenta. Our candidate genes included readers, writers and erasers of PTHMs, and chromatin remodelers.
Results
Arsenic exposure was associated with the expression of 27 of the 138 epigenetic genes analyzed. When the cohort was stratified by fetal sex, arsenic exposure was associated with the expression of 40 genes in male fetal placenta, and only 3 non-overlapping genes in female fetal placenta. In particular, we identified an inverse relationship between arsenic exposure and expression of the gene encoding the histone methyltransferase, PRDM6 (p < 0.001). Mutation of PRDM6 has been linked to the congenital heart defect, patent ductus arteriosus.
Conclusions
Our findings suggest that prenatal arsenic exposure may have sex-specific effects on the fetal epigenome, which could plausibly contribute to its subsequent health impacts.
Electronic supplementary material
The online version of this article (10.1186/s12940-019-0455-9) contains supplementary material, which is available to authorized users.
Dietary arsenic (As) contamination is a major public health issue. In the Middle East, the food supply relies primarily on the import of food commodities. Among different age groups the main source of As exposure is grains and grain-based food products, particularly rice and rice-based dietary products. Rice and rice products are a rich source of core macronutrients and act as a chief energy source across the world. The rate of rice consumption ranges from 250 to 650 g per day per person in South East Asian countries. The source of carbohydrates through rice is one of the leading causes of human As exposure. The Gulf population consumes primarily rice and ready-to-eat cereals as a large proportion of their meals. Exposure to arsenic leads to an increased risk of non-communicable diseases such as dysbiosis, obesity, metabolic syndrome, diabetes, chronic kidney disease, chronic heart disease, cancer, and maternal and fetal complications. The impact of arsenic-containing food items and their exposure on health outcomes are different among different age groups. In the Middle East countries, neurological deficit disorder (NDD) and autism spectrum disorder (ASD) cases are alarming issues. Arsenic exposure might be a causative factor that should be assessed by screening the population and regulatory bodies rechecking the limits of As among all age groups. Our goals for this review are to outline the source and distribution of arsenic in various foods and water and summarize the health complications linked with arsenic toxicity along with identified modifiers that add heterogeneity in biological responses and suggest improvements for multi-disciplinary interventions to minimize the global influence of arsenic. The development and validation of diverse analytical techniques to evaluate the toxic levels of different As contaminants in our food products is the need of the hour. Furthermore, standard parameters and guidelines for As-containing foods should be developed and implemented.
Studies have indicated that early-life exposure to toxic metals and fluoride affects the immune system, but evidence regarding their role in allergic disease development is scarce. We aimed to evaluate the relations of exposure to such compounds in 482 pregnant women and their infants (4 months of age) with food allergy and atopic eczema diagnosed by a paediatric allergologist at 1 year of age within the Swedish birth-cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Urinary cadmium and erythrocyte cadmium, lead, and mercury concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS), urinary inorganic arsenic metabolites by ICP-MS after separation by ion exchange chromatography, and urinary fluoride by an ion-selective electrode. The prevalence of food allergy and atopic eczema was 8 and 7%, respectively. Gestational urinary cadmium, reflecting chronic exposure, was associated with increased odds of infant food allergy (OR [95% CI]: 1.34 [1.09, 1.66] per IQR [0.08 μg/L]). Both gestational and infant urinary fluoride were associated, albeit at a statistically non-significant level, with increased atopic eczema odds (1.48 [0.98, 2.25], 1.36 [0.95, 1.95], per doubling, respectively). By contrast, gestational and infant erythrocyte lead was associated with decreased odds of atopic eczema (0.48 [0.26, 0.87] per IQR [6.6 μg/kg] and 0.38 [0.16, 0.91] per IQR [5.94 μg/kg], respectively), and infant lead with decreased odds of food allergy (0.39 [0.16, 0.93] per IQR [5.94 μg/kg]). Multivariable adjustment had marginal impact on the estimates above. After additional adjustment for fish intake biomarkers, the methylmercury associated atopic-eczema odds were considerably increased (1.29 [0.80, 2.06] per IQR [1.36 μg/kg]). In conclusion, our results indicate that gestational cadmium exposure might be associated with food allergy at 1 year of age and, possibly, early-life exposure to fluoride with atopic eczema. Further prospective and mechanistic studies are needed to establish causality.
Over the past decades, population boom, urbanization, and industrialization have overburdened the surface water sources rendering them non‐potable for consumption. A switch to relatively safer groundwater resource, to meet the demand for drinking and other activities, has led to a significant effect on its quality and quantity. Overextraction of groundwater has led to decline in the water table, thus, exposing it to contaminants that seep in from the soil surface, particularly during seepage of surface water. Considering the toxicity of pollutants in groundwater, particularly the inorganic pollutants like heavy metals, arsenic (As) in groundwater possess a serious threat to the exposed population. The source of arsenic in groundwater has been reported to be geogenic in nature; however, organic matter inflow by anthropogenic sources facilitated by microbial degradation of minerals (Fe and Mn) releases the soil‐absorbed arsenic into the groundwater. In India, As has been reported in the belt of Ganga‐Brahmaputra plains including West Bengal, Bihar, Chhattisgarh, and the North‐Eastern states. Scientific investigations in these regions have identified As concentration greater than the acceptable limit of 10 μg/L, leaving 360 million people vulnerable to groundwater As contamination. Arsenic can cause a wide range of chronic and acute illness when consumed in concentration above 10 μg/L in inorganic form, which usually occurs as trivalent arsenite (arsenous acid, As(III), H 3 AsO 3 ) or pentavalent arsenate (arsenic acid, As(V), H 3 AsO 4 ). The inorganic As is absorbed by the kidney, liver, and lungs and gets deposited in tissues of nails, hair, and skin. Long‐term exposure of As can cause pigmentation changes, skin lesions, or hyperkeratosis. Alternatively, As‐free groundwater sources and removal of As from the existing water source are the only viable options to prevent arsenic toxicity. Using alternative sources, like, harvested rainwater or reclaimed wastewater for irrigation can help to prevent As exposure to soil and crops. The crisis of arsenic poisoning can be curbed with techniques like cost‐effective watershed treatment along with creating proper awareness.
DNA damage constantly threatens genome integrity, and DNA repair deficiency is associated with increased cancer risk. An intuitive and widely accepted explanation for this relationship is that unrepaired DNA damage leads to carcinogenesis due to the accumulation of mutations in somatic cells. But DNA repair also plays key roles in the function of immune cells, and immunodeficiency is an important risk factor for many cancers. Thus, it is possible that emerging links between inter-individual variation in DNA repair capacity and cancer risk are driven, at least in part, by variation in immune function, but this idea is underexplored. In this review we present an overview of the current understanding of the links between cancer risk and both inter-individual variation in DNA repair capacity and inter-individual variation in immune function. We discuss factors that play a role in both types of variability, including age, lifestyle, and environmental exposures. In conclusion, we propose a research paradigm that incorporates functional studies of both genome integrity and the immune system to predict cancer risk and lay the groundwork for personalized prevention.
The association between prenatal exposure to the metal mixture and allergic diseases is poorly understood. We aimed to explore the individual effects and the combined effects of prenatal exposure to vanadium (V), chromium (Cr), nickel (Ni), arsenic (As), cadmium (Cd), thallium (Tl), and lead (Pb) on early childhood allergic disease based on a birth cohort study that included 628 mother-infant pairs. Metals were measured in maternal urine samples collected in the first, second, and third trimesters. Children were prospectively followed up at age 4 years to collect information on allergic rhinitis, wheeze, and eczema status. By applying logistic regression models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR), the different statistical analyses revealed urinary metals were only associated with early childhood allergic rhinitis. The averaged prenatal As exposure was significantly associated with an increased OR for allergic rhinitis in both single-metal (OR = 2.04, 95% CI: 1.35, 3.07) and multiple-metal logistic regression models (OR = 1.78, 95% CI: 1.15, 2.78). The WQS index of mixed metal exposure was positively associated with allergic rhinitis (OR = 1.66, 95% CI: 1.26, 2.19), and As and Tl had the largest weights in the WQS index (weighted 0.51 and 0.29, respectively). The BKMR analysis also showed the overall effect of the metal mixture was significantly associated with allergic rhinitis when all the metals were at their 55th percentile or above, compared to their 50th percentile. The effect of As and Tl on the risk of allergic rhinitis was significant when all of the other metals were fixed at the specific percentiles. Our findings suggested that prenatal co-exposure to higher levels of the seven metals increases the risk of allergic rhinitis in children, and As and Tl may contribute most to the combined risk.
Exposure to heavy metals as cadmium and arsenic during pregnancy may have unfavorable effects on pregnant women and their offsprings. The aim of the study is to characterize the concentrations of arsenic and cadmium in umbilical cord blood and maternal blood and to clarify their associations with certain epidemiological maternal variables and birth outcomes. This cross-sectional study was conducted on randomly chosen 113 pregnant mothers and their newborns. Full history and sociodemographic data were recorded. Inductively Couples Plasma Mass Spectrometry was used to assess the levels of arsenic and cadmium in maternal and cord blood serum samples. There was a significant negative association between gestational age and maternal serum level of arsenic (r=-0.368, P=0.04). There was a significant negative correlation between maternal serum levels of arsenic and cadmium with Apgar score at 1-minute (r=-0.352,-0.361, P= 0.04, 0.032 respectively). No significant correlation was found between maternal serum levels of arsenic and cadmium and neither maternal education nor maternal age. The current approach states that maternal exposure to arsenic and cadmium during pregnancy has been found to be harmful to the developing fetus. The outcomes of the present work highlight the importance of avoiding prenatal exposure to heavy metals.
Hand-to-mouth activity in children can be an important route for ingestion of soil and dust contaminated with inorganic arsenic. Estimating the relative bioavailability of arsenic present in these media is a critical element in assessing the risk associated with aggregate exposure to this toxic metalloid during early life. Here, we evaluated the performance of a mouse assay for arsenic bioavailability in two laboratories using a suite of 10 soils. This approach allowed us to examine both intra-laboratory and inter-laboratory variation in assay performance. Use of a single vendor for preparation of all amended test diets and of a single laboratory for arsenic analysis of samples generated in the participating laboratories minimized contributions of these potential sources of variability in assay performance. Intra-laboratory assay data showed that food and water intake and cumulative urine and feces production remained stable over several years. The stability of these measurements accounted for the reproducibility of estimates of arsenic bioavailability obtained from repeated intra-laboratory assays using sodium arsenate or soils as the test material. Inter-laboratory comparisons found estimates of variables used to evaluate assay performance (recovery, urinary excretion factor) were similar in the two laboratories. For all soils, estimates of arsenic relative bioavailability obtained in the two laboratories were highly correlated (r2= 0.98; slope = 0.9) in a linear regression model. Overall, these findings show that this mouse assay for arsenic bioavailability provides reproducible estimates using a variety of test soils. This robust model may be adaptable for use in other laboratory settings.
Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels.
Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from enrollees were homogenized and profiled for gene expression across a panel of candidate genes, including known arsenic regulated targets and genes involved in arsenic transport, metabolism, or disease susceptibility. Multivariable adjusted linear regression models were used to examine the relationship of candidate gene expression with arsenic exposure or with birth weight of the baby.
Placental expression of the arsenic transporter AQP9 was positively associated with maternal urinary arsenic levels during pregnancy (coefficient estimate: 0.25; 95% confidence interval: 0.05 -- 0.45). Placental expression of AQP9 related to expression of the phospholipase ENPP2 which was positively associated with infant birth weight (coefficient estimate: 0.28; 95% CI: 0.09 -- 0.47). A structural equation model indicated that these genes may mediate arsenic's effect on infant birth weight (coefficient estimate: -0.009; 95% confidence interval: -0.032 -- -0.001; 10,000 replications for bootstrapping).
We identified the expression of AQP9 as a potential fetal biomarker for arsenic exposure. Further, we identified a positive association between the placental expression of phospholipase ENPP2 and infant birth weight. These findings suggest a path by which arsenic may affect birth outcomes.
Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation.
Objectives: In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure.
Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24–28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels.
Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8+ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands (p = 0.009). Of those in CpG islands (n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure.
Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.
The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in the periphery. Fetal CD4(+) T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of fetal T cells and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis.
Food allergy is a major public health problem, for which there is no effective treatment. We examined the immunological changes that occurred in a group of children with significant cow's milk allergy undergoing a novel and rapid high-dose oral desensitization protocol enabled by treatment with omalizumab (anti-immunoglobulin (Ig)E monoclonal antibodies). Within a week of treatment, the CD4(+) T-cell response to milk was nearly eliminated, suggesting anergy in, or deletion of, milk-specific CD4(+) T cells. Over the following 3 months while the subjects remained on high doses of daily oral milk, the CD4(+) T-cell response returned, characterized by a shift from interleukin-4 to interferon-γ production. Desensitization was also associated with reduction in milk-specific IgE and a 15-fold increase in milk-specific IgG4. These studies suggest that high-dose oral allergen desensitization may be associated with deletion of allergen-specific T cells, without the apparent development of allergen-specific Foxp3(+) regulatory T cells.
Emerging data indicate that rice consumption may lead to potentially harmful arsenic exposure. However, few human data are available, and virtually none exist for vulnerable periods such as pregnancy. Here we document a positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women. At a 6-mo prenatal visit, we collected a urine sample and 3-d dietary record for water, fish/seafood, and rice. We also tested women's home tap water for arsenic, which we combined with tap water consumption to estimate arsenic exposure through water. Women who reported rice intake (n = 73) consumed a median of 28.3 g/d, which is ∼0.5 cup of cooked rice each day. In general linear models adjusted for age and urinary dilution, both rice consumption (g, dry mass/d) and arsenic exposure through water (μg/d) were significantly associated with natural log-transformed total urinary arsenic (βrice = 0.009, βwater = 0.028, both P < 0.0001), as well as inorganic arsenic, monomethylarsonic acid, and dimethylarsinic acid (each P < 0.005). Based on total arsenic, consumption of 0.56 cup/d of cooked rice was comparable to drinking 1 L/d of 10 μg As/L water, the current US maximum contaminant limit. US rice consumption varies, averaging ∼0.5 cup/d, with Asian Americans consuming an average of >2 cups/d. Rice arsenic content and speciation also vary, with some strains predominated by dimethylarsinic acid, particularly those grown in the United States. Our findings along with others indicate that rice consumption should be considered when designing arsenic reduction strategies in the United States.
The role of T cells in innate immunity is not well defined. In this report, we show that a subset of human peripheral blood CD4(+) T cells responds to IL-12 plus IL-18, but not to IL-12 or IL-18 alone, by producing IFN-γ in the absence of any antigenic stimulation or cell proliferation. Intracellular staining reveals a small percentage of resting CD4(+) T cells (0.5 to 1.5%) capable of producing IFN-γ in response to IL-12 plus IL-18. Interestingly, both naïve (CD45RA(+)) and memory (CD45RO(+)) CD4(+) populations were responsive to IL-12 plus IL-18 stimulation in producing IFN-γ. The expression of IFN-γinduced by IL-12 and IL-18 is sensitive to rapamycin and SB203580, indicating the possible involvement of mTOR and p38 MAP kinase, respectively, in this synergistic pathway. While p38MAP kinase is involved in transcription, mTOR is involved in message stabilization. We have also shown that NFκB family member, cRel, but not GADD45β and GADD45γ, plays an important role in IL-12 plus IL-18-induced IFN-γ transcription. Thus, the present study suggests that naïve CD4(+) T cells may participate in innate immunity or amplify adaptive immune responses through cytokine-induced antigen-independent cytokine production.
Infections in infants continue to be an important cause of morbidity and mortality worldwide. Understanding the immune mechanisms that operate in infants is necessary for the development of new approaches to improve the health of infants around the world.
Previous studies have reported associations between prenatal arsenic exposure and increased risk of infant mortality. An increase in infectious diseases has been proposed as the underlying cause of these associations, but there is no epidemiologic research to support the hypothesis.
We evaluated the association between arsenic exposure in pregnancy and morbidity during infancy.
This prospective population-based cohort study included 1,552 live-born infants of women enrolled during 2002-2004 in Matlab, Bangladesh. Arsenic exposure was assessed by the concentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestational weeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea in infants was collected by 7-day recalls at monthly home visits.
In total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjusted relative risk (RR) = 1.69; 95% confidence interval (CI), 1.36-2.09)] and 54% (RR = 1.54; 95% CI, 1.21-1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highest quintile (average of arsenic concentrations measured in early and late gestation, 262-977 µg/L) relative to those with exposure in the lowest quintile (< 39 µg/L). The corresponding figure for diarrhea was 20% (RR = 1.20; 95% CI, 1.01-1.43).
Arsenic exposure during pregnancy was associated with increased morbidity in infectious diseases during infancy. Taken together with the previous evidence of adverse effects on health, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.
Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues.
Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight.
In this study we aimed to elucidate the effects of As exposure on immune markers in the placenta and cord blood, and the involvement of oxidative stress.
Pregnant women were enrolled around gestational week (GW) 8 in our longitudinal, population-based, mother-child cohort in Matlab, an area in rural Bangladesh with large variations in As concentrations in well water. Women (n = 130) delivering at local clinics were included in the present study. We collected maternal urine twice during pregnancy (GW8 and GW30) for measurements of As, and placenta and cord blood at delivery for assessment of immune and inflammatory markers. Placental markers were measured by immunohistochemistry, and cord blood cytokines by multiplex cytokine assay.
In multivariable adjusted models, maternal urinary As (U-As) exposure both at GW8 and at GW30 was significantly positively associated with placental markers of 8-oxoguanine (8-oxoG) and interleukin-1β (IL-1β); U-As at GW8, with tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); and U-As at GW30, with leptin; U-As at GW8 was inversely associated with CD3+ T cells in the placenta. Cord blood cytokines (IL-1β, IL-8, IFNγ, TNFα) showed a U-shaped association with U-As at GW30. Placental 8-oxoG was significantly positively associated with placental proinflammatory cytokines. Multivariable adjusted analyses suggested that enhanced placental cytokine expression (TNFα and IFNγ) was primarily influenced by oxidative stress, whereas leptin expression appeared to be mostly mediated by As, and IL-1β appeared to be influenced by both oxidative stress and As.
As exposure during pregnancy appeared to enhance placental inflammatory responses (in part by increasing oxidative stress), reduce placental T cells, and alter cord blood cytokines. These findings suggest that effects of As on immune function may contribute to impaired fetal and infant health.
A prospective cohort study was conducted to evaluate the effect of arsenic (As) exposure from drinking water on respiratory symptoms using data from the Health Effects of Arsenic Exposure Longitudinal Study (HEALS), a large prospective cohort study established in Ariahazar, Bangladesh in 2000-2002. A total of 7.31, 9.95 and 2.03% of the 11 746 participants completing 4 years of active follow-up reported having a chronic cough, breathing problem or blood in their sputum, respectively, as assessed by trained physicians.
Cox regression models were used to estimate HRs for respiratory symptoms during the follow-up period in relation to levels of chronic As exposure assessed at baseline, adjusting for age, gender, smoking, body mass index, education and arsenic-related skin lesion status.
Significant positive associations were found between As exposure and respiratory symptoms. As compared with those with the lowest quintile of water As level (<or=7 microg/l), the HRs for having respiratory symptoms were 1.27 (95% CI 1.09 to 1.48), 1.39 (95% CI 1.19 to 1.63), 1.43 (95% CI 1.23 to 1.68) and 1.43 (95% CI 1.22 to 1.68) for the second to fifth quintiles of baseline water As concentrations (7-40, 40-90, 90-178 and >178 microg/l), respectively. Similarly, the corresponding HRs in relation to the second to fifth quintiles of urinary arsenic were 1.10 (95% CI 0.94 to 1.27), 1.11 (95% CI 0.95 to 1.29), 1.29 (95% CI 1.11 to 1.49) and 1.35 (95% CI 1.16 to 1.56), respectively. These associations did not differ appreciably by cigarette smoking status.
This prospective cohort study found a dose-response relationship between As exposure and clinical symptoms of respiratory diseases in Bangladesh. In particular, these adverse respiratory effects of As were clearly evident in the low to moderate dose range, suggesting that a large proportion of the country's population may be at risk of developing serious lung diseases in the future.
That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor-beta (TGF-beta) and interleukin (IL)-10). In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma if generated early enough in life. This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen. However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature. It is tempting to speculate that there is a window of opportunity in early life in the context of a relatively immature immune system that is permissive for the generation of iTregs specific to a spectrum of allergens that would regulate asthma for lifelong. The focus of this review is the relevance of nTregs and iTregs in controlling asthma from early life into adulthood, the mechanisms underlying Treg function, and the prospects for using our current concepts to harness the full potential of Tregs to limit disease development and progression.
Expressed in liver, aquaglyceroporin-9 (AQP9) is permeated by glycerol, arsenite, and other small, neutral solutes. To evaluate a possible protective role, AQP9-null mice were evaluated for in vivo arsenic toxicity. After injection with NaAsO(2), AQP9-null mice suffer reduced survival rates (LD(50), 12 mg/kg) compared with WT mice (LD(50), 15 mg/kg). The highest tissue level of arsenic is in heart, with AQP9-null mice accumulating 10-20 times more arsenic than WT mice. Within hours after NaAsO(2) injection, AQP9-null mice sustain profound bradycardia, despite normal serum electrolytes. Increased arsenic levels are also present in liver, lung, spleen, and testis of AQP9-null mice. Arsenic levels in the feces and urine of AQP9-null mice are only approximately 10% of the WT levels, and reduced clearance of multiple arsenic species by the AQP9-null mice suggests that AQP9 is involved in the export of multiple forms of arsenic. Immunohistochemical staining of liver sections revealed that AQP9 is most abundant in basolateral membrane of hepatocytes adjacent to the sinusoids. AQP9 is not detected in heart or kidney by PCR or immunohistochemistry. We propose that AQP9 provides a route for excretion of arsenic by the liver, thereby providing partial protection of the whole animal from arsenic toxicity.
Arsenic exposure is a significant worldwide environmental health concern. We recently reported that 5-week exposure to environmentally relevant levels (10 and 100 ppb) of As in drinking water significantly altered components of the innate immune response in mouse lung, which we hypothesize is an important contributor to the increased risk of lung disease in exposed human populations.
We investigated the effects of As exposure on respiratory influenza A (H1N1) virus infection, a common and potentially fatal disease.
In this study, we exposed C57BL/6J mice to 100 ppb As in drinking water for 5 weeks, followed by intranasal inoculation with a sub lethal dose of influenza A/PuertoRico/8/34 (H1N1) virus. Multiple end points were assessed postinfection.
Arsenic was associated with a number of significant changes in response to influenza, including an increase in morbidity and higher pulmonary influenza virus titers on day 7 post-infection. We also found many alterations in the immune response relative to As-unexposed controls, including a decrease in the number of dendritic cells in the mediastinal lymph nodes early in the course of infection.
Our data indicate that chronic As exposure significantly compromises the immune response to infection. Alterations in response to repeated lung infection may also contribute to other chronic illnesses, such as bronchiectasis, which is elevated by As exposure in epidemiology studies.
Chronic exposure to drinking water arsenic is a significant worldwide environmental health concern. Exposure to As is associated with an increased risk of lung disease, which may make it a unique toxicant, because lung toxicity is usually associated with inhalation rather than ingestion.
The goal of this study was to examine mRNA and protein expression changes in the lungs of mice exposed chronically to environmentally relevant concentrations of As in the food or drinking water, specifically examining the hypothesis that As may preferentially affect gene and protein expression related to immune function as part of its mechanism of toxicant action.
C57BL/6J mice fed a casein-based AIN-76A defined diet were exposed to 10 or 100 ppb As in drinking water or food for 5-6 weeks.
Whole genome transcriptome profiling of animal lungs revealed significant alterations in the expression of many genes with functions in cell adhesion and migration, channels, receptors, differentiation and proliferation, and, most strikingly, aspects of the innate immune response. Confirmation of mRNA and protein expression changes in key genes of this response revealed that genes for interleukin 1beta, interleukin 1 receptor, a number of toll-like receptors, and several cytokines and cytokine receptors were significantly altered in the lungs of As-exposed mice.
These findings indicate that chronic low-dose As exposure at the current U.S. drinking-water standard can elicit effects on the regulation of innate immunity, which may contribute to altered disease risk, particularly in lung.
In the United States, asthma prevalence is particularly high among urban children. Although the underlying immune mechanism contributing to asthma has not been identified, having impaired T regulatory (Treg) cells at birth may be a determining factor in urban children. The objective of this study was to compare Treg phenotype and function in cord blood (CB) of newborns to those in peripheral blood (PB) of a subset of participating mothers.
Treg numbers, expression, and suppressive function were quantified in subjects recruited prenatally from neighborhoods where >/= 20% of families have incomes below the poverty line. Proportion of Treg cells and expression of naïve (CD45RA) or activated (CD45RO, CD69, and HLA-DR) markers in CD4+T cells was measured by flow cytometry. Treg suppressive capacity was determined by quantifying PHA-stimulated lymphocyte proliferation in mononuclear cell samples with and without CD25 depletion.
In an urban cohort of 119 newborns and 82 mothers, we found that newborns had similar number of cells expressing FOXP3 as compared to the mothers but had reduced numbers of CD4+CD25+bright cells that predominantly expressed the naïve (CD45RA) rather than the activated/memory (CD45RO) phenotype found in the mothers. Additionally, the newborns had reduced mononuclear cell TGF-beta production, and reduced Treg suppression of PHA-stimulated lymphocyte proliferation compared to the mothers.
U.S. urban newborns have Treg cells that express FOXP3, albeit with an immature phenotype and function as compared to the mothers. Longitudinal follow-up is needed to delineate Treg cell maturation and subsequent risk for atopic diseases in this urban birth cohort.
Urinary arsenic metabolites (UAs) are used as biomarkers of exposure and metabolism.
To characterize inter- and intraindividual variability in UAs in healthy individuals.
In a longitudinal study conducted in Bangladesh, we collected water and spot urine samples from 196 participants every 3 months for 2 years. Water arsenic (As) was measured by inductively coupled plasma-mass spectrometry and urinary As [arsenite, arsenate, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were detected using high-performance liquid chromatography-hydride-generated atomic absorption spectrometry. We used linear mixed-effects models to compute variance components and evaluate the association between UAs and selected factors.
The concentrations of UAs were fairly reproducible within individuals, with intraclass correlation coefficients (ICCs) of 0.41, 0.35, 0.47, and 0.49 for inorganic As (InAs), MMA, DMA, and total urinary As (TUA). However, when expressed as a ratio, the percent InAs (%InAs), %MMA, and %DMA were poorly reproducible within individuals, with ICCs of 0.16, 0.16, and 0.17, respectively. Arsenic metabolism was significantly associated with sex, exposure, age, smoking, chewing betel nut, urinary creatinine, and season. Specificity and sensitivity analyses showed that a single urine sample adequately classified a participant's urinary As profile as high or low, but TUA had only moderate specificity for correctly classifying drinking water exposures.
Epidemiologic studies should use both urinary As concentrations and the relative proportion of UAs to minimize measurement error and to facilitate interpretation of factors that influence As metabolism.
CD4(+) recent thymic emigrants (RTEs) comprise a clinically and immunologically important T cell population that indicates thymic output and that is essential for maintaining a diverse alphabeta-T cell receptor (TCR) repertoire of the naive CD4(+) T cell compartment. However, their frequency and function are poorly understood because no known surface markers distinguish them from older non-RTE naive CD4(+) T cells. We demonstrate that protein tyrosine kinase 7 (PTK7) is a novel marker for human CD4(+) RTEs. Consistent with their recent thymic origin, human PTK7(+) RTEs contained higher levels of signal joint TCR gene excision circles and were more responsive to interleukin (IL)-7 compared with PTK7(-) naive CD4(+) T cells, and rapidly decreased after complete thymectomy. Importantly, CD4(+) RTEs proliferated less and produced less IL-2 and interferon-gamma than PTK7(-) naive CD4(+) T cells after alphabeta-TCR/CD3 and CD28 engagement. This immaturity in CD4(+) RTE effector function may contribute to the reduced CD4(+) T cell immunity observed in contexts in which CD4(+) RTEs predominate, such as in the fetus and neonate or after immune reconstitution. The ability to identify viable CD4(+) RTEs by PTK7 staining should be useful for monitoring thymic output in both healthy individuals and in patients with genetic or acquired CD4(+) T cell immunodeficiencies.
Chronic exposure to arsenic, a potent carcinogen and toxicant, via drinking water is a worldwide public health problem. Because little is known about early-life effects of arsenic on immunity, we evaluated the impact of in utero exposure on infant immune parameters and morbidity in a pilot study. Pregnant women were enrolled at 6-10 weeks of gestation in Matlab, a rural area of Bangladesh, extensively affected by arsenic contamination of tubewell water. Women (n=140) delivering at local clinics were included in the study. Anthropometry and morbidity data of the pregnant women and their children, as well as infant thymic size by sonography were collected. Maternal urine and breast milk were collected for immune marker and arsenic assessment. Maternal urinary arsenic during pregnancy showed significant negative correlation with interleukin-7 (IL-7) and lactoferrin (Ltf) in breast milk and child thymic index (TI). Urinary arsenic was also positively associated with fever and diarrhea during pregnancy and acute respiratory infections (ARI) in the infants. The effect of arsenic exposure on ARI was only evident in male children. The findings suggest that in utero arsenic exposure impaired child thymic development and enhanced morbidity, probably via immunosuppression. The effect seemed to be partially gender dependent. Arsenic exposure also affected breast milk content of trophic factors and maternal morbidity.
Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease.
Over six million people in nine districts of West Bengal, India are exposed to very high levels of arsenic primarily through their drinking water. More than 300,000 people showed arsenic-induced skin lesions in these districts. This is regarded as the greatest arsenic calamity in the world. Chronic arsenicosis causes varied dermatological signs ranging from pigmentation changes, hyperkeratosis to non-melanocytic cancer of skin, and also malignancies in different internal organs. Higher incidences of opportunistic infections are found in the arsenic-exposed individuals, indicating that their immune systems may be impaired somehow. We have thus investigated the effect of arsenic on T-cell proliferation and cytokine secretion in 20 individuals with arsenic-induced skin lesions and compared the results with 18 arsenic-unexposed individuals. A marked dose-dependent suppression of Concanavalin A (Con A) induced T-cell proliferation was observed in the arsenic-exposed individuals compared with the unexposed (P < 0.001) individuals. This correlated with a significant decrease in the levels of secreted cytokines by the T cells (TNF-alpha, IFN-gamma, IL2, IL10, IL5, and IL4) in the exposed individuals (P < 0.001). Thus it can be inferred that arsenic exposure can cause immunosuppression in humans.
The expression of Th2-skewed immunity against soluble protein Ags present in the normal environment is recognized as the primary cause of allergic inflammation in atopics. In contrast, nonallergic normal individuals display low level Th1-skewed immunity against the same Ags ("allergens"), which is perceived as conferring protection against Th2-dependent allergic sensitization. The type of T cell memory that develops against these Ags is currently believed to be the result of complex interactions between environmental and genetic susceptibility factors, which occur postnatally when the naive immune system directly confronts the outside environment. The results of the present study challenge this general concept. We demonstrate here for the first time that Th2-skewed responses to common environmental allergens, comprising IL-4, IL-5, IL-6, IL-9, and IL-13, are present in virtually all newborn infants and are dominated by high level production of IL-10. Moreover, these responses are demonstrable within 24 h of culture initiation, arguing against a significant contribution from covert in vitro T cell priming and/or differentiation. These findings imply that the key etiologic factor in atopic disease may not be the initial acquisition of allergen-specific Th2-skewed immunity per se, but instead may be the efficiency of immune deviation mechanisms, which in normal (nonatopic) individuals redirect these fetal immune responses toward the Th1 cytokine phenotype.
The search for reliable marker molecules discriminating between human Th1 and Th2 cells identified a gene encoding a novel member of the G protein-coupled leukocyte chemoattractant receptor family, which is selectively expressed in Th2 but not Th1 lineage cells, thereby named CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). Studies with anti-CRTH2 mAbs demonstrated that CRTH2 was expressed in a small population (0.4-6.5%) of CD4+ T cells in fresh PBMCs of healthy adults, but no remarkable expression was seen in B cells and NK cells. In some cases, CD8+ T cells ( approximately 3.5%) expressed CRTH2. Phenotypes of CD4+ T cells expressing CRTH2 were CD45RA-, CD45RO+, and CD25+, similar to those of Ag-activated effector/memory T cells. Freshly isolated CRTH2+ CD4+ T cells produced Th2- but little or no Th1-type cytokines upon stimulation with PMA and ionomycin. In addition, an allergen-induced proliferative response in fresh PBMCs was significantly and selectively reduced by subtracting CRTH2+ cells. Together, these results indicate that CRTH2 is selectively expressed in vivo in an activated state of Th2 cells including allergen-responsive Th2 cells, suggesting its pivotal roles in ongoing Th2-type immune reactions.
IntroductionWater Quality IssuesMethods of Arsenic RemovalAquifer Clean-upDisposing of Waste from Treatment ProcessesExamples and Operational Experience of Arsenic Removal TechnologiesCosts of Arsenic RemovalGuidance for Selecting Treatment Methods and TechnologiesCase Study of Water Treatment Requirements in BangladeshFuture Needs
Arsenic concentrations were measured in 992 drinking water samples collected from New Hampshire households using online hydride generation ICP-MS. These randomly selected household water samples contain much less arsenic than those voluntarily submitted for analysis to the New Hampshire Department of Environmental Services (NHDES). Extrapolation of the voluntarily submitted sample set to all New Hampshire residents significantly overestimates arsenic exposure. In randomly selected households, concentrations ranged from <0.0003 to 180 {micro}g/L, with water from domestic wells containing significantly more arsenic than water from municipal sources. Water samples from drilled bedrock wells had the highest arsenic concentrations, while samples from surficial wells had the lowest arsenic concentrations. The authors suggest that much of the groundwater arsenic in New Hampshire is derived from weathering of bedrock materials and not from anthropogenic contamination. The spatial distribution of elevated arsenic concentrations correlates with Late-Devonian Concord-type granitic bedrock. Field observations in the region exhibiting the highest groundwater arsenic concentrations revealed abundant pegmatite dikes associated with nearby granites. Analysis of rock digests indicates arsenic concentrations up to 60 mg/kg in pegmatites, with much lower values in surrounding schists and granites. Weak acid leaches show that approximately half of the total arsenic in the pegmatites is labile and therefore can be mobilized during rock-water interaction.
A variable span smoother based on local linear fits is described. Local cross- validation is used to estimate the optimal span as a function of abscissa value. Com- putationally efficient algorithms making use of updating formulas are presented.
Arsenic (As), a ubiquitous environmental toxicant, has recently been linked to disrupted immune function and enhanced infection susceptibility in highly exposed populations. In drinking water, as levels above the EPA maximum contaminant level occur in our US study area and are a particular health concern for pregnant women and infants. As a part of the New Hampshire Birth Cohort Study, we investigated whether in utero exposure to As affects risk of infant infections. We prospectively obtained information on 4-month-old infants (n=214) using a parental telephone survey on infant infections and symptoms, including respiratory infections, diarrhea and specific illnesses, as well as the duration and severity of infections. Using logistic regression and Poisson models, we evaluated the association between maternal urinary As during pregnancy and infection risks adjusted for potentially confounding factors. Maternal urinary As concentrations were related to total number of infections requiring a physician visit (relative risk (RR) per one-fold increase in As in urine=1.5; 95% confidence interval (CI)=1.0, 2.1) or prescription medication (RR=1.6; 95% CI=1.1, 2.4), as well as lower respiratory infections treated with prescription medication (RR=3.3; 95% CI=1.2, 9.0). Associations were observed with respiratory symptoms (RR=4.0; 95% CI=1.0, 15.8), upper respiratory infections (RR=1.6; 95% CI=1.0, 2.5), and colds treated with prescription medication (RR=2.3; 95% CI=1.0, 5.2). Our results provide initial evidence that in utero As exposure may be related to infant infection and infection severity and provide insight into the early life impacts of fetal As exposure.
This study describes the burden and epidemiologic features of infectious disease hospitalizations among infants in the United States.
Hospitalizations with an infectious disease listed as a primary diagnosis for infants (<1 year of age) in the United States during 2003 were examined by using the Kids' Inpatient Database. National estimates of infectious disease hospitalizations, hospitalization rates, and various hospital parameters were examined.
During 2003, an estimated 286,739 infectious disease hospitalizations occurred among infants in the United States and accounted for 42.8% of all infant hospitalizations. The national infectious disease hospitalization rate was 7010.8 hospitalizations per 100,000 live births, or approximately 1 infectious disease hospitalization for every 14 infants. The median length of stay was 3 days, and stays totaled >1 million hospital days for infants. Infectious disease hospitalization rates were highest among boys and nonwhite infants. The most commonly listed diagnoses among the infant infectious disease hospitalizations included lower respiratory tract infections (59.0%), kidney, urinary tract, and bladder infections (7.6%), upper respiratory tract infections (6.5%), and septicemia (6.5%). The median cost of an infectious disease hospitalization was $2235, with total annual hospital costs of approximately $690 million, among infants in the United States.
Infectious disease hospitalizations among infants account for substantial health care expenditures and hospital time in the United States, with respiratory disease hospitalizations constituting more than one half of all hospitalizations. Younger infants, boys, and nonwhite infants were at increased risk for infectious disease hospitalization. Measures to reduce racial disparities and the occurrence of respiratory tract infections should substantially decrease the infectious disease burden among infants.
Background:
This study aimed to investigate the influence of maternal allergy on cord blood regulatory and effector T cells and to evaluate their role as a predictor of atopic dermatitis (AD) during the first 2 yr of life.
Methods:
Seventy mother-infant pairs were recruited in this prospective birth cohort study (21 allergic and 49 non-allergic mothers). Cord blood samples were collected and assayed for the percentage of regulatory T cells (Treg), interferon-γ (IFN-γ), and interleukin-4 (IL-4) producing T cells (Th1 and Th2, respectively) using flow cytometry. Experiments were undertaken to assess the function of cord blood CD4(+) CD25(+) CD127(-) Treg cells by cell proliferation and cytokine responses. Their offspring at the age of 2 yr old were evaluated by dermatologists to determine whether they had AD.
Results:
During the first 2 yr of life, 15.7% of the children developed a physician-diagnosed AD. A significantly increased percentage of Th2 cell was observed in cord blood of newborns with maternal allergy. Treg/Th2 ratio significantly decreased among the offspring of allergic mothers. Treg cell-associated suppression of Th2 response was attenuated in Der p1-stimulated CD4(+) CD25(-) T cells from the offspring of allergic mothers. Children with reduced Th1/Th2 (p = 0.001, OR = 0.37) and Treg/Th2 (p = 0.001, OR = 0.47) ratio in cord blood had a higher risk of developing AD.
Conclusion:
Maternal allergic status is associated with increased percentage of IL-4(+) CD4(+) T cells and a reduced Treg/Th2 ratio in cord blood at their children's birth, which may predispose to an increased risk for developing AD.
Naive T-cells divide and mature, both functionally and phenotypically, upon stimulation through the T-cell receptor. Although much is known about the overall changes that occur in naive cells upon TCR stimulation, and the different memory/effector populations that arise following stimulation, the relationship between cell division and functional and phenotypical changes that occur after activation is poorly understood. Here, we examine the early stages of human naive and antigen-experienced T-cell activation, and the relationship between cell division and acquisition of effector function during the transition from resting antigen-experienced or naive T-cells into effector cells. Stimulated naive T-cells proliferate prior to acquisition of effector function, as measured by cytokine production and expression of effector-associated cell surface molecules. Additionally, we show that interlukin-7 (IL-7) can drive proliferation of naive T-cells without TCR:MHC peptide interactions. IL-7 alone does not, however, drive the proliferation of antigen-experienced T-cells. Memory T-cells will divide in response to exogenous IL-7 but only in the presence of naive T-cells and IL-2. This study contributes to the current understanding of the mechanistic differences between naive and memory T-cell responses by defining the functional and phenotypic changes that occur to T-cells after stimulation.
Arsenic trioxide (arsenite, As(III)) has shown a remarkable clinical efficacy, whereas its side effects are still a serious concern. Therefore, it is critical to understand the effects of As(III) on human-derived normal cells for revealing the mechanisms underlying these side effects. We examined the effects of As(III) on primary cultured chorion (C) and amnion (A) cells prepared from human fetal membranes. A significant dose-dependent As(III)-mediated cytotoxicity was observed in the C-cells accompanied with an increase of lactate dehydrogenase (LDH) release. Higher concentrations of As(III) were required for the A-cells to show cytotoxicity and LDH release, suggesting that the C-cells were more sensitive to As(III) than the A-cells. The expression levels of aquaporin 9 (AQP9) were approximately 2 times higher in the C-cells than those in the A-cells. Both intracellular arsenic accumulation and its cytotoxicity in the C-cells were significantly abrogated by sorbitol, a competitive AQP9 inhibitor, in a dose-dependent manner. The protein expression levels of multidrug resistance-associated protein (MRP) 2 were downregulated by As(III) in the C-cells, but not in the A-cells. No significant differences in the expression levels of MRP1 were observed between C- and A-cells. The protein expression of P-glycoprotein (P-gp) was hardly detected in both cells, although a detectable amount of its mRNA was observed. Cyclosporine A, a broad-spectrum inhibitor for ABC transporters, and MK571, a MRP inhibitor, but not PGP-4008, a P-gp specific inhibitor, potently sensitized both cells to As(III)-mediated cytotoxicity. These results suggest that AQP9 and MRP2 are involved in controlling arsenic accumulation in these normal cells, which then contribute to differential sensitivity to As(III) cytotoxicity between these cells.
It has been established that the permeability of the human placenta increases with advancing gestation. Indirect evidence has also proposed that aquaporins (AQPs) may be involved in the regulation of placental water flow but the mechanisms are poorly understood. Five AQPs have been found in the human placenta and fetal membranes [AQP1, 3, 4, 8 and 9]. However, the physiological function(s) and the regulation of these proteins remain unknown. Emerging evidence has shown that human fetal membrane AQPs may have a role in intramembranous amniotic fluid water regulation and that alterations in their expression are related to polyhydramnios and oligohydramnios. In addition, we have observed a high expression of AQP3 and AQP9 in the apical membrane of the syncytiotrophoblast. Moreover, AQP9 was found to be increased in preeclamptic placentas, but it could not be related to its functionality for the transport of water and mannitol. However, a significant urea flux was seen. Since preeclampsia is not known to be associated with an altered water flux to the fetus we propose that AQP9 might not have a key role in water transport in human placenta, but a function in the energy metabolism or the urea uptake and elimination across the placenta. However, the role of AQP9 in human placenta is still speculative and needs further studies. Insulin, hCG, cAMP and CFTR have been found to be involved in the regulation of the molecular and functional expression of AQPs. Further insights into these mechanisms may clarify how water moves between the mother and the fetus.
To investigate the frequency and function of CD4(+)CD25(+)CD127(dim/-) regulatory T (Treg) cells in decidua of patients with unexplained recurrent spontaneous miscarriage (URSM).
The decidual lymphocytes from patients who experienced URSM and normal pregnant women (controls) were collected by Ficoll density gradient centrifugation. CD4(+)CD25(+)CD127(dim/-) Treg cells were isolated by magnetic cell sorting. The proportion of Treg cells and IL-10, TGF-β in Treg cells were determined by flow cytometry. Inhibitory effects of Treg cells on effecter T cells were detected with or without the presentation of anti-IL-10 antibodies and anti-TGF-β antibodies.
The frequency of CD4(+)CD25(+)CD127(dim/-) Treg cells was decreased in URSM decidua compared to controls (2.09%±0.86% vs. 2.97%±1.19%, p=0.005), and the expression of IL-10 and TGF-β in Treg cells was lower in the URSM group than in the control group (p=0.04 and p=0.01, respectively). Furthermore, the suppressive effect of CD4(+)CD25(+)CD127(dim/-) Treg cells on the proliferation of effector T cells was decreased in URSM decidua (p<0.05). Suppression was mediated predominantly through IL-10 and TGF-β in decidua.
Decreased frequency and immunosuppressive capacity of CD4(+)CD25(+)CD127(dim/-) Treg cells was found in URSM decidua. Treg cells inhibit proliferation of effector T cells mainly via IL-10 and TGF-β in URSM decidua.
Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response.
To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores.
Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score.
Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P ≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P ≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P ≤ .05).
Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.
Human regulatory T cells (Tregs) play a critical role in preventing autoimmunity, and their failure contributes to autoimmune diseases. In recent years, our understanding of human Tregs has been greatly enhanced by improvements in the definition and isolation of pure human Tregs, as well as by the discovery of phenotypically and functionally distinct human Treg subsets. This progress has also yielded a better understanding of the mechanisms of human Treg suppression and the role of human Tregs in autoimmune diseases. An unexpected discovery is that human Tregs have considerable plasticity that allows them to produce the pro-inflammatory cytokine IL-17 under certain conditions. These recent advances highlight the importance of studying the roles of both mouse and human Tregs in autoimmunity.
Asthma influences pregnancy outcome and pregnancy affects asthma severity, but the immunologic mechanisms of these interactions are not fully elucidated.
The prevalence of lymphocyte subsets was identified by cell surface markers and intracellular FoxP3 staining, in healthy non-pregnant (HNP; N = 15), healthy pregnant (HP; N=33), asthmatic non-pregnant (ANP; N=62) and asthmatic pregnant (AP; N=61) women.
Regulatory T cell (Treg) prevalence was higher in HP than in HNP subjects and showed a positive correlation with fetal birth weight, which was blunted in AP group. Treg prevalence was lower and invariable natural killer T cell prevalence was higher in AP patients (compared to HP). Higher naive and lower effector T cell prevalence was observed in AP than in ANP group.
Pregnancy-induced increase in Treg cell prevalence is absent in asthmatic pregnancy that may interfere with physiological intrauterine growth. However, pregnancy-specific inhibition of asthmatic inflammation can be detected in uncomplicated asthmatic pregnancy.
The role of distinct CD4(+) T-cell populations in regulating the nature and strength of immune responses is well documented and in the past has principally focused on the cross-regulation of T-helper type 1 (Th1) and Th2 cells, which secrete interferon-gamma and interleukin-4, respectively. However, the identification of T cells capable of suppressing responses mediated by Th1 and Th2 cells, termed regulatory T cells (Treg cells), has prompted a paradigm shift in our understanding of the regulation of immune responses to infection and environmental antigens. This article focuses on the role of Treg cells in the lungs following infection with respiratory pathogens and discusses the targeting of Treg cells in the development of new therapies for immune-mediated respiratory diseases, such as allergy and asthma.
Allergy is a Th2-mediated disease that involves the formation of specific IgE antibodies against innocuous environmental substances. The prevalence of allergic diseases has dramatically increased over the past decades, affecting up to 30% of the population in industrialized countries. The understanding of mechanisms underlying allergic diseases as well as those operating in non-allergic healthy responses and allergen-specific immunotherapy has experienced exciting advances over the past 15 years. Studies in healthy non-atopic individuals and several clinical trials of allergen-specific immunotherapy have demonstrated that the induction of a tolerant state in peripheral T cells represent a key step in healthy immune responses to allergens. Both naturally occurring thymus-derived CD4+CD25+FOXP3+ Treg and inducible type 1 Treg inhibit the development of allergy via several mechanisms, including suppression of other effector Th1, Th2, Th17 cells; suppression of eosinophils, mast cells and basophils; Ab isotype change from IgE to IgG4; suppression of inflammatory DC; and suppression of inflammatory cell migration to tissues. The identification of the molecules involved in these processes will contribute to the development of more efficient and safer treatment modalities.
Arsenic is a carcinogen that is associated with an increased risk of human skin cancer. On the other hand, arsenic trioxide (As(2)O(3)) has potential anticancer activity against a wide range of carcinomas. The mechanisms involved in these two opposing processes remain unclear.
We used normal human keratinocytes (NHK), the human keratinocyte HaCaT cell line and human epidermal carcinoma cells (A431 cell line) to investigate potential pathways involved in the effects on cell proliferation and growth inhibition by different concentrations of As(2)O(3).
At low concentrations (0.5-32 nM), As(2)O(3) enhanced keratinocyte proliferation and regulated the expression of about 172 genes. Among them, cell cycling pathway genes (including CDK4 and E2F1) were significantly upregulated. At high concentrations (0.5-10 microM), As(2)O(3) inhibited cell growth in NHK and HaCaT cells, but not in A431 cells. As(2)O(3) significantly induced NHK and HaCaT apoptosis through the activation of caspase-3, as well as cell cycle arrest at the G2-M phase.
Our data suggest that different pathways are involved in As(2)O(3)-mediated proliferation and growth inhibition. In addition, skin carcinoma cells were resistant to As(2)O(3)-induced cell growth inhibition and apoptosis when compared to NHK and HaCaT cells. Therefore, As(2)O(3) may not be appropriate for treatment of skin carcinomas.
Epigenetic mechanisms provide new insights into how environmental changes may mediate the increasing propensity for complex immune diseases such as allergic disease. There is now strong evidence that early environmental exposures play a key role in activating or silencing genes by altering DNA and histone methylation, histone acetylation and chromatin structure. These modifications determine the degree of DNA compaction and accessibility for gene transcription, altering gene expression, phenotype and disease susceptibility. While there is already evidence that a number of early environmental exposures are associated with an increased risk of allergic disease, several new studies indicate in utero microbial and dietary exposures can modify gene expression and allergic disease propensity through epigenetic modification. This review explores the evidence that immune development is under clear epigenetic regulation, including the pattern of T helper (Th)1 and Th2 cell differentiation, regulatory T cell differentiation, and more recently, Th17 development. It also considers the mechanisms of epigenetic regulation and early immune defects in allergy prone neonates. The inherent plasticity conferred by epigenetic mechanisms clearly also provides opportunities for environmental strategies that can re-programme gene expression for disease prevention. Identifying genes that are differentially silenced or activated in relation to subsequent disease will not only assist in identifying causal pathways, but may also help identify the contributing environmental factors.
The neonate is born with a distinct immune system that is biased against the production of T-helper cell 1 (Th1) cytokines. Birth imposes a great challenge on the neonatal immune system, which is confronted with an outside world rich in foreign antigens. Exposure to these antigens shapes the developing neonatal immune system. Inducing Th-1 or Th-2 polarized responses that may extend beyond the neonatal age and counteract or promote allergic sensitization. This review describes how engagement of the innate immune system might contribute to the development of allergy in children.
The exact role of innate immune stimulation in the development of allergies is a controversial area. Epidemiological literature suggests that microbial exposure in early childhood protects against the development of allergies, whereas a large amount of experimental data demonstrates that innate immune stimulation enhances Th2 responses upon primary and secondary antigen exposure.
Dose, site and timing of allergen exposure are likely to modulate the innate immune response, polarizing the maturing neonatal immune system towards Th1 or Th2-type responses, thereby protecting from or predisposing to asthma and allergies. Modulation of neonatal innate immune responses may be a novel approach to prevent asthma and allergies.
Aquaporin (AQP) 9 is a member of the aquaglyceroporin subfamily of AQPs in the transfer of water and small solutes such as glycerol and arsenite. It is well recognized that arsenic toxicity is associated with intracellular accumulation of this metalloid. In the present study, we examined the contribution of AQP9 to the uptake of inorganic arsenite, thereby increasing arsenic-induced cytotoxicity in primary mouse hepatocytes. Pretreatment with sorbitol as a competitive inhibitor of AQP9 and siRNA-mediated knockdown of AQP9 resulted in a significant decrease of arsenite uptake in the cell and its cytotoxicity. Furthermore, overexpression of AQP9 in HEK293 cells led to the enhancement of intracellular arsenic concentration, resulting in enhanced cytotoxicity after arsenite exposure. These results suggest that AQP9 is a channel to define arsenite sensitivity in primary mouse hepatocytes.
Pregnant females are susceptible to intracellular pathogens and are biased towards humoral rather than cell-mediated immunity. Since TH1 cytokines compromise pregnancy and TH2 cytokines are produced at the maternal-fetal interface, we hypothesize that these TH2 cytokines inhibit TH1 responses, improving fetal survival but impairing responses against some pathogens.
A previous study has shown a twofold increase in prevalence of asthma and allergic rhinitis (AR) in Swedish recruits during the 1970s. The increase was higher in more northerly colder regions.
To follow up the previously found trend to increasing prevalences with time as well as the climatic variations within the country.
The prevalences of asthma, allergic rhinitis and eczema were assessed using two questionnaire studies, 12 years apart (1979 and 1991) with identical questions about the diseases. The study comprised representative samples of children from the Göteborg area on the south-western coast (in 1979: 7-year-olds, n = 4255, in 1991: 7-year-olds, n = 1649) and in Kiruna, a mining town in the northernmost inland mountains (in 1979: 7-year-olds, n = 427, in 1991: 7-9-year-olds, n = 832). In 1991 there was also a personal interview and a skin-prick test (SPT) on subsamples.
The prevalence of all these diseases present over the last year had roughly doubled over the 12-year period. On both occasions, most symptoms were more prevalent in the northern area. In 1991, the prevalence of one or more symptoms in Göteborg was 23.8% and 32.5% and in Kiruna 29.9% and 44.8% in the questionnaire and the interview, respectively.
Asthma, AR and eczema increase continuously in prevalence in Sweden and the climatic distribution of the prevalences suggests possible major risk factors to be found in a closed indoor climate.
Because of the lack of data on the exposure to and toxic effects of inorganic arsenic during early human development, the transfer of arsenic to the fetus and suckling infant was studied in a native Andean population, living in the village San Antonio de los Cobres in the North west of Argentina, where the drinking water contains about 200 micrograms/liter. The concentration of arsenic in cord blood (median, 9 micrograms/liter) was almost as high as in maternal blood (median, 11 micrograms/liter), and there was a significant correlation between the two. Thus, at least in late gestation, arsenic is easily transferred to the fetus. The median concentration of arsenic in the placenta was 34 micrograms/kg, compared with 7 micrograms/kg previously reported for nonexposed women. Interestingly, essentially all arsenic in the blood plasma of both the newborns and their mothers was in the form of dimethylarsinic acid (DMA), the end product of inorganic arsenic metabolism. Similarly, about 90% of the arsenic in the urine of both the newborns and mothers in late gestation was present as DMA, compared with about 70% in nonpregnant women (p < 0.001). This may indicate that methylation of arsenic is increased during pregnancy and that DMA is the major form of arsenic transferred to the fetus. The increased methylation in late gestation was associated with lower arsenic concentrations in blood and higher concentrations in urine, compared with a few months postpartum. The arsenic concentrations in the urine of the infants decreased from about 80 micrograms/liter during the first 2 days of life to less than 30 micrograms/liter at 4.4 months (p = 0.025). This could be explained by the low concentrations of arsenic in the breast milk, about 3 micrograms/kg.