Urinary concentrations of bisphenol A and its alternatives: Potential predictors of and associations with antral follicle count among women from an infertility clinic in Northern China.

BACKGROUND: Experimental studies have suggested exposure to bisphenol A (BPA) and its alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), may exert adverse effects on ovarian reserve, but human evidence is limited. Moreover, the potential predictors of exposure to bisphenols among women seeking infertility treatment have not been reported. OBJECTIVE: To explore whether individual or mixture of BPA, BPF, and BPS were related to antral follicle count (AFC), and further identify the predictors of exposure to bisphenols among women seeking assisted reproductive treatment. METHODS: A total of 111 women from a reproductive center in Shenyang, China were enrolled in this study from September 2020 to February 2021. The concentrations of urinary BPA, BPF, and BPS were measured using ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). AFC was measured by two infertility physicians through transvaginal ultrasonography on the 2-5 days of a natural cycle. Demographic characteristics, dietary habits, and lifestyles were obtained by questionnaires. The associations between individual and mixture of urinary bisphenols concentrations (BPA, BPF, and BPS) and AFC were assessed by the Poisson regression models and the quantile-based g-computation (QGC) model, respectively. The potential predictors of exposure to bisphenols were identified by the multivariate linear regression models. RESULTS: After adjusting for confounders, elevated urinary concentrations of BPA, BPF and BPS were associated with reduced AFC (ß = -0.016; 95%CI: -0.025, -0.006 in BPA; ß = -0.017; 95%CI: -0.029, -0.004 in BPF; ß = -0.128; 95%CI: -0.197, -0.060 in BPS). A quantile increase in the bisphenols mixture was negatively associated with AFC (ß = -0.101; 95%CI: -0.173, -0.030). Intake of fried food had higher urinary concentrations of BPF, BPS, and total bisphenols (∑BPs) than women who did not eat, and age was related to increased urinary BPF concentrations. CONCLUSION: Our findings indicated that exposure to individual BPA, BPF, BPS and bisphenol mixtures were associated with impaired ovarian reserve. Furthermore, the intake of fried food, as identified in this study, could serve as an important bisphenols exposure route for reproductive-aged women.

Measurement of Bisphenol A Diglycidyl Ether (BADGE), BADGE derivatives, and Bisphenol F Diglycidyl Ether (BFDGE) in Japanese infants with NICU hospitalization history.

BACKGROUND: Bisphenol A diglycidyl ether (BADGE) and Bisphenol F diglycidyl ether (BFDGE) are used in medical devices, such as intravenous sets, syringes, and catheters. Several studies have reported that these compounds are endocrine disruptors, cytotoxic, and genotoxic, raising concerns about their adverse effects on infants, in a stage of remarkable growth and development. The present study aimed to measure the serum concentrations of BADGE, derivatives of BADGE, and BFDGE in infants and examine the factors that influence them. METHODS: Ten infants admitted to the neonatal intensive care unit (NICU) were enrolled in the present study. Blood samples from each infant and questionnaires from their mothers were collected twice, at 1-2 months and 7 months of age. BADGE, BADGE·H2O, BADGE·2H2O, and BFDGE were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Serum BADGE·2H2O was identified in all infants, at both 1-2 months (2.30-157.58 ng/ml) and 7 months of age (0.86-122.85 ng/ml). One of the two infants who received invasive ventilation showed a substantially increased BADGE·2H2O concentration. There was no significant difference in BADGE·2H2O concentrations at 7 months of age between the group that ate commercial baby food at least ≥ 1 time per week and the group that did not. CONCLUSIONS: BADGE·2H2O was detected in the serum of all infants with a history of NICU hospitalization. Future studies are needed to determine the source of BADGE exposure and investigate its effects on infant development.

The association between prenatal bisphenol F exposure and infant neurodevelopment: The mediating role of placental estradiol.

BACKGROUND: There are limited population studies on the neurodevelopmental effects of bisphenol F (BPF), a substitute for bisphenol A. Furthermore, the role of placental estradiol as a potential mediator linking these two factors remains unclear. OBJECTIVE: To examine the association between maternal prenatal BPF exposure and infant neurodevelopment in a prospective cohort study and to explore the mediating effects of placental estradiol between BPF exposure and neurodevelopment in a nested case-control study. METHODS: The prospective cohort study included 1077 mother-neonate pairs from the Wuhu city cohort study in China. Maternal BPF was determined using the liquid/liquid extraction and Ultra-performance liquid chromatography tandem mass spectrometry method. Children's neurodevelopment was assessed at ages 3, 6, and 12 months using Ages and Stages Questionnaires. The nested case-control study included 150 neurodevelopmental delay cases and 150 healthy controls. Placental estradiol levels were measured using enzyme-linked immunosorbent assay kits. Generalized estimating equation models and robust Poisson regression models were used to examine the associations between BPF exposure and children's neurodevelopment. In the nested case-control study, causal mediation analysis was conducted to assess the role of placental estradiol as a mediator in multivariate models. RESULTS: In the prospective cohort study, the pregnancy-average BPF concentration was positively associated with developmental delays in gross-motor, fine-motor, and problem-solving ( ORtotal ASQ: 1.14(1.05, 1.25), ORgross-motor: 1.22(1.10, 1.36), ORfine-motor: 1.19(1.07, 1.31), ORproblem-solving: 1.11(1.01, 1.23)). After sex-stratified analyses, pregnancy-average BPF concentration was associated with an increased risk of neurodevelopmental delays in the gross-motor (ORgross-motor:1.30(1.12, 1.51)) and fine-motor (ORfine-motor: 1.22(1.06, 1.40)) domains in boys. In the nested case-control study, placental estradiol mediated 16.6% (95%CI: 4.4%, 35.0%) of the effects of prenatal BPF exposure on developmental delay. CONCLUSIONS: Our study supports an inverse relationship between prenatal BPF exposure and child neurodevelopment in infancy, particularly in boys. Decreased placental estradiol may be an underlying biological pathway linking prenatal BPF exposure to neurodevelopmental delay in offspring.

Epigenetic Methylation Changes in Pregnant Women: Bisphenol Exposure and Atopic Dermatitis.

Bisphenol is a chemical substance widely used in plastic products and food containers. In this study, we observed a relationship between DNA methylation and atopic dermatitis (AD) in the peripheral blood mononuclear cells (PBMCs) of pregnant women exposed to bisphenol A (BPA) and its alternatives, bisphenol S (BPS) and bisphenol F (BPF). DNA methylation is an epigenetic mechanism that regulates gene expression, which can be altered by environmental factors, and affects the onset and progression of diseases. We found that genes belonging to the JAK-STAT and PI3K-AKT signaling pathways were hypomethylated in the blood of pregnant women exposed to bisphenols. These genes play important roles in skin barrier function and immune responses, and may influence AD. Therefore, we suggest that not only BPA, but also BPS and BPF, which are used as alternatives, can have a negative impact on AD through epigenetic mechanisms.

Effects of bisphenol F, bisphenol S, and bisphenol AF on cultured human osteoblasts.

Bisphenol A (BPA) analogs, like BPA, could have adverse effects on human health including bone health. The aim was to determine the effect of BPF, BPS and BPAF on the growth and differentiation of cultured human osteoblasts. Osteoblasts primary culture from bone chips harvested during routine dental work and treated with BPF, BPS, or BPAF for 24 h at doses of 10-5, 10-6, and 10-7 M. Next, cell proliferation was studied, apoptosis induction, and alkaline phosphatase (ALP) activity. In addition, mineralization was evaluated at 7, 14, and 21 days of cell culture in an osteogenic medium supplemented with BP analog at the studied doses. BPS treatment inhibited proliferation in a dose-dependent manner at all three doses by inducing apoptosis; BPF exerted a significant inhibitory effect on cell proliferation at the highest dose alone by an increase of apoptosis; while BPAF had no effect on proliferation or cell viability. Cell differentiation was adversely affected by treatment with BPA analogs in a dose-dependent, observing a reduction in calcium nodule formation at 21 days. According to the results obtained, these BPA analogs could potentially pose a threat to bone health, depending on their concentration in the organism.

Associations of bisphenol F and S, as substitutes for bisphenol A, with cardiovascular disease in American adults.

Bisphenol A (BPA) exposure may be positively associated with cardiovascular disease (CVD). For more than a past decade, exposure to bisphenol F (BPF) and bisphenol S (BPS), as substitutes for BPA, has gradually increased in the population. Whether BPF and BPS exposure are associated with CVD remains unclear. We used data from the United States National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016. A total of 3,502 participants, including 368 with CVD, were enrolled in the final analysis. Associations of BPA, BPF and BPS with CVD were determined using multivariate logistic regression analysis. The highest level of urinary BPA (≥2.5 ng/ml) was significantly associated with a higher CVD prevalence (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.08-2.3) among all participants in the quartile analysis. In stratified analyses, the highest level of urinary BPA was positively associated with CVD prevalence in males (1.86, 1.1-3.13) and the elderly population (≥60 years old) (1.89, 1.2-2.97). Higher levels of urinary BPF were positively associated with CVD prevalence in females (Q2: 1.81, 1.03-3.18; Q4: 1.73, 1.07-2.79) and in the elderly population (Q3: 1.7, 1.16-2.48). No associations were found between urinary BPS levels and CVD, regardless of whether the participants were stratified by age or sex. In conclusion, exposure to BPA or BPF was positively correlated with CVD prevalence, but an association was not found for exposure to BPS. BPF may not be as safe as assumed for human health.

Urinary bisphenol A and S are associated with diminished ovarian reserve in women from an infertility clinic in Northern China.

Bisphenol A (BPA) has been demonstrated to cause ovarian toxicity including disruption of steroidogenesis and inhibition of follicle growth. Still, human evidence is lacking on its analogs such as bisphenol F (BPF) and bisphenol S (BPS). In this study, we aimed to investigate the associations between exposure to BPA, BPF, and BPS with ovarian reserve in women of childbearing age. We recruited 111 women from an infertility clinic in Shenyang, North China between September 2020 and February 2021. Anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) were measured as indicators of ovarian reserve. Urinary BPA, BPF, and BPS concentrations were quantified by ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). Linear and logistic regression models were applied to assess the associations between urinary BPA, BPF, and BPS levels and indicators of ovarian reserve and DOR, respectively. Restricted cubic spline (RCS) models were further utilized to explore potential non-linear associations. Our results showed that urinary BPS concentrations were negatively associated with AMH (ß = - 0.287, 95 %CI: - 0.505, - 0.070, P = 0.010) and this inverse relationship was further confirmed in the RCS model. In addition, higher levels of BPA and BPS exposure were associated with increased DOR risk (BPA: OR = 7.112, 95 %CI: 1.247, 40.588, P = 0.027; BPS: OR = 6.851, 95 %CI: 1.241, 37.818, P = 0.027). No significant associations of BPF exposure with ovarian reserve. Our findings implied that higher BPA and BPS exposure may be related to decreased ovarian reserve.

Comparative evaluation of the effects of bisphenol derivatives on oxidative stress parameters in HepG2 cells.

Bisphenol A (BPA) BPA is an endocrine-disrupting chemical that has a wide range of uses. Exposure to BPA can be by oral, inhalation, and parenteral routes. Although its use in several products is limited, there is still concern on its adverse health effects, particularly for susceptible populations like children. Alternative bisphenols, such as bisphenol S (BPS) and bisphenol F (BPF), are now being used instead of BPA, although there is little information on the toxicity of these bisphenols. BPF is used as a plasticizer in the production of several industrial materials as well as in the coating of drinks and food cans. BPS is used in curing fast-drying epoxy glues, as a corrosion inhibitor and as a reactant in polymer reactions. In this study, the possible toxic effects of BPA, BPS, and BPF in HepG2 cells were evaluated comparatively. For this purpose, their effects on cytotoxicity, production of intracellular reactive oxygen species (ROS), oxidant/antioxidant parameters, and DNA damage have been examined. The cytotoxicity potentials of different bisphenols were found to be as BPS > BPF > BPA. All bisphenol derivatives caused increases in intracellular ROS production. We observed that all bisphenol derivatives cause an imbalance in some oxidant/antioxidant parameters. Bisphenols also caused significant DNA damage in order of BPF > BPA > BPS. We can suggest that both of the bisphenol derivatives used as alternatives to BPA also showed similar toxicities and may not be considered as safe alternatives. Mechanistic studies are needed to elucidate this issue.

Activation of NLRP3 Inflammasome in Liver of Long Evans Lactating Rats and Its Perinatal Effects in the Offspring after Bisphenol F Exposure.

The liver is the organ responsible for the metabolism and detoxification of BPF, the BPA analogue that is replacing it in plastic-based products. It is not known whether BPF can trigger inflammatory responses via the NLRP3 inflammasome, which plays a major role in the development of liver disease. The aim of this study was to evaluate nitrosative stress species (RNS) and NLRP3 inflammasome activation in the liver of lactating dams after BPF exposure. Moreover, it was studied whether this effect could also be observed in the liver of female and male offspring at postnatal day 6 (PND6). 36 Long Evans rats were randomly distributed according to oral treatment into three groups: Control, BPF-low dose (LBPF; 0.0365 mg/kg b.w./day) group and BPF-high dose (HBPF; 3.65 mg/kg b.w./day) group. The levels of nitrosative stress-inducing proteins (eNOS, iNOS, HO-1d), NLRP3 inflammasome components (NLRP3, PyCARD, CASP1) and proinflammatory cytokines (IL-1ß, IL-18, IFN-γ and TNF-α) were measured by gene and protein expression in the liver of lactating dams and in female and male PND6 offspring. Lactating dams treated with LBPF showed a significant increase in iNOS and HO-1d, activation of NLRP3 components (NLRP3, PyCARD, CASP1) and promoted the release of proinflammatory cytokines such as IL-1ß, IL-18, IFN-γ and TNF-α. Similar effects were found in female and male PND6 offspring after perinatal exposure. LBPF oral administration and perinatal exposure caused an increase of nitrosative stress markers and proinflammatory cytokines. Also, NLRP3 inflammasome activation was significantly increased in in the liver of lactating dams and PND6 offspring.

Transcriptome Analysis of the Developmental Effects of Bisphenol F Exposure in Chinese Medaka (Oryzias sinensis).

Bisphenol F (BPF) has been used in the syntheses of polymers, which are widely used in coatings, varnishes, adhesives, and other plastics. During the past decades, BPF contamination in the aquatic environment has dramatically increased due to its release from manmade products. Concerns have driven much attention to whether it may adversely impact aquatic lives or human beings. The present study performed an acute toxic exposure experiment and a 15 d developmental exposure of BPF at environmental concentrations (20, 200, and 2000 ng/L) using Chinese medaka (Oryzias sinensis). In the acute toxic exposure, the LC50 of BPF to Chinese medaka is 87.90 mg/L at 96 h. Developmental exposure induced a significant increase in the frequency of larvae with abnormalities in the 2000 ng/L BPF group compared to the control group. Transcriptomic analysis of the whole larvae revealed 565 up-regulated and 493 down-regulated genes in the 2000 ng/L BPF exposure group. Analysis of gene ontology and KEGG pathways enrichments indicated endocrine disorders to be associated with BPF-induced developmental toxicity. The present results suggest that BPF is developmentally toxic at 2000 ng/L concentration in Chinese medaka and causes endocrine-related aberrations in the transcriptional network of genes.

Modulation of Osteogenic Gene Expression by Human Osteoblasts Cultured in the Presence of Bisphenols BPF, BPS, or BPAF.

Bone effects attributed to bisphenols (BPs) include the inhibition of growth and differentiation. This study analyzes the effect of BPA analogs (BPS, BPF, and BPAF) on the gene expression of the osteogenic markers RUNX2, osterix (OSX), bone morphogenetic protein-2 (BMP-2), BMP-7, alkaline phosphatase (ALP), collagen-1 (COL-1), and osteocalcin (OSC). Human osteoblasts were obtained by primary culture from bone chips harvested during routine dental work in healthy volunteers and were treated with BPF, BPS, or BPAF for 24 h at doses of 10-5, 10-6, and 10-7 M. Untreated cells were used as controls. Real-time PCR was used to determine the expression of the osteogenic marker genes RUNX2, OSX, BMP-2, BMP-7, ALP, COL-1, and OSC. The expression of all studied markers was inhibited in the presence of each analog; some markers (COL-1; OSC, BMP2) were inhibited at all three doses and others only at the highest doses (10-5 and 10-6 M). Results obtained for the gene expression of osteogenic markers reveal an adverse effect of BPA analogs (BPF, BPS, and BPAF) on the physiology of human osteoblasts. The impact on ALP, COL-1, and OSC synthesis and therefore on bone matrix formation and mineralization is similar to that observed after exposure to BPA. Further research is warranted to determine the possible contribution of BP exposure to the development of bone diseases such as osteoporosis.

A Fast Method for Determination of Seven Bisphenols in Human Breast Milk Samples with the Use of HPLC-FLD.

Plastic pollution, where bisphenol A (BPA) is widely used in its production, has gained popularity. BPA omnipresence and toxicity, especially for infants, has led food safety authorities to place restrictions on BPA usage. It has led to the introduction of the marked 'BPA-free'-labelled products, where BPA is often replaced by other bisphenols (BPs) which are suspected of being similar or even more toxic than BPA. Moreover, the free forms of BPs are more dangerous than their conjugated forms and the conjugation of BPs is less effective in infants than in adults. Considering that human breast milk is the main source of nutrition for infants, the constant biomonitoring not only of BPA, but the wider group of BPs in such crucial matrices seems to be vital. In this study, a fast, simple, 'green' and cost-effective DLLME-based extraction technique combined with HPLC-FLD was optimized for the determination of seven selected bisphenols simultaneously. The procedure has satisfactory recovery values of 67-110% with the most RSD% at 17%. The LODs and LOQs ranged from 0.5 ng/mL to 2.1 ng/mL and 1.4 ng/mL to 6.3 ng/mL, respectively. The procedure was successfully applied to the biomonitoring of free forms of BPs in 10 real human breast milk samples.

Effects of BPA substitutes on the prenatal and cardiovascular systems.

Bisphenol A (BPA) is a ubiquitous chemical compound constantly being released into the environment, making it one of the most persistent endocrine-disrupting chemical (EDC) in nature. This EDC has already been associated with developing various pathologies, such as diabetes, obesity, and cardiovascular, renal, and behavioral complications, among others. Therefore, over the years, BPA has been replaced, gradually, by its analog compounds. However, these compounds are structurally similar to BPA, so, in recent years, questions have been raised concerning their safety for human health. Numerous investigations have been performed to determine the effects BPA substitutes may cause, particularly during pregnancy and prenatal life. On the other hand, studies investigating the association of these compounds with the development of cardiovascular diseases (CVD) have been developed. In this sense, this review summarizes the existing literature on the transgenerational transfer of BPA substitutes and the consequent effects on maternal and offspring health following prenatal exposure. In addition, these compounds' effects on the cardiovascular system and the susceptibility to develop CVD will be presented. Therefore, this review aims to highlight the need to investigate further the safety and benefits, or hazards, associated with replacing BPA with its analogs.

Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ERß and calcineurin A-DRP1 signaling pathway.

Bisphenol F (BPF) is a replacement to bisphenol A, which has been extensively used in industrial manufacturing. Its wide detection in various human samples raises increasing concern on its safety. Currently, whether a low dose of BPF compromises cardiac function is still unknown. This study provides the first evidence that low-dose BPF can induce cardiac hypertrophy by using cardiomyocytes derived from human embryonic stem cells (hES). Non-cytotoxic BPF increased cytosolic Ca 2+ influx ([Ca2+ ]c), which was most remarkable at low dose (7 ng/ml) rather than at higher doses. Significant changes in the morphological parameters of mitochondria and significant decreases in ATP production were induced by 7 ng/ml BPF, representing a classic hypertrophic cardiomyocyte. After eliminating the direct effects on mitochondrial fission-related DRP1 by administration of the DRP1 inhibitor Mdivi-1, we examined the changes in [Ca 2+ ]c levels induced by BPF, which enhanced the calcineurin (Cn) activity and induced the abnormal mitochondrial fission via the CnAß-DRP1 signaling pathway. BPF triggered excessive Ca 2+ influx by disrupting the L-type Ca 2+channel in cardiomyocytes. The interaction between ERß and CnAß cooperatively involved in the BPF-induced Ca 2+ influx, which resulted in the abnormal mitochondrial fission and compromised the cardiac function. Our findings provide a feasible molecular mechanism for explaining low-dose BPF-induced cardiac hypertrophy in vitro, preliminarily suggesting that BPF may not be as safe as assumed in humans.

Bisphenol F Impaired Zebrafish Cognitive Ability through Inducing Neural Cell Heterogeneous Responses.

The central nervous system (CNS) is a sensitive target for endocrine-disrupting chemicals, such as bisphenol analogues. Bisphenol A (BPA) usage is associated with the occurrence of many neurological diseases. With the restricted use of BPA, bisphenol F (BPF) has been greatly introduced for industrial manufacture and brings new hazards to public CNS health. To understand how BPF affects the neural system, we performed a cognitive test for zebrafish that are continuously exposed to environmentally relevant concentrations (0.5 and 5.0 µg/L) of BPF since embryonic stage and identified suppressed cognitive ability in adulthood. Single-cell RNA sequencing of neural cells revealed a cell composition shift in zebrafish brain post BPF exposure, including increase in microglia and decrease in neurons; these changes were further validated by immune staining. At the same time, a significant inflammatory response and increased phagocytic activity were detected in zebrafish brain post BPF exposure, which were consistent with the activation of microglia. Cell-specific transcriptomic profiles showed that abnormal phagocytosis, activated brain cell death, and apoptosis occurred in microglia post BPF exposure, which are responsible for the neuron loss. In addition, certain neurological diseases were affected by BPF in both excitatory and inhibitory neurons, such as the movement disorder and neural muscular disease, however, with distinctly involved genes. These findings indicate that BPF exposure could lead to an abnormal cognitive behavior of zebrafish through inducing heterogeneous changes of neural cells in brain and revealed the dominating role of microglia in mediating this effect.

Simple preparation of surface molecularly imprinted polymer based on silica particles for trace level assay of bisphenol F.

A new electrochemical sensor based on molecularly imprinted tetraethyl orthosilicate (TEOS)-based porous interface was developed for selective recognition of bisphenol F (BPF) in this study. The sensor was prepared by depositing the solution containing TEOS and L-tryptophan (L-Trp) in the presence of cetyltrimethylammonium bromide (CTAB) as a pore-maker via hydrolysis/condensation reaction on the glassy carbon electrode (GCE). While the surface morphology and structure characterization were carried out using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), electrochemical characterization was performed through electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The resulted MIP(TEOS:L-Trp)@GCE achieved a wide linear range of 1 × 10-15-1 × 10-14 M for BPF detection with an excellent detection limit of 0.291 fM. Furthermore, the recovery of BPF from spiked bottled water and serum samples varied between 98.83 and 101.03%. These results demonstrate that MIP(TEOS:L-Trp)@GCE was found to be a simple, sensitive, and selective smart interface to detect trace pollution even from complicated samples.

Associations between urinary concentrations of bisphenols and serum concentrations of sex hormones among US. Males.

BACKGROUND: Bisphenol A (BPA) exposure and its structural analogs (BPS and BPF) might cause endocrine alterations and adverse physiological effects. Few studies to date have directly explored the association between its structural analogs (BPS, BPF) and sex hormones in adult male participants. Therefore, we aimed to assess the associations between BPA, BPS, BPF, and sex hormones in American adult men. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey 2011-2016. We excluded participants without data available on sex hormones and urinary bisphenols. Furthermore, participants consuming sex hormone medications were excluded. Multivariable regression models were performed to assess the association between bisphenols and sex hormones. RESULTS: In this study, 2367 participants were included. Of 2367, in 1575 participants, the data on BPS and BPF were available. We found that a per unit increase in BPF was associated with 0.575 ng/dL higher total testosterone (TT) (Model 2: 95% CI: 0.047, 1.103, P = 0.033). However, there was no significant association between BPA or BPS and TT. Furthermore, increased BPA and BPS levels were associated with higher levels of sex hormone-binding globulin (SHBG) (Model 2: ß = 0.364, 95% CI: 0.158, 0.571; ß = 0.25, 95% CI: 0.071, 0.429, respectively). Additionally, participants in the highest BPA exposure quartile (quartile 4) had 4.072 nmol/L higher levels of SHBG than those in quartile 1 (Model 2: 95% CI: 0.746, 7.397, P = 0.017; P for trend =0.005). Both BPA and BPS were negatively associated with free testosterone (FT, nmol/L) after full adjustment (Model 2, ß = - 0.01%, P = 0.0211, P = 0.0211; Model 2, ß = - 0.01%, P = 0.0258, respectively). However, BPF was positively associated with FT (Model 2, ß = 0.0029%, P = 0.0028). CONCLUSION: Our study indicated that exposure to both BPA and its substitutions could alter sex hormone levels. This finding supports the possibility that human exposure to bisphenols at environmental levels might affect the endogenous hormone balance.

Biotransformation of bisphenol F by white-rot fungus Phanerochaete sordida YK-624 under non-ligninolytic condition.

Environmental bisphenol F (BPF) has a cyclic endocrine disruption effect, seriously threatening animal and human health. It is frequently detected in environmental samples worldwide. For BPF remediation, biological methods are more environmentally friendly than physicochemical methods. White-rot fungi have been increasingly studied due to their potential capability to degrade environmental pollutants. Phanerochaete sordida YK-624 has been shown to degrade BPF by ligninolytic enzymes under ligninolytic conditions. In the present study, degradation of BPF under non-ligninolytic conditions (no production of ligninolytic enzymes) was investigated. Our results showed that BPF could be completely removed after 7-d incubation. A metabolite of BPF, 4,4'-dihydroxybenzophenone (DHBP) was identified by mass spectrometry and nuclear magnetic resonance, and DHBP was further degraded by this fungus to form 4-hydroxyphenyl 4-hydroxybenzoate (HPHB). DHBP and HPHB were the intermediate metabolites of BPF and would be further degraded by P. sordida YK-624. We also found that cytochrome P450s played an important role in BPF degradation. Additionally, transcriptomic analysis further supported the involvement of these enzymes in the action of BPF degradation. Therefore, BPF is transformed to DHBP and then to HPHB likely oxidized by cytochrome P450s in P. sordida YK-624. Furthermore, the toxicological studies demonstrated that the order of endocrine-disrupting activity for BPF and its metabolites was HPHB > BPF > DHBP. KEY POINTS: • White-rot fungus Phanerochaete sordida YK-624 could degrade BPF. • Cytochrome P450s were involved in the BPF degradation. • The order of endocrine disrupting activity was: HPHB > BPF > DHBP.

Pharmacokinetics and toxicity evaluation following oral exposure to bisphenol F.

Bisphenol F is a substitute material for bisphenol A and is widely used in household products as a raw material for polycarbonate resin, epoxy resin, and plastic reinforcement. It is known to be mainly used in food containers, thermal paper for receipts, and coatings for water pipes. In some countries, bisphenol F has been detected in drinking water and human urine samples. However, due to the lack of safety evaluation data on bisphenol F, it is difficult to establish appropriate guidelines for the proper use of the substance, and social anxiety is increasing accordingly. This study investigated the use, exposure route, and distribution flow of bisphenol F, a household chemical. To determine the no-observed-adverse-effect level (NOAEL) and target organ of bisphenol F after exposure, a single-dose oral toxicity, dose-range finding (28 day oral), repeated dose toxicity (90 day oral), and genotoxicity (reverse mutation, chromosomal abnormality, in vivo micronucleus test) tests were performed. The pharmacokinetic profile was also obtained. The test results are as follows: in the pharmacokinetic study, it was confirmed that single oral exposure to BPF resulted in systemic exposure; in single oral dose toxicity test, the approximate lethal dose was found to be 4000 mg/kg and confusion and convulsion was shown in the test animals; NOAEL was determined to be 2 mg/kg/day for male and 5 mg/kg/day for female, and the no-observed-effect level (NOEL) was determined to be 2 mg/kg/day for males and 1 mg/kg/day for females, and the target organ was the small intestine; genotoxicity tests confirmed that BPF does not induce genotoxicity.

Toxicological profile of bisphenol F via comprehensive and extensive toxicity evaluations following dermal exposure.

Bisphenol F (BPF) is classified as a harmful substance by the U.S. Environmental Protection Agency. Although previous studies focused on human exposure to BPF via direct consumption or inhalation, few investigators assessed potential toxicological effects following skin contact. The aim of this study was to examine (1) the degree and pattern by which BPF is absorbed onto the skin in vivo, and (2) determination of toxicity and safety using the following tests: acute dermal; a 28-day repeat dermal; a skin irritation; an eye irritation; and a skin sensitization. As indicated by the amount of BPF remaining in the epidermis or dermis, data demonstrated that BPF was absorbed through the skin at a 26.5% rate. BPF penetrated the subcutaneous layer at a "fast rate" (Kp: 2.2E-02). Although no toxicological changes or local irritation were observed following skin exposure, BPF induced potent sensitization. In summary, the findings of this study showed that BPF penetrated and was absorbed into the skin at a high rate which was associated with enhanced chemical-induced skin sensitization and this may have significant implications following exposure of skin to BPF.