Figure - available from: Scientific Reports
This content is subject to copyright. Terms and conditions apply.
The effects of OVA/DEHP exposure on nasal mucosa histology damage demonstrated with HE-staining. (a) NC group; (b) DEHP group; (c) OVA group; and (d) OVA + DEHP group (original magnification: (a–d), × 400, Scale bars = 20 μm).
Source publication
Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract. Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and belongs to environmental endocrine disruptors (EDCs). It can be entered the human body which is harmful to health. The relationship between DEHP and AR is still inconclusive. This study a...
Citations
... 18,19 A large number of studies have confirmed that DEHP affected the male reproductive function through a classical nuclear receptor-mediated pathway. 20,21 For example, the male mice exposure to DEHP induced disruption of the androgen receptor (AR) signaling pathway, inhibited capacity to biosynthesize testosterone, and affected spermatogenesis in the testes. 22 Furthermore, parental exposure to environmental concentrations of DEHP resulted in increased mortality in their unexposed offspring and reduced hatching enzymes in zebrafish embryos by interfering with the HPT axis, leading to delayed hatching. ...
... Further, DEHP has been shown to induce mixed granulocytic airway inflammation by enhancement of Th17 cells through increase in IL-6 secretion from DCs [24]. Normal mice treated with DEHP have also shown a trend towards increased Th17 cell development and higher serum levels of inflammatory cytokines such as IL-17A, and TNF-α which could be due to concurrent increase in IL-6 expression in DCs in past studies [28,49,50]. DEHP in vitro treatment has also been reported to enhance expression of IL-6/TNF-α from monocytes of normal children [27,51]. ...
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.
... The allergic rhinitis animal study found that serum IL-33 levels and nasal mucosal oxidative stress significantly increased in the OVA + DEHP group than those in the OVA group. The AhR protein and its mRNA expression were also significantly increased in the OVA + DEHP group than in the OVA group (34). A previous study showed that the expression of AhR and IL-10 production was increased by lipopolysaccharide (LPS) stimulation in RAW264.7 cells. ...
Background
Few studies assess cord blood biomarkers to predict prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) on the development of allergic diseases later in childhood. IL-33 has been indicated to play an important role in allergic diseases. We evaluated the association of prenatal DEHP exposure and IL-33 in cord blood on the development of allergic diseases. We also investigated the mechanism of DEHP in human lung epithelial cells and asthma animal models.
Methods
66 pregnant women were recruited, and their children followed when they were aged 3 years. Maternal urinary DEHP metabolites were determined using liquid chromatography-electrospray-ionization-tandem mass spectrometry. The effect of DEHP on IL-33 production was investigated in human lung epithelial cells and club cell-specific aryl hydrocarbon receptor (AhR) deficiency mice. ELISA and RT-PCR, respectively, measured the IL-33 cytokine concentration and mRNA expression.
Results
The concentrations of maternal urinary DEHP metabolites and serum IL-33 in cord blood with childhood allergy were significantly higher than those in the non-childhood allergy group. DEHP and MEHP could induce IL-33 production and reverse by AhR antagonist and flavonoids in vitro. Enhanced ovalbumin-induced IL-4 and IL-33 production in bronchoalveolar lavage fluid (BALF) by DEHP exposure and suppressed in club cell-specific AhR null mice. Kaempferol has significantly reversed the DEHP effect in the asthma animal model.
Conclusions
Cord blood IL-33 level was correlated to childhood allergy and associated with maternal DEHP exposure. IL-33 might be a potential target to assess the development of DEHP-related childhood allergic disease. Flavonoids might be the natural antidotes for DEHP.
... Di (2-ethylhexyl) phthalate (DEHP) is the most common member of the class of phthalates, and several studies indicated that humans are highly exposed to DEHP (3,4). Indeed, DEHP exposure was considered a potential risk to human health (5)(6)(7). The estimated daily intake of DEHP for adult humans was 0.5-30 mg/kg/day, although some studies have reported higher levels of exposure to this phthalate (8)(9)(10). ...
Introduction:
DEHP is an endocrine disruptor widely used in the production of malleable plastics. DEHP exposure was associated with altered hypothalamic-pituitary-thyroid (HPT) axis function. Although previous studies reported deleterious effects of DEHP exposure during the intrauterine period, few studies have evaluated the direct effects triggered by this endocrine disruptor on the offspring animals' thyroid function. This study aimed to investigate the impact of intrauterine exposure to DEHP on the HPT axis function programming of the offspring animals during adulthood.
Methods:
Pregnant Wistar rats were orally treated with corn oil or corn oil supplemented with DEHP (0.48 or 4.8 mg/kg/day) throughout the gestational period. The offspring rats were euthanized on the 90th postnatal day. Hypothalamus, pituitary, thyroid, and liver were collected to analyze gene expression and protein content through qPCR and Western Blot. Blood was collected to determine TSH and thyroid hormone levels through fluorometric or chemiluminescence immunoassays.
Results:
In the adult F1 female rats, the highest dose of DEHP decreased TSH serum levels. In the thyroid, DEHP reduced the gene expression and/or protein content of NIS, TSHR, TG, TPO, MCT8, NKX2.1, PAX8, and FOXE1. These data are consistent with the reduction in T4 serum levels of the F1 DEHP-exposed female rats. In the liver, DEHP exposure increased the mRNA expression of Dio1 and Ttr, while the highest dose of DEHP reduced the mRNA expression of Ugt1a1 and Ugt1a6. Conversely, in the F1 male adult rats, TSHB expression and TSH serum levels were increased in DEHP-exposed animals. In the thyroid, except for the reduced protein content of TSHR, none of the evaluated genes/proteins were altered by DEHP. TH serum levels were not changed in the DEHP-exposed F1 male rats compared to the control group. Additionally, there were no significant alterations in the expression of hepatic enzymes in these animals.
Discussion/conclusions:
Our results demonstrated, for the first time, that intrauterine exposure to DEHP disrupts the HPT axis function in male and female offspring rats and strongly suggest that DEHP exposure increases the susceptibility of the offspring animals to develop thyroid dysfunctions during adulthood.
... AhR regulates allergic diseases in both canonical and non-canonical pathways. It has been found that Di(2-ethylhexyl) phthalate (DEHP), a plasticizer, boosts the ovalbumin-induced allergic rhinitis by activating the AhR canonical pathway (108). However, a detailed understanding of the impact of the AhR-canonical signaling pathway on the AhR-non-canonical signaling pathway hasn't been studied. ...
The aryl hydrocarbon receptor (AhR) is a widely studied ligand-activated cytosolic transcriptional factor that has been associated with the initiation and progression of various diseases, including autoimmune diseases, cancers, metabolic syndromes, and allergies. Generally, AhR responds and binds to environmental toxins/ligands, dietary ligands, and allergens to regulate toxicological, biological, cellular responses. In a canonical signaling manner, activation of AhR is responsible for the increase in cytochrome P450 enzymes which help individuals to degrade and metabolize these environmental toxins and ligands. However, canonical signaling cannot be applied to all the effects mediated by AhR. Recent findings indicate that activation of AhR signaling also interacts with some non-canonical factors like Kruppel-like-factor-6 (KLF6) or estrogen-receptor-alpha (Erα) to affect the expression of downstream genes. Meanwhile, enormous research has been conducted to evaluate the effect of AhR signaling on innate and adaptive immunity. It has been shown that AhR exerts numerous effects on mast cells, B cells, macrophages, antigen-presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells, thus, playing a significant role in allergens-induced diseases. This review discussed how AhR mediates immune responses in allergic diseases. Meanwhile, we believe that understanding the role of AhR in immune responses will enhance our knowledge of AhR-mediated immune regulation in allergic diseases. Also, it will help researchers to understand the role of AhR in regulating immune responses in autoimmune diseases, cancers, metabolic syndromes, and infectious diseases.
... In addition, DEHP aff ects fat and carbohydrate metabolism and alters the intestinal fl ora [17]. MEHP activates peroxisome proliferator-activated receptors, promotes preadipocyte diff erentiation, and aff ects glucose uptake and triacylglycerol deposition, which may increase the risk of metabolic diseases and promote obesity [18]. International studies have confi rmed that BPH development is associated with metabolic syndrome. ...
The metabolism of plasticizing phthalates may correlate with an increased risk of benign prostatic hyperplasia in humans. Diethylphthalate (DEHP) and its metabolites interfere with sex hormone function, causing inflammation and oxidative stress at low doses. The effects may contribute to the development of benign prostate hyperplasia.
... Therefore, in this study, we used the results of previous animal experiments on allergic or immune reactions for our reference doses (RfDs). We adopted the lowest-observed-adverse-effect levels (LOAELs) of Zou et al. for DEHP (3 mg/kg/body) [43], Li et al. for DBP (4 mg/kg/body) [44], and Sadakane et al. for diisononyl phthalate (DiNP; 15 mg/kg/body) [45]. We then used these LOAELs to evaluate no-observed-adverse-effect levels (NOAELs) according to the recommendations of the US Environmental Protection Agency. ...
... In an animal experiment involving injection and oral and nasal instillation, Zou et al. highlighted that although DEHP exposure did not affect immune responses in the absence of sensitization, DEHP increased the production of reactive oxygen species and MDA at 3 mg/kg/body. [43]. In another animal experiment, Li et al. used skin sensitization and fluorescein isothiocyanate to compare sensitized and nonsensitized groups. ...
... However, they observed no significant differences in DiNP exposure at the highest concentration of 15 mg/kg/body [45]. Therefore, in this study, we adopted the LOAELs of Zou et al. for DEHP (3 mg/kg/body) [43], Li et al. for DBP (4 mg/kg/body) [44], and Sadakane et al. for DiNP (15 mg/kg/body) [45]. The RfDs that we obtained for DEHP, DBP, and DiNP were lower than the TDI values set by the EFSA and WHO, which resulted in a high rate of HI exceedance (larger than 1). ...
Childhood asthma has become one of the most common chronic diseases in children and adolescents. However, few case–control studies investigating the relationship between phthalate exposure and asthma in children and adolescents have been conducted, especially in Asia. Therefore, we assessed the potential associations between phthalate exposure and asthma among children and adolescents in Taiwan. Because various demographic and environmental variables may influence the incidence and prognosis of asthma, we performed a case–control study with propensity score matching. Out of 615 Childhood Environment and Allergic Diseases Study participants, we conditionally matched 41 children with clinically diagnosed asthma with 111 controls. We then analyzed 11 phthalate metabolites by using liquid chromatography with tandem mass spectrometry. Compared with the control group, the median urinary phthalate levels for most phthalate metabolites in the case group were slightly increased, including monomethyl phthalate, mono-n-butyl phthalate, monobenzyl phthalate, monoethylhexyl phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, and mono-(2-carboxymethylhexyl) phthalate. Hence, our results suggest that phthalate exposure may be associated with the development of asthma. In addition, prenatal environmental factors, such as active or passive smoking during pregnancy, may increase the risk of asthma.
... Since DEHP is not covalently attached to PVC products, it is easy to release into various environmental media [7]. It enters the body through the skin, digestive tract, and respiratory tract [8]. DEHP is hydrolyzed rapidly in vivo by esterase into mono (2-ethylhexyl) phthalate (MEHP), a biologically active monoester metabolite which is a reproductive poison [9]. ...
Di (2-ethyl-hexyl) phthalate (DEHP) is a wildly used plasticizer. Maternal exposure to DEHP during pregnancy blocks the placental cell cycle at the G2/M phase by reducing the efficiency of the DNA repair pathways and affects the health of offsprings. However, the mechanism by which DEHP inhibits the repair of DNA damage remains unclear. In this study, we demonstrated that DEHP inhibits DNA damage repair by reducing the activity of the DNA repair factor recruitment molecule PARP1. NAD⁺ and ATP are two substrates necessary for PARP1 activity. DEHP abated NAD⁺ in the nucleus by reducing the level of NAD⁺ synthase NMNAT1 and elevated NAD⁺ in the mitochondrial by promoting synthesis. Furthermore, DEHP destroyed the mitochondrial respiratory chain, affected the structure and quantity of mitochondria, and decreased ATP production. Therefore, DEHP inhibits PARP1 activity by reducing the amount of NAD⁺ and ATP, which hinders the DNA damage repair pathways. The supplement of NAD⁺ precursor NAM can partially rescue the DNA and mitochondria damage. It provides a new idea for the prevention of health problems of offsprings caused by DEHP injury to the placenta.
... Researchers have revealed that oral administration of DEHP could result in an MEHP concentration several orders of magnitude higher than that of the general population exposure level [7]. More importantly, as environmental-endocrine disrupting chemicals (EDCs), MEHP and DEHP consistently produce developmental, reproductive, immune, respiratory, and hepatic toxicity [8][9][10][11]. Moreover, MEHP is reported to be the ultimate toxicant of DEHP, and both DEHP and MEHP can induce apoptosis in the cells of immune system. ...
Mono-(2-ethylhexyl) phthalate (MEHP) is one of the main active metabolites of di-(2-ethylhexyl) phthalate (DEHP). In our previous works, by using rat and Drosophila models, we showed a disruption of neural function due to DEHP. However, the exact neural effects of MEHP are still unclear. To explore the effects of MEHP on the central nervous system, the electrophysiological properties of spontaneous action potential (sAP), mini-excitatory postsynaptic currents (mEPSCs), ion channels, including Na+, Ca2+, and K+ channels from rat CA3 hippocampal neurons area were assessed. Our data showed that MEHP (at the concentrations of 100 or 300 μM) decreased the amplitude of sAP and the frequency of mEPSCs. Additionally, MEHP (100 or 300 μM) significantly reduced the peak current density of Ca2+ channels, whereas only the concentration of 300 μM decreased the peak current density of Na+ and K+ channels. Therefore, our results indicate that exposure to MEHP could affect the neuronal excitability and synaptic plasticity of rat CA3 hippocampal neurons by inhibiting ion channels’ activity, implying the distinct role of MEHP in neural transmission.
... While profoundly increased levels of DEHP-induced oxidative stress were detected in both erythrocyte and dendritic cell cultures, neutrophils displayed only a slight increase (Figure 3a-c). Mechanistically, enhanced ROS formation in response to DEHP is linked to the activation of the aryl hydrocarbon receptor (AhR), leading to increased activity of both Cyp1a1 and Cyp1b1 [7,26,29]. In support of these findings, we identified DEHP-mediated increases in AhR protein levels when administered at concentrations as low as 2.56 µM (1 µg/mL). ...
Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An analysis of the underlying mechanism revealed that MEHP promotes increases in reactive oxygen species (ROS) by reducing the activity of superoxide dismutase in all lineages, possibly via its actions at the aryl hydrocarbon receptor. This leads to a metabolic shift away from glycolysis toward the pentose phosphate pathway and ultimately results in the death of hematopoietic cells that rely on glycolysis for energy production. By contrast, cells that utilize fatty acid oxidation for energy production are not susceptible to this outcome due to their capacity to uncouple ATP production. These responses were also detected in non-hematopoietic cells exposed to alternate inducers of ROS.
