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Effect of DEHP treatment on DNA damage (total score) in cardiac tissues of experimental mice after treatment of 30 days. Values represent mean ± SD (six animals were treated per group); ***P < 0.001, values are significantly different from the control group; b P < 0.01 and c P < 0.001, values are significantly different from group treated with 50 mg/kg of DEHP; f P < 0.001, values are significantly different from group treated with 200 mg/kg of DEHP
Source publication
Because of the extensive use of phthalates for domestic, medical, and industrial applications, the evaluation of their toxic effects is of major concern to public health. The aim of the present study was to assess the propensity of di (2-ethylhexyl) phthalate (DEHP), one of the most used phthalates, to cause oxidative cardiac damage in mice. DEHP w...
Citations
... This work provides evidence that the ubiquitous environmental contaminant DEHP might further aggravate clinical severity of the disease due to deficiency of Nrf2 signaling in mice with psoriasiform inflammation. Previous investigations have shown that DEHP induces the activation of antioxidant Nrf2 signaling in normal conditions [31,58,59]. The findings presented in this study indicate a potential causal association between environmental pollutant, namely DEHP, and dysregulation of Nrf2 signaling in immune cells. ...
... Numerous studies demonstrate that one of the main ways in which environmental pollutants like DEHP have a negative impact on health is through oxidative stress. It has been shown that DEHP and its metabolites, through distinct pathways, induce oxidative stress in a variety of organs in both humans and animals [42,58,65,66]. Several human investigations have found a relationship between phthalates or their metabolites and biomarkers of oxidative inflammation such as malondialdehyde, hydroxydeoxyguanosine, and 8-isoprostane [46]. ...
Psoriasis is a devastating autoimmune illness resulting from excessive keratinocyte growth and leukocyte infiltration into the dermis/epidermis. In the pathogenesis of psoriasis, different immune cells such as myeloid cells and CD4 + T cells play a key role. Th17/Th1 immune responses and oxidant-antioxidant responses are critical in regulation of psoriatic inflammation. Di-2-ethylhexyl phthalate (DEHP) is one of the well-known plasticizers and has widespread use worldwide. DEHP exposure through ingestion may produce harmful effects on the skin through systemic inflammation and oxidative stress, which may modify psoriatic inflammation. However, the effect of oral DEHP exposure on inflammatory cytokines and Nrf2/iNOS signaling in myeloid cells and CD4 + T cells in the context of psoriatic inflammation has not been investigated earlier. Therefore, this study explored the effect of DEHP on systemic inflammation in myeloid cells (IL-6, IL-17A, IL-23), Th17 (p-STAT3, IL-17A, IL-23R, TNF-α), Th1 (IFN-γ), Treg (Foxp3, IL-10), and Nrf2/iNOS signaling in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our study showed increased Th17 signaling in imiquimod model which was further aggravated by DEHP exposure. Further, Nrf2 and iNOS signaling were also elevated in IMQ model where DEHP exposure further increased iNOS expression but did not modify the Nrf2 expression. Most importantly, IL-17A levels were also elevated in myeloid cells along with IL-6 which were further elevated by DEHP exposure. Overall, this study shows that IL-17A signaling is upregulated, whereas there is deficiency of Nrf2/HO-1 signaling by DEHP exposure in mice with psoriasiform inflammation. These observations suggest that DEHP aggravates IL-17A-mediated signaling both in CD4 + T cells as well as myeloid cells which is linked to exacerbation of IMQ-induced psoriatic inflammation in mice. Strategies that counteract the effect of DEHP exposure in the context of psoriatic inflammation through downregulation of IL-17A may be fruitful.
... Baum and Duffy (2011) reported that pathological stimuli can enhance secretion of collagen fibers and TGF-β from resident cardiac fibroblasts. Amara et al. (2019) and Liu et al. (2019) attributed fibrosis in DEHP group to the occurrence of oxidative stress through production of ROS. On the other hand, the significant decrease in fibrosis after G-CSF administration was explained by Sugano et al. (2005) who attributed it to an increase in reparative collagen production in damaged areas. ...
Phthalates are common plasticizers present in medical-grade plastics and other everyday products. Di-ethylhexyl phthalate (DEHP) has been noted as a causative risk factor for the initiation and augmentation of cardiovascular functional disorders. G-CSF is a glycoprotein found in numerous tissues throughout the body and is currently applied in clinical practice and has been tested in congestive heart failure. We aimed to examine in depth the effect of DEHP on the histological and biochemical structure of the cardiac muscle in adult male albino rats and the mechanisms underlying the possible ameliorative effect of G-CSF. Forty-eight adult male albino rats were divided into control group, DEHP group, DEHP+ G-CSF group and DEHP-recovery group. We measured serum levels of aspartate aminotransferase (AST), creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Left ventricular sections were processed for light and electron microscope examination, and immunohistochemical staining of Desmin, activated Caspase-3 and CD34. DEHP significantly increased enzyme levels, markedly distorted the normal architecture of cardiac muscle fibers, downregulated Desmin protein levels and enhanced fibrosis, and apoptosis. G-CSF treatment significantly decreased the enzyme levels compared to DEHP group. It enhanced CD34 positive stem cells recruitment to injured cardiac muscle, therefore improved the ultrastructural features of most cardiac muscle fibers via anti-fibrotic and anti-apoptotic effects in addition to increased Desmin protein expression levels. The recovery group showed partial improvement due to persistent DEHP effect. In conclusion, administration of G-CSF effectively corrected the histopathological, immunohistochemical and biochemical alterations in the cardiac muscle after DEHP administration by stem cells recruitment, Desmin protein regulation, antifibrotic and antiapoptotic mechanisms.
... Majority of micronutrients have pleiotropic effects on immunological function. Hence, Spirulina, as a natural "functional food", should be investigated regarding its potential to ameliorate nutritional shortages and protect the immune system [20][21][22][23][24][25][26][27][28][29][30][31][32][33] . ...
Background: Phthalates are known to be major environmental hazards. Dibutyl phthalate (DBP), a commonly used phthalate ester, is present in a variety of products. Humans can be exposed to DBP from various sources, which can release it into biological fluids and cause various health problems by penetrating different tissues in the body. Aims: The aim of this study was to investigate the effects of DBP on pulmonary alveoli in rats and to assess the mitigating influence of S. platensis. Methods: The study involved 30 young adult male albino rats, which were divided into 3 groups (n = 10 each): control, group II (rats treated with phthalate ester (DBP; 50 mg/kg body weight/day)), and group III (Spirulina-protected animals given phthalate ester (DBP; 50 mg/kg body weight + Spirulina (200 mg/kg body weight/day)). Results: The study revealed that alveolar tissues in the groups treated with DBP showed significant increases in collagen deposition and inflammatory cellular infiltration. Furthermore, the numbers of type-II pneumocytes and alveolar macrophages were significantly increased. However, most of these effects were ameliorated by Spirulina platensis. Conclusion: These findings suggest that Spirulina may have potentially beneficial effects on pulmonary alveoli by mitigating the toxic effects of DBP.
... Previous epidemiological studies and experimental animal research have shown that urinary phthalate metabolites are associated with an increased risk of CVD events and mortality (10, 26,27). A cross-sectional study based on two cycles of NHANES survey data (2001)(2002)(2003)(2004) reported that MCPP and MnBP metabolites were associated with a higher risk of stroke after being fully adjusted from the general population (28). ...
Background
The study regarding phthalate metabolites and mortality among diabetes mellitus (DM) is limited. We aimed to examine the association of urinary phthalate metabolites with all-cause and cardiovascular disease (CVD) mortality among adults with DM.
Methods
This study included 8,931 adults from the National Health and Nutrition Examination Survey (NHANES) from 2005–2006 to 2013–2014. Mortality data were linked to National Death Index public access files through December 31, 2015. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidences (CIs) for mortality.
Results
We identified 1,603 adults with DM [mean ± SE age, 47.08 ± 0.30 years; 50.5% (833) were men]. Mono-(carboxynonyl) phthalate (MCNP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of Di (2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHP) were positively associated with DM (MCNP: OR = 1.53, 95%CI = 1.16–2.01; MECPP: OR = 1.17, 95% CI = 1.03–1.32; ∑DEHP: OR = 1.14, 95% CI = 1.00–1.29). Among DM patients, mono-(3-carboxypropyl) phthalate (MCPP) was associated with a 34% (HR 1.34, 95% CI 1.12–1.61) increased risk of all-cause mortality while the HRs (95%CI) of CVD mortality were 2.02 (1.13–3.64) for MCPP, 2.17 (1.26–3.75) for mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), 2.47 (1.43–4.28) for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), 2.65 (1.51–4.63) for MECPP, and 2.56 (1.46–4.46) for ∑DEHP, respectively.
Conclusion
This study is an academic exploration of the association between urinary phthalate metabolites and mortality among adults with DM, suggesting that exposure to phthalates might be associated with an increased risk of all-cause and CVD mortality in DM. These findings suggest that patients with DM should carefully use plastics products.
... In previous studies, DEHP has been shown to have adverse effects on the heart, liver, thyroid, testis, and other tissues by inducing oxidative stress (Amara et al., 2019;Goudarzi et al., 2020;Awny et al., 2021;Wu et al., 2021). Oxidative stress is defined as the imbalance between the biochemical process of reactive oxygen species (ROS) production and removal. ...
Di-2-Ethylhexyl Phthalate (DEHP) is often used as an additive in polyvinyl chloride (PVC) to give plastics flexibility, which makes DEHP widely used in food packaging, daily necessities, medical equipment, and other products. However, due to the unstable combination of DEHP and polymer, it will migrate to the environment in the materials and eventually contact the human body. It has been recorded that low-dose DEHP will increase neurotoxicity in the nervous system, and the human health effects of DEHP have been paid attention to because of the extensive exposure to DEHP and its high absorption during brain development. In this study, we review the evidence that DEHP exposure is associated with neurodevelopmental abnormalities and neurological diseases based on human epidemiological and animal behavioral studies. Besides, we also summarized the oxidative damage, apoptosis, and signal transduction disorder related to neurobehavioral abnormalities and nerve injury, and described the potential mechanisms of neurotoxicity caused by DEHP. Overall, we found exposure to DEHP during the critical developmental period will increase the risk of neurobehavioral abnormalities, depression, and autism spectrum disorders. This effect is sex-specific and will continue to adulthood and even have an intergenerational effect. However, the research results on the sex-dependence of DEHP neurotoxicity are inconsistent, and there is a lack of systematic mechanisms research as theoretical support. Future investigations need to be carried out in a large-scale population and model organisms to produce more consistent and convincing results. And we emphasize the importance of mechanism research, which can enhance the understanding of the environmental and human health risks of DEHP exposure.
... DEHP-induced oxidative stress and cardiotoxicity were examined in research by Amara et al. (13) Authors tested six-week-old male mice intraperitoneally for 30 days with varying dosages of DEHP to see if oxidative damage may cause severe cardiac tissue damages. A considerable rise in both markers was identified as compared to the control group; in fact, malondialdehyde levels were higher in the heart tissue of myocardial damaged mice, indicating an overproduction of reactive oxygen species among these tissues. ...
... A number of genes linked to heart development appear to be affected by phthalates, although the processes behind this are yet unknown. There is a need for further research on the cardiac effects of each phthalate on animals so that human studies on the heart may be developed (13) . ...
Background: Several ailments, including cancer and cardiovascular disease, have been linked to today's sedentary lifestyle and unhealthy eating habits. However, environmental toxins have also been linked to this rise in recent decades. Phthalates, a chemical found in plastics, are a concern because of the amount of time people spend in contact with them on a daily basis. Phthalates exposure has been linked to cardiovascular health in several studies, which have already established a favorable correlation with hypertension and atherosclerosis development in adults and some cardiovascular risk factors in kids, pregnant women as well as adults Objective: Assessment of possible effects of di ethyl phthalate on different functions of cardiovascular system. Methods: Di ethyl phthalate, and cardiovascular system were all looked for in PubMed, Google scholar, and Science direct. References from relevant literature were also evaluated by the authors, but only the most recent or complete study from January 2000 to May 2021 was included. Due to the lack of sources for translation, documents in languages other than English have been ruled out. Papers that did not fall under the purview of major scientific investigations, such as unpublished manuscripts, oral presentations, conference abstracts, and dissertations, were omitted. Conclusion: Cardiovascular health may be adversely affected by phthalate exposure, with changes in blood pressure and the risk of atherosclerosis as well as metabolic syndromes occurring as a result of early childhood and adult exposure. © 2022, Ain Shams University Faculty of Medicine. All rights reserved.
... Significantly, increasing epidemiological studies have shown the close association between DEHP and its metabolites and CVDs (Lin et al., 2016a;Lin et al., 2016b;Su et al., 2019a;Trasande and Attina, 2015;Zhang et al., 2018;Lin et al., 2022). Further, experimental researches have also found the effect and possible mechanism of DEHP and its main metabolite MEHP on CV impairments and eventually CVDs, where several well-characterized pathologic mechanistic frameworks are especially prominent (Amara et al., 2019;Sun et al., 2021;Svoboda et al., 2020;Trasande and Attina, 2015;Zhao et al., 2016;Zheng et al., 2020). Intriguingly, some chemical compounds might target specially and effectively in the prevention or treatment of CVDs, which are induced by DEHP/MEHP Deng et al., 2019;Kim, 2020;Tang et al., 2019;Wang et al., 2019;Wang et al., 2021;Yang et al., 2017). ...
... It is well acknowledged that exposure to DEHP can disrupt cardiac energy metabolism and contribute to abnormal changes in cardiac metabolic processes, particularly cardiac glucose and lipid metabolic disorders (Amara et al., 2019;Cai et al., 2019;Carli et al., 2022;Li et al., 2018;Mangala Priya et al., 2014;Parsanathan et al., 2019;Posnack, 2014;Schaedlich et al., 2015). ...
... Moreover, intraperitoneal injection of 5, 50 and 200 mg/kg/d DEHP disturbed lipid oxidative metabolism and enhanced cardiac lipid peroxidation, malondialdehyde (MDA), protein carbonyl (PC) and DNA fragmentations in cardiac tissues of male mice in a dose-dependent manner (Amara et al., 2019). As the concentration of DEHP increased, cardiac inflammation, hemorrhage and fibrous disarrangement occurred in sequence in vivo (Amara et al., 2019). ...
Currently, cardiovascular disease (CVD) is a health hazard that is associated with progressive deterioration upon exposure to environmental pollutants. Di(2-ethylhexyl) phthalate (DEHP) has been one of the focuses of emerging concern due to its ubiquitous nature and its toxicity to the cardiovascular (CV) system. DEHP has been noted as a causative risk factor or a risk indicator for the initiation and augment of CVDs. DEHP represents a precursor that contributes to the pathogenesis of CVDs through its active metabolites, which mainly include mono (2-ethylhexyl) phthalate (MEHP). Herein, we systematically presented the association between DEHP and its metabolites and adverse CV outcomes and discussed the corresponding effects, underlying mechanisms and possibly interventions. Epidemiological and experimental evidence has suggested that DEHP and its metabolites have significant impacts on processes and factors involved in CVD, such as cardiac developmental toxicity, cardiac injury and apoptosis, cardiac arrhythmogenesis, cardiac metabolic disorders, vascular structural damage, atherogenesis, coronary heart disease and hypertension. DNA methylation, PPAR-related pathways, oxidative stress and inflammation, Ca²⁺ homeostasis disturbance may pinpoint the relevant mechanisms. The preventive and therapeutic measures are potentially related with P-glycoprotein, heat-shock proteins, some antioxidants, curcumin, apigenin, β-thujaplicin, glucagon-like peptide-1 receptor agonists and Ang-converting enzyme inhibitors and so on. Promisingly, future investigations should aid in thoroughly assessing the causal relationship and molecular interactions between CVD and DEHP and its metabolites and explore feasible prevention and treatment measures accordingly.
... DEHP was injected intraperitoneally into mice for 30 days at doses of 5, 50 and 200 mg/kg body weight. Even at a DEHP dose of 5 mg/kg, DEHP resulted in an increase in inflammatory cell migration between myocardial bundles [40]. Additionally, malondialdehyde (MDA) levels, protein carbon (PC) concentrations, and DNA fragmentation were all increased in heart tissue. ...
... Additionally, malondialdehyde (MDA) levels, protein carbon (PC) concentrations, and DNA fragmentation were all increased in heart tissue. Increases in enzymatic (CAT) and superoxide dismutase (SOD) activities and decreases in nonenzymatic (protein bound sulfhydryl concentration (PSH)) activities and inhibited cardiac AChE activity were observed [40]. Several papillary muscle cells showed lipid droplets after oral administration of 100 mg/kg DEHP for 35 days in male mice. ...
Background
Plasticizers, also called phthalates, are a group of chemicals widely used in daily life. A previous report showed no significant association between phthalate metabolite concentrations and mortality. We investigated the association of urinary phthalate levels and individual phthalate metabolite levels with all-cause and cardiovascular disease (CVD) mortality after standardizing the phthalate concentration.
Methods
A total of 6,625 participants were recruited from a nationally representative sample of adults aged 40 years or older who were enrolled in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2014 and were followed up through December 31, 2015. Data were analyzed from January 2021 to June 2021. NHANES-linked updated National Death Index public access files were used to acquire information on mortality status and cause of death. The present study conducted extended follow-up of an earlier analysis. Cox proportional hazard models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of covariate-adjusted creatinine standardization urinary phthalate concentrations with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables.
Results
The mean ± standard deviation age of all participants in the final study was 59.9±12.6 years old, and 49.6% of the participants were male. The median follow-up time was 73 months (range 1-157 months). At the censoring date of December 31, 2015, 3,023 participants were identified as deceased (13.4%). A fully adjusted Cox model showed that a urinary di(2-ethylhexyl) phthalate (DEHP) concentration >= 83.4 ng/mL was associated with a slight increase in all-cause mortality (HR 1.27, 95% CI 1.03, 1.57, P for trend= 0.014) and CVD mortality (HR 2.19, 95% CI 1.35, 3.54, P for trend= 0.002). Similarly, urinary mono-2-ethyl-5-carboxypentyl phthalate (MECPP) levels >= 39.2 ng/mL were associated with increased CVD mortality (HR 2.33, 95% CI 1.45, 3.73, P for trend < 0.001). Restricted cubic spline analyses suggested linear associations of DEHP and MECPP levels with all-cause and CVD mortality.
Conclusion
In this large nationally representative sample of American adults, high urinary DEHP and MECPP were significantly associated with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables.
... Phthalates may also induce metabolic syndrome via direct effects on the PPAR family of nuclear receptors [39 & ]. There is evidence that treatment with DEHP (50 mg to 500 mg/kg/day) on rodents affects fat distribution in female mice [40,41] and in male mice on a high fat diet [42]. Additionally, mice treated with DEHP (5-200 mg/ kg/day) show signs of general liver toxicity and altered lipid profiles, higher cholesterol and triglycerides and decrease high-density lipoproteins (HDL) [42]. ...
... There is evidence that treatment with DEHP (50 mg to 500 mg/kg/day) on rodents affects fat distribution in female mice [40,41] and in male mice on a high fat diet [42]. Additionally, mice treated with DEHP (5-200 mg/ kg/day) show signs of general liver toxicity and altered lipid profiles, higher cholesterol and triglycerides and decrease high-density lipoproteins (HDL) [42]. ...
Purpose of review:
There is substantive and accumulating evidence that endemic exposure to plastic-associated chemicals (PACs) contribute to the pathophysiology of metabolic conditions, like obesity, diabetes, and heart disease. The consequences of this endemic exposure in inducing a pro-inflammatory state in adipose tissues as a critical link between exposure and disease is reviewed.
Recent findings:
In general, PACs are classified as nonpersistent in vivo because of their rapid metabolism to easily excreted forms. The parental chemicals, however, are typically lipophilic, with the potential to bioaccumulate. Recent data from selected association studies suggest exposure to PACs drive predisease states like obesity and inflammation of the adipose tissues. A range of experimental studies are discussed with a focus on biological mechanisms that are susceptible to the influence of PACs and which may promote metabolic disease, the detection of PACs within susceptible tissues and biological effects that are detectable at doses that correspond to real-life exposures to these chemicals.
Summary:
If we hypothesize the toxic pressure from chronic exposure to PACs will progress disease processes, then individuals with comprehensively characterized indicators of premetabolic disease could undergo trials of quantifiable interventions to reduce exposure to PACs to test if the trajectory of disease-associated analytes, is altered.
... Martinelli suggested that DEHP exposure to animal skeletal muscle could disrupt glucose metabolism [58]. Amara showed that DEHP exposed mice have altered lipid profiles with higher triglycerides, cholesterol and high and low lipoproteins [59]. Human children aged 6-18 exposed to the metabolite MEHP had increased obesity, triglycerides, and increased blood pressure [60]. ...
Phthalates are a ubiquitous group of industrial compounds used as industrial solvents and as additives to plastics to make products softer avnd more flexible. Phthalates are found in a variety of products including medical devices, personal care products, flooring, and food packaging. Infants in the neonatal intensive care unit are exposed to phthalates both in the building materials, but more importantly in the medical supplies and devices. Toxicity from phthalates has been of concern to researchers for many decades. Toxicity concerns to neonates includes male reproductive toxicity, hepatotoxicity, cardiotoxicity (including hypertension), neurotoxicity, and neurodevelopmental abnormalities. Limited recommendations have been given for reducing phthalate exposures to premature infants. These include avoiding infusing lipids or blood products through intravenous tubing containing phthalates. Storage of blood in containers made with phthalates has been a strong recommendation and has largely been accomplished. A comprehensive plan for phthalate reduction has heretofore been missing. This chapter has the goal of identifying the problem of phthalate exposure in premature infants, with some practical solutions that can be done today, as well as suggestions for manufacturers to complete the work.
