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Bisphenol S (BPS) is commonly used for the industrial production of thermal paper, polycarbonate plastics, epoxy resins and other materials. Studies have reported that BPS can lead to triglyceride (TAG) or/and cholesterol (CHO) accumulation in the liver in zebrafish and mice, but the reasons for the different types of lipids that accumulate in the liver following BPS exposure are unclear. Here, the influences of lower-dose (10 mg/kg body weight/day) and high-dose (50 mg/kg body weight/day) BPS exposure to male SD rats on the accumulation of different lipids in the liver were explored. The results indicated that BPS treatment increased the levels of acetyl-CoA and glycogen in the liver. A lower dose of BPS upregulated the mRNA and protein expression levels of sterol regulatory element-binding protein 1 (srebp1), which is involved in the de novo synthesis of TAG in the liver, thus promoting the synthesis of glycerides (diacetylglyceride and TAG). However, a higher dose of BPS induced CHO accumulation, but inhibited the mRNA expression of genes (i.e., srebp2, hmgcr and hmgcs) involved in the de novo synthesis of CHO in the liver. Excessive accumulation of glycerides and CHO led to destruction of the physiological structure of rat liver, causing disorders in liver function. Our data provide new insight into the different mechanisms by which glyceride and CHO accumulate in the liver after BPS exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As a replacement for bisphenol A (BPA), bisphenol AF (BPAF) showed stronger maternal transfer and higher fetal accumulation than BPA. Therefore, concerns should be raised about the health risks of maternal exposure to BPAF during gestation on the offspring. In this study, SD rats were exposed to BPAF (0, 50, and 100 mg/kg/day) during gestation to investigate the bioaccumulation and adverse effects in liver, spleen, and kidney tissues of the offspring at weaning period. Bioaccumulation of BPAF in these tissues with concentrations ranging from 1.56 ng/mg (in spleen of males) to 55.44 ng/mg (in liver of females) led to adverse effects at different biological levels, including increased relative weights of spleen and kidneys, histopathological damage in liver, spleen, and kidney, organ functional damage in liver, spleen, and kidney, upregulated expression of genes related to lipid metabolism (in liver), oxidative stress response (in kidney), immunity and inflammatory (in spleen). Furthermore, dysregulated metabolomics was identified in spleen, with 217 differential metabolites screened and 9 KEGG pathways significantly enriched. This study provides a comprehensive insight into the systemic toxicities of prenatal exposure to BPAF in SD rats. Given the broad applications and widespread occurrence of BPAF, its safety should be re-considered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many environmental pollutants have neurotoxic effects, but the initial molecular events involved in these effects are unclear. Here, zebrafish were exposed to the neurotoxicant bisphenol S (BPS, 1, 10, or 100 μg/L) from the embryonic stage to the larval stage to explore the ability of BPS to interfere with energy metabolism in the brain. BPS, which is similar to a glucose transporter 1 (GLUT1) inhibitor, inhibited GLUT1 function but increased mitochondrial activity in the brains of larval zebrafish. Interestingly, GLUT1 inhibitor treatment and BPS exposure did not reduce energy production in the brain; instead, they increased ATP production by inducing the preferential use of ketone bodies. Moreover, BPS promoted the protein expression of the purinergic 2X receptor but inhibited the purinergic 2Y-mediated phosphatidylinositol signaling pathway, indicating that excess ATP acts as a neurotransmitter to activate the purinergic 2X receptor under the BPS-induced restriction of GLUT1 function. BPS-induced inhibition of GLUT1 increased the number of neurons but promoted apoptosis by activating ATP-purinergic 2X receptors in the brain, causing ATP excitatory neurotoxicity. Our data reveal a potential neurotoxic mechanism induced by BPS that may represent a new adverse outcome pathway.

Bisphenol S (BPS) is a common pollutant in the environment and has posed a potential threat to aquatic animals and human health. To accurately assess the pollution level and ecological risk of BPS, there is an urgent need to establish simple and sensitive detection methods for BPS. In this study, BPS complete antigen was successfully prepared by introducing methyl 4-bromobutyrate and coupling bovine serum albumin (BSA). The monoclonal antibody against BPS (anti-BPS mAb) with high affinity (1: 256,000) was developed based on the BPS complete antigen, which showed low cross-reactivity with BPS structural analogues. Then, an electrochemical immunosensor was constructed to detect BPS using multi-walled carbon nanotubes and gold nanoflower composites as signal amplification elements and using anti-BPS mAb as the probe. The electrochemical immunosensor had a linear range from 1 to 250 ng⋅mL -1 and a limit of detection (LOD) down to 0.6 ng⋅mL -1 . Additionally, a more stable and sensitive lateral flow immunoassay (LFIA) for BPS was developed based on iridium oxide nanoparticles, with a visual detection limit of 1 ng⋅mL -1 , which was 10 times lower than that of classical Au-NPs LFIA. After evaluation of their stability and specificity, the reliability of these two methods were further validated by measuring BPS concentrations in the water and fish tissues. Thus, this study provides sensitive, robust and rapid methods for the detection of BPS in the environment and organisms, which can provide a methodological reference for monitoring environmental contaminants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Estrogen excess in females has been linked to a diverse array of chronic and acute diseases. Emerging research shows that exposure to estrogen-like compounds such as bisphenol S leads to increases in 17β-estradiol levels, but the mechanism of action is unclear. The aim of this study was to reveal the underlying signaling pathway-mediated mechanisms, target site and target molecule of action of bisphenol S causing excessive estrogen synthesis. Human ovarian granulosa cells SVOG were exposed to bisphenol S at environmentally relevant concentrations (1 μg/L, 10 μg/L, and 100 μg/L) for 48 h. The results confirms that bisphenol S accumulates mainly on the cell membrane, binds to follicle stimulating hormone receptor (FSHR) located on the cell membrane, and subsequently activates the downstream cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway, leading to enhanced conversion of testosterone to 17β-estradiol. This study deepens our knowledge of the mechanisms of environmental factors in pathogenesis of hyperestrogenism., (© 2024. The Author(s).)

Whether bisphenols, as plasticizers, can influence bacterial uptake of antibiotic resistance genes (ARGs) in natural environment, as well as the underlying mechanism remains largely unknown. Our results showed that four commonly used bisphenols (bisphenol A, S, F, and AF) at their environmental relative concentrations can significantly promote transmission of ARGs by 2.97-3.56 times in Acinetobacter baylyi ADP1. Intriguingly, we observed ADP1 acquired resistance by integrating plasmids uptake and cellular metabolic adaptations other than through reactive oxygen species mediated pathway. Metabolic adaptations including upregulation of capsules polysaccharide biosynthesis and intracellularly metabolic enzymes, which enabled formation of thicker capsules for capturing free plasmids, and degradation of accumulated compounds. Simultaneously, genes encoding DNA uptake and translocation machinery were incorporated to enhance natural transformation of antibiotic resistance carrying plasmids. We further exposed aquatic fish to bisphenols for 120 days to monitor their long-term effects in aquatic environment, which showed that intestinal bacteria communities were dominated by a drug resistant microbiome. Our study provides new insight into the mechanism of enhanced natural transformation of ARGs by bisphenols, and highlights the investigations for unexpectedly-elevated antibiotic-resistant risks by structurally related environmental chemicals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bisphenol S (BPS), as a substitute for bisphenol A, was frequently detected in human urine and blood. It has been reported that BPS could disrupt fat metabolism in vivo and vitro although mechanisms remain unclear. Additionally, there is no study that the disruptive effect of BPS on parental fat metabolism indirectly interferes with the lipid metabolism of offspring. Here, after 120-d exposure to 1, 10, 100, and 1000 μg/L BPS, the transcription level of genes involved in lipid metabolism in liver and feeding regulation of brain-gut axis, as well as the hepatic triacylglycerol (TAG) and plasma lipid levels were investigated in both male and female zebrafish. Results showed that in male liver, fatty acid synthesis and degradation were inhibited by reducing transcription levels of srebp1 and pparα, and the synthesis of TAG was significantly increased using fatty acid as a precursor by elevating agpat4 and dgat2 mRNA expression levels. As a consequence, fat accumulation and the increased TAG levels were observed in male liver, and lipid levels were also elevated in male plasma. In female liver, there was no excessive fat accumulation and BPS exposure had a non-monotonic effect on the gene expression of fasn, dagt2, and pparα. Notably, the unexposed offspring showed a large amount of yolk lipid remain at 5 days post fertilization. This study obviously demonstrated that long-term BPS exposure increases the risk of non-alcoholic fatty liver disease in male zebrafish and life-cycle exposure hazard on offspring is noteworthy., (Copyright © 2019. Published by Elsevier Ltd.)

Bisphenol S (BPS), exhibiting estrogenic activity, has been reported to promote cell proliferation in MCF-7 breast cancer cells; however, the underlying mechanism remains unclear. In this study, BPS (1-100 μM) significantly promoted cell proliferation in ERα positive MCF-7 cells, but not in ERα negative MDA-MB-231 or SK-BR-3 cells, confirming the important role of ERα in BPS-induced cell proliferation. Results of the flow cytometry analysis indicated that 10 μM BPS promoted MCF-7 proliferation by accelerating G 1 to S phase transition of the cell cycle. BPS increased cyclin D1 expression and phospho-retinoblastoma (p-Rb) levels, resulting in the release of E2F transcription factors and the increased expression of downstream cyclin E2 and cyclin A2 genes to promote the cell cycle progression. Moreover, BPS-induced Rb phosphorylation and cell cycle progression were prevented by the ERα inhibitor ICI 182,780 and methylpiperidino pyrazole, as well as cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitor PD 0332991, indicating that the underlying mechanisms involve ERα-dependent pathways but also mediated by cyclin D-CDK4/6. Overall, our result showed, for the first time, that BPS promoted cell cycle progression and cell proliferation through the ERα-cyclin D-CDK4/6-pRb pathway in MCF-7 breast cancer cells. This study provides a novel insight regarding the potential role of cyclin D-CDK4/6-pRb pathway in mediating the proliferative effects of BPS in breast cancer cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bisphenol F (BPF) is a substitute of bisphenol A in the production of epoxy resin and polycarbonate. Its extensive use in consumer products leads to a wide human exposure at high levels. Although the adverse effects of BPF on animal health are of increasing public concern, its risks on systematic glucose metabolism and blood glucose concentrations still remain largely unknown. Using zebrafish larvae as the model animal, we investigated the disturbance of BPF exposure on glucose metabolism and the underlying mechanisms. Zebrafish larvae at 96 h post fertilization were exposed to 0.1, 1, 10, and 100 μg/L of BPF for 48 h. Compared with the control group, glucose levels of larvae increased significantly in the 10 and 100 μg/L exposure groups, which are associated with enhancement of gluconeogenesis and suppression of glycolysis induced by high doses of BPF. Additionally, both mRNA expressions and protein levels of insulin increased significantly in the 10 and 100 μg/L exposure groups, while transcription levels of genes encoding insulin receptor substrates decreased significantly in these groups, indicating a possibly decreased insulin sensitivity due to impairment of insulin signaling transduction downstream of insulin receptor. Further, compared with BPF alone, co-exposure of larvae to BPF and rosiglitazone, an insulin sensitizer, significantly attenuates increases in both glucose levels and mRNA expressions of a key gluconeogenesis enzyme. Our data therefore indicate impairing insulin signaling transduction may be the main mechanism through which BPF disrupts glucose metabolism and induces hyperglycemia. Results of the present study inform the health risk assessment of BPF and also suggest the use of zebrafish larvae in large-scale screening of chemicals with possible glucose metabolism disturbing effect., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Maternal thyroid hormones (THs) play an essential role in the embryonic and larval development of fish. Previous studies in fish have reported that parental exposure to thyroid disrupting chemicals (TDCs) changed maternal TH levels in the offspring; however, whether this transgenerational thyroid endocrine disruption can further disturb the early development of the offspring still remains largely unknown. Bisphenol S (BPS), a substitute of bisphenol A, has been reported to be a potential TDC. In this study, zebrafish (F0) were exposed to environmentally relevant concentrations (1, 10, and 100 μg/L) of BPS from 2 h post-fertilization to 120 days post-fertilization and then paired to spawn. Plasma levels of thyroxine (T4) were significantly decreased in F0 females while 3,5,3'-triiodothyronine (T3) plasma levels were significantly increased in F0 females and males; moreover, TH content in eggs (F1) spawned by exposed F0 generation exhibited similar changes as the F0 females, with significant decreases in T4 and increases in T3, demonstrating BPS-induced maternal transfer of thyroid endocrine disruption. Further, excessive levels of maternal T3 in the offspring resulted in delayed embryonic development and hatching, swim bladder inflation defect, reduction in motility, developmental neurotoxicity, and lateral stripe hypopigmentation in non-exposed F1 embryos and larvae. These results highlight the adverse effects on the early development of offspring induced by transgenerational thyroid endocrine disruption, which have been ignored by previous studies. Therefore, these results can further improve our understanding of the ecological risks of TDCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It has been suggested that dramatic increase in obesity may be caused by growing exposure to environmental chemicals. In vitro data has suggested bisphenol S (BPS), a compound widely used in polycarbonate plastic production, can induce lipid accumulation in preadipocytes. However, the mechanisms responsible for BPS-induced obesity in vivo remain unclear. In this study, we used translucent zebrafish (Danio rerio) larvae as a model to investigate the effect of environmentally relevant BPS exposure (1, 10, and 100 μg/L from 2 h to 15 d post fertilization) on lipid accumulation, triacylglycerol (TAG) and lipoproteins content, and mRNA expression of genes involved in the regulation of lipid synthesis, transport, degradation, and storage. We also analyzed activities of two enzymes critical to TAG metabolism: lipoprotein lipase and diglyceride acyltransferase. Overfed, obese larvae were used as positive control. The results indicated that BPS-treated and overfed larvae had much higher TAG levels and visceral fat accumulation compared with control. BPS exhibited obesogenic effects by interfering with lipid metabolism as evidenced by (a) upregulation of the mRNA expression of fasn, acc1, and agpat4 genes encoding enzymes involved in the de novo synthesis of TAG in the liver, (b) downregulation of apolipoprotein expression, which should reduce TAG transport from the liver, and (c) increase in rxrα expression, which should promote visceral fat accumulation. Our study is the first to demonstrate that the obesogenic effects of BPS in zebrafish are related to the disruption of TAG metabolism., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bisphenol S (BPS) is widely detected in aquatic environments and in human bodies. BPS has reproductive and thyroid disrupting effects, but its effect on the visual system remains unknown. In the present study, zebrafish embryos were exposed to BPS at concentrations of 1, 10, 100 and 1000 μg l -1 until 120 days post-fertilization in a semistatic system, and the effect of BPS on the visual behavior was examined using the optokinetic response and the optomotor response tests in male zebrafish. The retinal histology, mRNA expression of photoreceptor opsin genes (zfrho, zfblue, zfgr1, zfred and zfuv) and apoptosis-related genes (bax and bcl-2) were also assessed. Long-term BPS exposure decreased the tracking capability of male zebrafish, consistent with structural damage to the retina. BPS induced different amounts of vacuoles in the retinal pigment epithelium, and 1000 μg l -1 BPS exposure decreased the length of the inner plexiform layer, ganglion cell layer and retina, and induced an irregular arrangement of photoreceptor cells. The expression levels of the opsin genes (zfred, zfgr1 and zfrho) were significantly elevated, indicating an enhanced spectral sensitivity to red, green and dim light to compensate for the reduction of the optomotor response. Together, the results showed for the first time that long-term exposure to BPS damaged the structure of male zebrafish retina and reduced their tracking capability., (Copyright © 2017 John Wiley & Sons, Ltd.)

Bisphenol S (BPS) is a substitute of the plastic additive bisphenol A (BPA). Its concentrations detected in surface waters and urine samples are on the same order of magnitude as BPA. Human exposure to BPA has been implicated in the development of diabetes mellitus; however, whether BPS can disrupt glucose homeostasis and increase blood glucose concentration remains unclear. We extensively investigated the effects of environmentally relevant concentrations of BPS on glucose metabolism in male zebrafish (Danio rerio) and the underlying mechanisms of these effects. Male zebrafish were exposed to 1, 10, or 100μg/L of BPS for 28 d. Fasting blood glucose (FBG) levels, glycogen levels in the liver and muscle, and mRNA levels of key glucose metabolic enzymes and the activities of the encoded proteins in tissues were evaluated to assess the effect of BPS on glucose metabolism. Plasma insulin levels and expression of preproinsulin and glucagon genes in the visceral tissue were also evaluated. Compared with the control group, exposure to 1 and 10μg/L of BPS significantly increased FBG levels but decreased insulin levels. Gluconeogenesis and glycogenolysis in the liver were promoted, and glycogen synthesis in the liver and muscle and glycolysis in the muscle were inhibited. Exposure to 100μg/L of BPS did not significantly alter plasma insulin and blood glucose levels, but nonetheless pronouncedly interfered with gluconeogenesis, glycogenolysis, glycolysis, and glycogen synthesis. Our data indicates that BPS at environmentally relevant concentrations impairs glucose homeostasis of male zebrafish possibly by hampering the physiological effect of insulin; higher BPS doses also pronouncedly interfered with glucose metabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The binding affinity of bisphenol A (BPA) to estrogen receptors (ERs) is much lower than that of 17β-estradiol (E 2 ), and whether there are other molecular mechanisms responsible for the estrogenic action of BPA in vivo currently remains unknown. The objective of this study was to explore the potential association between the estrogenic effect induced by bisphenol A in vivo and changes of endogenous E 2 and gene specific DNA methylation levels. After a waterborne exposure of male zebrafish to 500, 1000, or 1500μg/L of BPA for 21d, vitellogenin (VTG) concentration in whole body homogenate, plasma E 2 and testosterone levels, hepatic ERs mRNA expressions, gonadal cyp19a1a and cyp17a1 mRNA expressions, and methylation levels of hepatic esr1 and gonadal cyp19a1a's promoters were determined. Our results indicated that for the 500 and 1500μg/L treatment groups, VTG might be induced mainly by the elevated E 2 levels; increases of E 2 levels could be partly explained by the up-regulated expression of gonadal aromatase, mRNA levels of which were found to be negatively related to the methylation levels of both its promoter and one CpG site. In addition, upon BPA exposure, hepatic esr1 mRNA levels were also negatively related to the methylation levels of both its promoter and one CpG site. These observations provide evidence for the non-ERs mediated mechanisms underlying the estrogenic action of BPA on male zebrafish., (Copyright © 2017 Elsevier Inc. All rights reserved.)