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Dose-Response Curve Parameters for PFOA and PFDA Induction of Vtg PFOA PFDA

Dose-Response Curve Parameters for PFOA and PFDA Induction of Vtg PFOA PFDA

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The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species...

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... post hoc tests indicated that the lowest observed effect level (LOEL) for PFOA exposure was at the 80 ppm diet (1.6 mg/kg bw/day) level or 35.4lM PFOA in blood plasma (Table 1). Alternatively, the LOEL for PFDA was much lower at 0.64 ppm (12.8 lg/kg bw/day) or 2.0lM PFDA in blood plasma. ...
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... this lower EC 50 value did not correlate with a lower PFOA dietary exposure, likely a result of the higher half-life and lower elimination rate of PFDA in trout compared with PFOA ( Martin et al., 2003). The corresponding amount of dietary PFOA to achieve the EC 50 value of 182lM is 458 ppm, whereas a dietary PFDA concentration of 214 ppm corresponds with its EC 50 value of 360lM (Table 1). A dose- dependent effect of increasing diet concentrations of PFOA and PFDA on relative liver size was less evident in this experiment, as only the highest diet concentrations significantly increased LSI values, 2000 ppm for PFOA and > 400 ppm for PFDA (Supplementary table 3). ...
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... nine additional tables, including a list of PFCs investigated in this report (Suppl. Table 1) and morphometric data from the in vivo experiments described above (Suppl. Tables 2 and 3). ...

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... PFAS may promote modifications of endogenous hormone regulation in humans and in wildlife [19,[53][54][55]. PFAS showed weak estrogenic effects in animal experiments, which manifested in increased estrogen and progesterone concentrations or mimicked the effect of endogenous estrogen [56][57][58]. PFAS can modulate the endocrine system by up-or downregulation of the expression of proteins responsible for cholesterol transport and ovarian steroidogenesis [53,59,60]. PFOAtreated ovary-intact mice had significantly increased serum progesterone (P) levels [56]. ...
... Cytological findings suggest that PFOS inhibits the conversion of P to testosterone by inhibiting CYP17 [61]. PFOA, PFNA, PFDA, and PFOS are all efficiently combined with estrogen receptors alpha (ERα) in different species [57]. Meanwhile, PFOS induced E2 production and reduced testosterone (T) production in a concentration-dependent manner in the H295R cells [61]. ...
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... There is evidence for PFAS affecting ER signaling in humans and animals although it is not consistent [190]. Study reports suggest an ability of PFAS to modulate and/or further activate ER-mediated effects [36,99,104,109,195,196] with some effects only observed in aquatic organisms [106,119,197]. Microarray analyses of human primary hepatocytes confirmed that PFOA activated the ER pathway [131]. ...
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... Both in vivo and in vitro studies on different test organisms and cells have documented the ability of PFAS to alter steroidogenesis and the binding to the estrogen receptor, androgen receptor and thyroid hormone receptor [2,6]. PFOA interference with the expression or activity of aromatase, a key enzyme for estrogen synthesis from androgens, and PFOA estrogen-like activity have been reported in fish [7][8][9][10]. ...
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... The placenta has been shown to be vulnerable to environmental insults, to be a common target of PFAS, and to accumulate across gestation via the maternal circulation (20)(21)(22). No consensus has been reached on the exact biological mechanism by which PFAS influence fetal growth; however, proposed hypotheses include impacts on bone development, maternal hormone disruptionparticularly sex and thyroid hormones-and adverse effects on placental development and function (23)(24)(25)(26)(27)(28)(29)(30). Several recent meta-analyses and systematic literature reviews suggest that prenatal exposure to PFOA and PFOS is associated with lower infant birthweight (8,(31)(32)(33)(34). ...
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... In vivo and in vitro experiments demonstrate that PFAS can bind to ERs and exert environmental xenoestrogenic activity [19]. Moreover, animal studies show that PFAS exposure increases estradiol (E 2 ) production and decreases testosterone (T 2 ) production [20][21][22]. ...
... Indeed, the study in China [17] revealed that the prenatal effects of PFAS differed or disappeared according to the timing of AGD measurement, and the authors mentioned that AGD might be affected by postnatal PFAS exposure. Previous in vitro studies showed that PFOA exerts agonistic activity via ERα, though which it exerts its estrogenic activity [19], significantly induces ER transactivity [37], and results in higher expression of ESR1 [20]. An animal study in rats demonstrated that PFOA exposure increased ERα expression [38], and cord blood PFOA levels were reportedly positively associated with E 2 levels in human fetuses [39]. ...
... The toxicokinetics of PFDoDA, which has been used as an alternative of PFOA or PFOS, are less studied. Some reports show that PFDoDA affects androgen or estrogen biosynthesis [45,46] and reportedly acts as an ER agonist [19] or is involved in dose-dependent increase in ERS1 mRNA [47]. These reports suggest that PFDoDA, in addition to PFOA, might activate ERα expression. ...
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... In addition, both animal and human studies have shown that PFOS and PFOA may negatively impact birth outcomes (13,30,32). Recent studies have indicated that PFAS may influence human sex hormone biosynthesis, serum levels, and receptors (33)(34)(35). However, the specific mechanism involved remains largely unknown. ...
... Furthermore, the modify effect of gender seems to be more pronounced in an inverse relationship between long-chain PFAS exposure and height (61) as well as weight later in life (40). The potential mechanism involved may be related to the effect of PFAS on human sex hormone biosynthesis (34,39), insulin-like growth factor-1 serum levels (35) and estrogen receptor function (33), even though some in vitro tests remain questionable (108). ...
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... Proposed pathways include increased cholesterol absorption or synthesis, impaired mobilization, reduced reverse transportation , reduced turnover to bile acids (Behr et al. 2020), and sterol imbalance (Monroe and Dobs 2013). These processes may be impacted through PFAS-activation of transcription factors, such as PPARa (Bijland et al. 2011), constitutive androstane receptor (CAR) (Abe et al. 2017), Pregnane X Receptor (PXR) (Bijland et al. 2011), and endocrine receptor a (ERa) (Benninghoff et al. 2011). Evidence for these pathways mainly comes from in vitro or animal studies that have shown hypocholesteremia and reduced triglycerides upon PFAS exposure (Bijland et al. 2011). ...
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... PFASs could interfere with the estrogen receptor of the human body (Kjeldsen and Bonefeld-Jørgensen 2013). PFASs could also affect the expression of the estrogen response gene and cause the change of estrogen synthesis (Benninghoff et al. 2011). Exposure to PFASs might affect the estrogen homeostasis and fetal growth during pregnancy (Wang et al. 2019), resulting in LBW. ...
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Some studies have shown that maternal perfluoroalkylated substances (PFAS) exposure may be associated with low birth weight (LBW) of offspring. We conducted a meta-analysis to assess the association between maternal PFASs exposure and LBW in offspring. The researchers searched PubMed, Science Direct, Scopus, Google Scholar, Web of Science, and Embase to find all the articles before October 2020. The Newcastle-Ottawa Scale was used to evaluate the quality of the studies. Finally, six articles were included for meta-analysis. Our meta-analysis showed no significant correlation between maternal perfluorooctanoic acid (PFOA) exposure and LBW of offspring: odds ratio (OR) = 0.90, 95% confidence interval (95% CI) = 0.80–1.01, with low heterogeneity (I² = 18.4%, P = 0.289); there was a significant positive correlation between maternal perfluorooctane sulfonate (PFOS) exposure and LBW of offspring (OR = 1.32, 95% CI = 1.09–1.55) with no heterogeneity (I² = 0.00%, P = 0.570). The grouping analysis of PFOS showed was a significant positive correlation between maternal PFOS exposure and LBW of offspring in American (OR = 1.44, 95% CI = 1.15–1.72). This study provided a systematic review and meta-analysis evidence for the relationship between maternal PFASs exposure and LBW of offspring through a small number of studies. Researchers should conduct further studies between different regions.
... These methods save time, money, and the number of tested animals . However, molecular docking studies of PFASs only focus on a few NHRs, such as androgen receptor (AR) and estrogen receptor (ER) (Azhagiya Singam et al., 2020;Benninghoff et al., 2011;Cao et al., 2019;Li et al., 2020;Taylor et al., 2014). The Endocrine Disruptome tool can simultaneously predict the binding of a compound to 14 agonistic NHR conformations and 4 antagonistic conformations, including AR, ERα/β, thyroid hormone receptor (TRα/β), liver X receptors (LXRα/β), peroxisome proliferator-activated receptor (PPARα/β/γ), retinoid X receptor (RXRα), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), AR an, ERα an, ERβ an, and GR an (Kolšek et al., 2014). ...
... Relevant literature on PFASs disrupting receptor endocrine function was retrieved (Benninghoff et al., 2011;Di Nisio et al., 2019;Kjeldsen and Bonefeld-Jørgensen, 2013;La Rocca et al., 2012;Young et al., 2021). All PFASs and receptors mentioned in the literature are denoted by asterisks in Table 1. ...
... The serum samples of infertile patients tended to have higher PFOS levels as well as higher levels of ERα, ERβ, and AR gene expression (La Rocca et al., 2012). ER binding assays revealed that PFOA, PFNA, PFDA, PFUdA, and PFOS can enhance human ERα-dependent transcriptional activation, and docking simulation showed that PFOA, PFNA, PFDA, PFOS, and PFUdA effectively docked with human ERα and formed hydrogen bonds on Arg394 (Benninghoff et al., 2011). In AR an, 49 PFASs had moderate or high binding probability. ...
Article
The toxic effects of per- and polyfluoroalkyl substances (PFASs) on humans are mediated by nuclear hormone receptors (NHRs). However, data on the interaction of PFASs and NHRs is limited. Endocrine Disruptome, an inverse docking tool, was used in this study to simulate the docking of 49 common PFASs with 14 different types of human NHRs. According to the findings, 25 PFASs have a high or moderately high probability of binding to more than five NHRs, with androgen receptor (AR) and mineralocorticoid receptor (MR) being the most likely target NHRs. Molecular docking analyses revealed that the binding modes of PFASs with the two NHRs were similar to those of their corresponding co-crystallized ligands. PFASs, in particular, may disrupt the endocrine system by binding to MR. This finding is consistent with epidemiological research that has linked PFASs to MR-related diseases. Our findings may contribute to a better understanding of the health risks posed by PFASs.
... PFAS interact directly with estrogen receptor α (ERα) in trout liver in vivo, although they have a weak affinity and they are noted to induce an estrogenic effect (Benninghoff et al., 2010). In male mice, PFOS exposure was observed to down-regulate ERα and up-regulate estrogen receptor β, which increased cell apoptosis and decreased cell proliferation in the testes (Qu et al., 2016). ...
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In this review article, we compiled peer-reviewed literature describing PFAS exposure and reproductive effects in animals and humans. The aim was to compare environmental occurrence and effects of the most prominent long-chain PFAS compounds and their short-chain replacements. Long-chain PFAS compounds are known to persist in the environment due to their chemical stability, and also known to bioaccumulate; hence, these compounds are being replaced globally. Indeed, PFOA and PFOS are considered long-chain “forever pollutants,” and thus the potential reproductive risk may continue for decades. Much less is known about their short-chain replacements despite the fact that they becoming more widespread in the environment. Short-chain PFAS are generally less bioaccumulative than long-chain, but they are more mobile and persistent in aquatic ecosystems. The three most prominent of these are commonly referred to as GenX, ADONA and F53B. The short-chain PFAS have similar physical and chemical properties as their predecessors; however, because they are relatively new, much less is known about the potential to disrupt reproduction. Indeed, high-quality epidemiological studies are needed to determine associations between short-chain PFAS exposure and effects on reproductive health. However, epidemiological evidence is mounting that long-chain PFAS exposure is associated with reproductive effects (i.e., decrease in fertility, reduced fetal growth and birth weight, pregnancy-induced hypertension and preeclampsia, thyroid hormone disruption during pregnancy, and preterm birth). Evidence from animal models and human cell lines indicates that short-chain PFAS similarly affect reproductive endpoints; however, epidemiological studies are scarce and inconsistent. Although short-chain PFAS have been quantified in drinking water and sediment worldwide, most of these studies did not focus on quantitation of GenX, ADONA, and F53B. There are also many other short-chain PFAS byproducts of manufacturing that have yet to be identified and studied. When sum total concentration of long- and short-chain PFAS are considered, the concentration rises by an order or magnitude or greater, as will the risk of exposure and subsequent reproductive effects.