Widespread use of bisphenol A (BPA) and other bisphenol analogues has attracted increasing attention for their potential adverse effects. As environmental endocrine-disrupting compounds (EDCs), ...bisphenols (BPs) may activate a variety of nuclear receptors, including glucocorticoid receptor (GR). In this work, the binding of 11 BPs to GR was investigated by fluorescence polarization (FP) assay in combination with molecular dynamics simulations. The human glucocorticoid receptor was prepared as a soluble recombinant protein. A fluorescein-labeled dexamethasone derivative (Dex-fl) was employed as tracer. Competitive displacement of Dex-fl from GR by BPs showed that the binding affinities of bisphenol analogues were largely dependent on their characteristic functional groups. In order to further understand the relationship between BPs structures and their GR-mediated activities, molecular docking was utilized to explore the binding modes at the atomic level. The results confirmed that structural variations of bisphenol analogues contributed to different interactions of BPs with GR, potentially causing distinct toxic effects. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (
R
2
= 0.8266), which might be helpful for the design of environmentally benign materials with reduced toxicities. In addition, the established FP assay based on GR exhibited the potential to offer an alternative to traditional methods for the detection of bisphenols.
Background: Human exposure to bisphenol A (BPA) is widespread. After exposure, BPA is rapidly metabolized and eliminated in urine. Therefore, there is considerable within-person and betweenperson ...variability of BPA concentrations in spot urine samples. However, no information exists on the within-day variability of urinary BPA concentrations. Objectives: We examined the between-person and within-person and between-day and withinday variability in the urinary BPA concentrations of eight adults who collected all voids for 1 week to investigate the impact of sampling strategy in the exposure assessment of BPA using spot, first morning, or 24-hr urine collections. Methods: We determined the urinary concentrations of BPA using on-line solid-phase extraction coupled to isotope dilution high-performance liquid chromatography/tandem mass spectrometry. Results: The between-day and within-person variability was the primary contributor to the total variance both for first morning voids (77%) and 24-hr urine collections (88%). For the spot collections, we observed considerable within-day variance (70%), which outweighed the between-person (9%) and between-day and within-person (21%) variances. Conclusions: Regardless of the type of void (spot, first morning, 24-hr collection), urinary BPA concentrations for a given adult changed considerably—both within a day and for the 7 days of the study period. Single 24-hr urine collections accurately reflect daily exposure but can misrepresent variability in daily exposures over time. Of interest, when the population investigated is sufficiently large and samples are randomly collected relative to meal ingestion times and bladder emptying times, the single spot—sampling approach may adequately reflect the average exposure of the population to BPA.
Background: It is commonly stated in the literature on human exposure to bisphenol A (BPA) that food is the predominant BPA exposure source, and that BPA is rapidly and completely cleared from the ...body. If this is correct, BPA levels in fasting individuals should decrease with increased fasting time. Objectives: We set out to investigate the relationship between urine BPA concentration and fasting time in a population-based sample. Methods: We modeled log BPA urine concentration as a function of fasting time, adjusted for urine creatinine and other confounders, in 1,469 adult participants in the 2003-2004 National Health and Nutrition Examination Survey. We estimated the BPA "population-based half-life"$({\rm pop}^{{\textstyle\frac{1}{2}}})$for a fasting time of 0-24 hr, < 4.5 hr, 4.5-8.5 hr, and > 8.5 hr. Results: The overall${\rm pop}^{{\textstyle\frac{1}{2}}}$for the 0- to 24-hr interval was 43 hr 95% confidence interval (CI), 26-119 hr. Among those reporting fasting times of 4.5-8.5 hr (n = 441), BPA declined significantly with fasting time, with a${\rm pop}^{{\textstyle\frac{1}{2}}}$of 4.1 hr (95% CI, 2.6-10.6 hr). However, within the fasting time intervals of 0-4.5 hr (n = 129) and 8.5-24 hr (n = 899), we saw no appreciable decline. Fasting time did not significantly predict highest (> 12 ng/mL) or lowest (below limit of detection) BPA levels. Conclusions: Overall, BPA levels did not decline rapidly with fasting time in this sample. This suggests substantial nonfood exposure, accumulation in body tissues such as fat, or both. Explaining these findings may require experimental pharmacokinetic studies of chronic BPA exposure, further examination of BPA levels and effects in fat, and a search for important nonfood sources.
Little is known with regard to the occurrence of potentially toxic chemicals in textiles and clothes. In this study, 77 textiles and infant clothing pieces were analyzed for the determination of ...bisphenols including bisphenol A (BPA) and bisphenol S (BPS), benzophenones, bisphenol A diglycidyl ethers (BADGEs), and novolac glycidyl ethers (NOGEs). BPA and BPS occurred in 82% and 53% of the textile samples, respectively, and at mean concentrations of 366 and 15 ng/g, respectively. Benzophenone-3 (BP3) occurred in 70% of the samples at a mean concentration of 11.3 ng/g. Among 11 BADGEs and NOGEs analyzed, BFDGE was the predominant compound, with a mean concentration of 13.6 ng/g. Concentrations of target chemicals were assessed by fabric type, color, and uses. Socks contained the highest concentrations of BPA (mean: 1810 ng/g) with concentrations as high as 13 300 ng/g in a 97% polyester fabric marketed for infants. Calculated dermal exposure dose to BPA by infants via textiles was as high as 7280 pg/kg BW/d. This is the first study to report the occurrence of, and exposure to, BPA, BPS, BADGEs, and NOGEs in textiles and clothing.
Bisphenol A (BPA) is an endocrine disruptor that affects fetal growth in experimental studies. Bisphenol F (BPF) and bisphenol S (BPS), which have been substituted for BPA in some consumer products, ...have also shown endocrine-disrupting effects in experimental models. However, the effects of BPF and BPS on fetal growth in humans are unknown.
Our goal was to investigate trimester-specific associations of urinary concentrations of BPA, BPF, and BPS with size at birth.
The present study included 845 pregnant women from Wuhan, China (2013-2015), who provided one urine sample in each of the first, second, and third trimesters. Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with birth weight, birth length, and ponderal index. Linear mixed-effects models were used to identify potential critical windows of susceptibility to bisphenols by comparing the exposure patterns of newborns in the 10th percentile of each birth anthropometric measurement to that of those in the 90th percentile.
Medians (25th-75th percentiles) of urinary concentrations of BPA, BPF, and BPS were 1.40 (0.19-3.85), 0.65 (0.34-1.39), and 0.38 (0.13-1.11) ng/mL, respectively. Urinary BPA concentrations in different trimesters were inversely, but not significantly, associated with birth weight and ponderal index. Urinary concentrations of BPF and BPS during some trimesters were associated with significantly lower birth weight, birth length, or ponderal index, with significant trend
-values (
) across quartiles of BPF and BPS concentrations. The observed associations were unchanged after additionally adjusting for other bisphenols. In addition, newborns in the 10th percentile of each birth anthropometry measure had higher BPF and BPS exposures during pregnancy than newborns in the 90th percentile of each outcome.
Prenatal exposure to BPF and BPS was inversely associated with size at birth in this cohort. Replication in other populations is needed. https://doi.org/10.1289/EHP4664.
Bisphenol analogues (BPs) including bisphenol a (BPA) have been broadly utilized as industrial feedstocks and unavoidably discharged into water bodies. However, there is little published data on the ...occurrence, distribution, and environmental risks of other BPs in surface water. In this study, ten BPs besides BPA were analyzed in surface water from the Pearl River, South China. Among these detected BPs, BPA, bisphenol F (BPF), bisphenol AF (BPAF), and bisphenol S (BPS) were the most frequently detected compounds. The median concentrations of the measured BPs were ranked in the order of BPA (34.9 ng/L) > BPS (24.8 ng/L) > BPAF (10.1 ng/L) > bisphenol F (BPF) (9.0 ng/L) > bisphenol B (BPB) (7.6 ng/L) > bisphenol C (BPC) (1.2 ng/L). Among them, BPA and BPS were predominant BPs, contributing 68% of the total ten BPs in surface water of the Pearl River. These results demonstrated that BPA and BPS were the most extensively utilized and manufactured BPs in this region. The source analysis of BPs suggested that the BPs may be originated from domestic wastewater, wastewater treatment plant (WWTP) effluent, and the leaching of microplastic in surface water of the Pearl River. The calculated BP-derived estrogenic activity exhibited low to medium risks in surface water, but their combined estrogenic effects with other endocrine disrupting compounds should not be ignored.
Background: The causes of the current obesity pandemic have not been fully elucidated. Implication of environmental endocrine disruptors such as bisphenol A (BPA) on adipose tissue development has ...been poorly investigated. Objectives: The aim of the present study was to evaluate the effects of perinatal exposure to BPA on early adipose storage at weaning. Methods: Pregnant Sprague-Dawley rats had access to drinking water containing 1mg/LBPA from day 6 of gestation through the end of lactation. Pups were weaned on postnatal day (PND) 21. At that time, we investigated perigonadal adipose tissue of pups (weight, histology, gene expression). For the remaining animals, we recorded body weight and food intake for animals on either standard chow or a high-fat diet. Results: Gestational exposure to BPA did not alter the sex ratio or litter size at birth. On PND1, the weight of male and female BPA-exposed pups was increased. On PND21, body weight was increased only in females, in which parametrial white adipose tissue (pWAT) weight was increased about 3-fold. This excess of pWAT was associated with adipocyte hypertrophy and overexpression of lipogenic genes such as C/EBP-α (CAAT enhancer binding protein alpha), PPAR-y (peroxisome proliferator-activated receptor gamma), SREBP-1C (sterol regulatory element binding protein-1C), LPL (lipoprotein lipase), FAS (fatty acid synthase), and SCD-1 (stearoyl-CoA desaturase 1). In addition, gene expression of SREBP-1C, FAS, and ACC (acetyl-CoA carboxylase) was also increased in liver from BPA-exposed females at PND21, without a change in circulating lipids and glucose. After weaning, perinatal BPA exposure predisposed to overweight in a sex-and diet-dependent manner. We observed no change in food intake due to perinatal BPA exposure in rats on either standard chow or a high-fat diet. Conclusions: Perinatal exposure to a low dose of BPA increased adipogenesis in females at weaning. Adult body weight may be programmed during early life, leading to changes dependent on the sex and the nutritional status. Although further studies are required to understand the mechanisms of BPA action in early life, these results are particularly important with regard to the increasing prevalence of childhood obesity and the context-dependent action of endocrine disruptors.
Contaminants of emerging concern (CEC) localize in the biome in variable combinations of complex mixtures that are often environmentally persistent, bioaccumulate and biomagnify, prompting a need for ...extensive monitoring. Many cosmetics include UV filters that are listed as CECs, such as benzophenone derivatives (oxybenzone, OXYB), cinnamates (2-ethylhexyl 4-methoxycinnamate, EMC) and camphor derivatives (4-methylbenzylidene-camphor, 4MBC). Furthermore, in numerous water sources, these UV filters have been detected together with Bisphenols (BPs), which are commonly used in plastics and can be physiologically detrimental. We utilized bioluminescent bacteria (Microtox assay) to monitor these CEC mixtures at environmentally relevant doses, and performed the first systematic study involving three sunscreen components (OXYB, 4MBC and EMC) and three BPs (BPA, BPS or BPF). Moreover, a breast cell line and cell viability assay were employed to determine the possible effect of these mixtures on human cells. Toxicity modeling, with concentration addition (CA) and independent action (IA) approaches, was performed, followed by data interpretation using Model Deviation Ratio (MDR) evaluation. The results show that UV filter sunscreen constituents and BPs interact at environmentally relevant concentrations. Of notable interest, mixtures containing any pair of three BPs (e.g., BPA + BPS, BPA + BPF and BPS + BPF), together with one sunscreen component (OXYB, 4MBC or EMC), showed strong synergy or overadditive effects. On the other hand, mixtures containing two UV filters (any pair of OXYB, 4MBC and EMC) and one BP (BPA, BPS or BPF) had a strong propensity towards concentration dependent underestimation. The three-component mixtures of UV filters (4MBC, EMC and OXYB) acted in an antagonistic manner toward each other, which was confirmed using a human cell line model. This study is one of the most comprehensive involving sunscreen constituents and BPs in complex mixtures, and provides new insights into potentially important interactions between these compounds.
Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrinedisrupting chemicals, ...including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand-PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LSI 80 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR's ligandbinding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LSI80 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans.
•BPA, BPS and BPF were determined in 76 sewage sludge from the USA.•Bisphenols were found at concentrations ranging from 12.8 to 4730ng/gdw in sludge.•Only 0.02% of the total BPA production volume ...was emitted through sludge disposal.•The estrogenic activity of BPA was lower than that of natural estrogens in sludge.
As health concerns over bisphenol A (BPA) in consumer products are mounting, this weak estrogen mimicking compound is gradually being replaced with structural analogs, whose environmental occurrence and estrogen risks are not well understood yet. We used high performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) to determine the concentrations of eight bisphenol analogs in 76 sewage sludge samples collected by the U.S. Environmental Protection Agency (EPA) in 2006/2007 from 74 wastewater treatment plants (WWTPs) in 35 states. Bisphenols were detected at the following concentration ranges (ng/g dry weight) and detection frequencies: BPA (6.5–4700; 100%); bisphenol S (BPS; <1.79–1480; 84%); bisphenol F (BPF; <1.79–242; 68%); bisphenol AF (BPAF; <1.79–72.2; 46%); bisphenol P (BPP; <1.79–6.42; <5%), bisphenol B (BPB; <1.79–5.60; <5%), and bisphenol Z (BPZ; <1.79––66.7; <5%). Bisphenol AP (BPAP) was not detected in any of the samples (<1.79ng/gdw). Concentrations of BPA in sewage sludge were an order of magnitude higher than those reported in China but similar to those in Germany. The calculated 17β-estradiol equivalents (E2EQ) of bisphenols present in sludge samples were 7.74 (0.26–90.5)pg/gdw, which were three orders of magnitude lower than the estrogenic activity contributed by natural estrogens present in the sludge. The calculated mass loading of bisphenols through the disposal of sludge and wastewater was <0.02% of the total U.S. production. As the usage of BPA is expected to decline further, environmental emissions of BPS, BPF, and BPAF are likely to increase in the future. This study establishes baseline levels and estrogenic activity of diverse bisphenol analogs in sewage sludge.
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