Urinary Concentrations of Bisphenol Mixtures during Pregnancy and Birth Outcomes: The MAKE Study
Seyoung KimEun‐Jung ParkEunkyo ParkSeulbi LeeJeoung-A KwonBohye ShinSora KangEun‐Young ParkByungmi Kim
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Bisphenols are endocrine disruptors that may be associated with altered fetal growth in humans, and they have similar biological functions to mimic hormones. In addition, aggregated chemicals showed an adverse effect although individual concentration was at a low level. However, most studies between bisphenols and birth outcomes have focused on the effect of individual bisphenol. Thus, we explored the associations of urinary bisphenol mixtures with birth outcomes. We conducted a prospective birth cohort study in South Korea. One hundred eighty mother-infant pairs were recruited from 2017 to 2019. Bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) in one spot urine were analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. We used two statistical approaches to examine potential associations of BPA, BPF, and BPS with birth weight and gestational age: (1) multivariable linear regression; (2) Bayesian kernel machine regression (BKMR). The geometric means of BPA, BPF, and BPS were 2.1, 0.2, and 0.1 μg/L, respectively. In stratified linear analyses by each median value, a higher BPF was positively associated with birth weight (g) (β = 125.5; 95% CI: 45.0 to 205.9). Mixture analyses using BKMR suggested an inverse association between bisphenol mixtures and birth weight. Our findings suggest that in utero bisphenol exposure may influence birth weight and that such relationships may differ considering non-linearity and the combined effect.Keywords:
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Exposure to bisphenol analogues can occur in several ways throughout the food production chain, with their presence at higher concentrations representing a risk to human health. This study aimed to develop effective analytical methods to simultaneously quantify BPA and fifteen bisphenol analogues (i.e., bisphenol AF, bisphenol AP, bisphenol B, bisphenol BP, bisphenol C, bisphenol E, bisphenol F, bisphenol G, bisphenol M, bisphenol P, bisphenol PH, bisphenol S, bisphenol Z, bisphenol TMC, and tetramethyl bisphenol F) present in canned foods and beverages. Samples of foods and beverages available in the Swiss and EU markets (n = 22), including canned pineapples, ravioli, and beer, were prepared and analyzed using QuEChERS GC-MS. The quantification method was compared to a QuEChERS LC-MS/MS analysis. This allowed for the selective and efficient simultaneous quantitative analysis of bisphenol analogues. Quantities of these analogues were present in 20 of the 22 samples tested, with the most frequent analytes at higher concentrations: BPA and BPS were discovered in 78% and 48% of cases, respectively. The study demonstrates the robustness of QuEChERS GC-MS for determining low quantities of bisphenol analogues in canned foods. However, further studies are necessary to achieve full knowledge of the extent of bisphenol contamination in the food production chain and its associated toxicity.
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Restrictions on the use of bisphenol A (BPA) in consumer products led to its replacement by various bisphenol (BP) analogues, yet young children's exposure to these analogues has been poorly characterized so far. This study aimed to characterize infants' and toddlers' exposure to BPA and 14 emerging BP analogues (i.e., bisphenol AF, bisphenol AP, bisphenol B, bisphenol BP, bisphenol C (BPC), bisphenol E, bisphenol F (BPF), bisphenol G, bisphenol M (BPM), bisphenol P, bisphenol PH, bisphenol S (BPS), bisphenol TMC, and bisphenol Z). We extracted infants' and toddlers' urine from diapers (
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Minor structural modifications of bisphenol A strongly affect physiological responses of HepG2 cells
Bisphenols represent a large group of structurally similar compounds. In contrast to bisphenol A (BPA) and bisphenol S (BPS), however, toxicological data are usually scarce, thus making bisphenols an ideal candidate for read-across assessments. BPA, bisphenol C (BPC) and a newly synthesized bisphenol A/C (BPA/C) differ only by one methyl group attached to the phenolic ring. Their EC50 values for cytotoxicity and logPOW values are comparable. However, the estrogenic activities of these bisphenols are not comparable and among this group only BPC leads to a decrease of the mitochondrial membrane potential and ATP concentration in HepG2 cells. Conversely, the cell division rate was decreased by BPS, BPA, BPC and BPA/C at 10% toxicity (EC10). At lower concentrations, only BPC significantly affected proliferation. The pro-inflammatory cytokines TGFB1 and TNF were significantly upregulated by BPC only, while SPP1 was upregulated by BPA, BPA/C and BPS. BPC led to the release of cytochrome c from mitochondria, indicating that this compound is capable of inducing apoptosis. In conclusion, the read-across approach revealed non-applicable in the case of the various structurally and physicochemically comparable bisphenols tested in this study, as the presence of one or two additional methyl group(s) attached at the phenol ring profoundly affected cellular physiology.
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Bisphenol A (BPA) is a high production volume chemical widely used in plastics, food packaging, and many other products. It is well known that endocrine-disrupting chemicals might be harmful to human health due to interference with normal hormone actions. Recent studies report widespread usage and exposure to many BPA-like chemicals (BPs) that are structurally or functionally similar to BPA. However, the biological actions and toxicity of those BPs are still relatively unknown. To address this data gap, we used in vitro cell models to evaluate the ability of 22 BPs to induce or inhibit estrogenic and androgenic activity. BPA, Bisphenol AF (BPAF), bisphenol Z (BPZ), bisphenol C (BPC), tetramethyl bisphenol A (TMBPA), bisphenol S (BPS), bisphenol E (BPE), 4,4-bisphenol F (4,4-BPF), bisphenol AP (BPAP), bisphenol B (BPB), tetrachlorobisphenol A (TCBPA), and benzylparaben (PHBB) induced estrogen receptor (ER)α and/or ERβ-mediated activity. With the exception of BPS, TCBPA, and PHBB, these same BPs were also androgen receptor (AR) antagonists. Only 3 BPs were found to be ER antagonists. Bisphenol P (BPP) selectively inhibited ERβ-mediated activity and 4-(4-phenylmethoxyphenyl)sulfonylphenol (BPS-MPE) and 2,4-bisphenol S (2,4-BPS) selectively inhibited ERα-mediated activity. None of the BPs induced AR-mediated activity. In addition, we identify that the BPs can bind to ER or AR with varying degrees by a molecular modeling analysis. Taken together, these findings help us to understand the molecular mechanism of BPs and further consideration of their usage in consumer products.
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Bisphenol F (BPF) and bisphenol S (BPS) have become popular substitutes for bisphenol A (BPA) in the plastic industry due to concerns over BPA's adverse effects. However, there is limited information on children's exposure to these chemicals. This study aims to assess the extent of BPA, BPF, and BPS exposure and determine factors that influence such exposure. A group of Thai children (age 6-13 years, N = 358) were recruited between October 2019 and 2020. Two first-morning voids were collected one week apart. Demographic and exposure-related information was gathered. Urinary concentrations of bisphenols were analyzed by liquid chromatography and tandem mass spectrometry. Correlation between bisphenol concentrations with age, body weight, and sources of bisphenol exposure, was determined using generalized estimating equations with linear model. BPA, BPF, and BPS were detected at 79.6%, 31.0%, and 16.8%, with geometric mean (GM) concentrations of 1.41, 0.013, and 0.014 ng/mL, respectively. Younger children aged <10 years exhibited 1.3-1.6 times higher GM levels of all bisphenols compared to older children. Exposure to food stored in plastic containers was associated with higher levels of BPF and BPS. In conclusion, BPA was the most frequently detected bisphenol in urine samples from Thai children, followed by BPF and BPS.
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Because of regulatory actions and public concerns, the use of bisphenol A (BPA) may decrease, while the use of BPA alternatives may increase. Although BPA alternatives are considered safer than BPA, their effects on health are still largely unknown. For risk assessment, understanding exposure to these chemicals is necessary. We measured the urinary concentrations of BPA and three bisphenol analogs, bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), in 616 archived samples collected from convenience samplings of U.S. adults at eight time points between 2000 and 2014. We detected BPA at the highest frequency and geometric mean (GM) concentrations (74-99%, 0.36-2.07 μg/L), followed by BPF (42-88%, 0.15-0.54 μg/L) and BPS (19-74%, < 0.1-0.25 μg/L); BPAF was rarely detected (<3% of all samples). Although concentrations of BPF were generally lower than for other bisphenols, the 95th percentile concentration of BPF was often comparable or higher than that of BPA. We did not observe obvious exposure trends for BPF. However, the significant changes in GM concentrations of BPA and BPS suggest that exposures may be declining (BPA) or on the rise (BPS). Nationally representative data will be useful to confirm these findings and to allow monitoring future exposure trends to BPA and some of its bisphenol alternatives.
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Bisphenol A (BPA) has been widely reported to exert endocrine disrupting effects, including the induction of adipogenesis in cultured preadipocytes and intact animals. Because of the potential harm to human health, BPA is being substituted by structurally related bisphenols. Whether or not such BPA analogues are safe substitutes, however, remains largely unknown. Here, we investigated the potential of bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF), bisphenol S (BPS), and 4-cumylphenol (4-CP) to affect lipid and hormone levels in 3 T3-L1 cells. We found that BPB, BPE, BPF, BPS, and 4-CP all affected lipid accumulation and leptin levels to the same extent and potencies as BPA. Based on these and other results, we conclude that these BPA analogues and 4-CP most likely will elicit similar effects on adipocytes as BPA. Using them to substitute BPA in products should be done with caution.
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