RESUMO
Endocrine disrupting chemicals (EDCs) such as bisphenol S (BPS) are xenobiotic compounds that can disrupt endocrine signaling due to steric similarities to endogenous hormones. EDCs have been shown to induce disruptions in normal epigenetic programming (epimutations) and differentially expressed genes (DEGs) that predispose disease states. Most interestingly, the prevalence of epimutations following exposure to many EDCs persists over multiple generations. Many studies have described direct and prolonged effects of EDC exposure in animal models, but many questions remain about molecular mechanisms by which EDC-induced epimutations are introduced or subsequently propagated, whether there are cell type-specific susceptibilities to the same EDC, and whether this correlates with differential expression of relevant hormone receptors. We exposed cultured pluripotent (iPS), somatic (Sertoli and granulosa), and primordial germ cell-like (PGCLC) cells to BPS and found that differential incidences of BPS-induced epimutations and DEGs correlated with differential expression of relevant hormone receptors inducing epimutations near relevant hormone response elements in somatic and pluripotent, but not germ cell types. Most interestingly, we found that when iPS cells were exposed to BPS and then induced to differentiate into PGCLCs, the prevalence of epimutations and DEGs was largely retained, however, >90% of the specific epimutations and DEGs were replaced by novel epimutations and DEGs. These results suggest a unique mechanism by which an EDC-induced epimutated state may be propagated transgenerationally.
Assuntos
Disruptores Endócrinos , Fenóis , Disruptores Endócrinos/toxicidade , Animais , Fenóis/toxicidade , Camundongos , Epigênese Genética/efeitos dos fármacos , Sulfonas/efeitos adversos , Sulfonas/toxicidade , Mutação , Masculino , FemininoRESUMO
BACKGROUND: A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring. OBJECTIVES: Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP. METHODS: Pregnant ICR mice were exposed to 5µg/kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids. RESULTS: Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22±0.25 ng/g and 0.69±0.27 ng/g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo, chromatin immunoprecipitation analysis revealed that the binding of ERα protein to key genes such as Hmgcr, Pcsk9, and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro, the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr, Ldlr, and Cyp7a1, to levels comparable to the controls was only achieved when treated with a combination of ERα agonist and ERß agonist. DISCUSSION: Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ERα played a crucial role both in vivo and in vitro. Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations. https://doi.org/10.1289/EHP14643.
Assuntos
Colesterol , Fígado , Camundongos Endogâmicos ICR , Fenóis , Animais , Feminino , Masculino , Camundongos , Colesterol/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Gravidez , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Sulfonas/toxicidade , Exposição MaternaRESUMO
Bisphenol S (BPS) is widely used in plastic products, food packaging, electronic products, and other applications. In recent years, BPS emissions have increasingly impacted aquatic ecosystems. The effects of BPS exposure on aquatic animal health have been documented; however, our understanding of its toxicology remains limited. This study aimed to explore the mechanisms of lipid metabolism disorders, oxidative stress, and autophagy dysfunction induced in freshwater crayfish (Procambarus clarkii) by exposure to different concentrations of BPS (0 µg/L, 1 µg/L, 10 µg/L, and 100 µg/L) over 14 d. The results indicated that BPS exposure led to oxidative stress by inducing elevated levels of reactive oxygen species (ROS) and inhibiting the activity of antioxidant-related enzymes. Additionally, BPS exposure led to increased lipid content in the serum and hepatopancreas, which was associated with elevated lipid-related enzyme activity and increased expression of related genes. Furthermore, BPS exposure decreased levels of phosphatidylcholine (PC) and phosphatidylinositol (PI), disrupted glycerophospholipid (GPI) metabolism, and caused lipid deposition in the hepatopancreatic. These phenomena may have occurred because BPS exposure reduced the transport of fatty acids and led to hepatopancreatic lipid deposition by inhibiting the transport and synthesis of PC and PI in the hepatopancreas, thereby inhibiting the PI3K-AMPK pathway. In conclusion, BPS exposure induced oxidative stress, promoted lipid accumulation, and led to autophagy dysfunction in the hepatopancreas of freshwater crayfish. Collectively, our findings provide the first evidence that environmentally relevant levels of BPS exposure can induce hepatopancreatic lipid deposition through multiple pathways, raising concerns about the potential population-level harm of BPS and other bisphenol analogues.
Assuntos
Astacoidea , Autofagia , Metabolismo dos Lipídeos , Estresse Oxidativo , Fenóis , Sulfonas , Poluentes Químicos da Água , Animais , Astacoidea/efeitos dos fármacos , Astacoidea/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Hepatopâncreas/patologiaRESUMO
Thyroid hormones play a crucial role in numerous physiological processes, including reproduction. Bisphenol S (BPS) is a structural analog of Bisphenol A known for its toxic effects. Interference of this substitute with normal thyroid function has been described. To investigate the effect of thyroid disruption on ovarian development following maternal exposure to BPS, female rats were exposed, daily, to either AT 1-850 (a thyroid hormone receptor antagonist) (10 nmol/rat) or BPS (0.2 mg/kg) during gestation and lactation. The effects on reproductive outcome, offspring development, histological structures, hormone levels, oxidative status, cytoskeleton proteins expression, and oocyte development gene expression were examined. Our results are in favor of offspring ovarian development disruption due to thyroid disturbance in adult pregnant females. During both fetal and postnatal stages, BPS considerably altered the histological structure of the thyroid tissue as well as oocyte and follicular development, which led to premature ovarian failure and stimulation of oocyte atresia, being accompanied with oxidative stress, hypothalamic-pituitary-ovarian axis disorders, and cytoskeletal dynamic disturbance. Crucially, our study underscores that BPS may induce reproductive toxicity by blocking nuclear thyroid hormone receptors, evidenced by the parallelism and the perfect meshing between the data obtained following exposure to AT 1-850 and those after the treatment by this substitute.
Assuntos
Exposição Materna , Ovário , Fenóis , Sulfonas , Glândula Tireoide , Feminino , Animais , Fenóis/toxicidade , Sulfonas/toxicidade , Ratos , Ovário/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , GravidezRESUMO
In this presented study, the aim was to investigate the toxic effects of bisphenol S (BPS), one of the bisphenol A analogues, on the thyroid glands of male Wistar albino rats. Toward this aim, the rats (n = 28) were given a vehicle (control) or BPS at 3 different doses, comprising 20, 100, and 500 mg/kg of body weight (bw) via oral gavage for 28 days. According to the results, BPS led to numerous histopathological changes in the thyroid tissue. The average proliferation index values among the thyroid follicular cells (TFCs) displayed increases in all of the BPS groups, and significant differences were observed in the BPS-20 and BPS-100 groups. The average apoptotic index values in the TFCs were increased significantly in the BPS-500 group. The serum thyroid-stimulating hormone and serum free thyroxine levels did not show significant changes after exposure to BPS; however, the serum free triiodothyronine levels displayed significant decreases in all 3 of the BPS groups. BPS was determined to cause significant increases in the antioxidant enzyme activities of catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, as well as a significantly decreased content of reduced glutathione. The malondialdehyde level in the thyroid tissue was elevated significantly in the BPS-500 group. The data obtained herein revealed that BPS has thyroid-disrupting potential based on structural changes, follicle cell responses, and biochemical alterations including a decreased serum free triiodothyronine level and increased oxidative stress.
Assuntos
Apoptose , Proliferação de Células , Fenóis , Ratos Wistar , Sulfonas , Glândula Tireoide , Animais , Masculino , Fenóis/toxicidade , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Ratos , Sulfonas/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Tri-Iodotironina/sangue , Tiroxina/sangue , Tireotropina/sangue , Superóxido Dismutase/metabolismoRESUMO
Bisphenol S (BPS) is extensively utilized in various industries such as plastic manufacturing, food packaging, and electronics. The release of BPS into aquatic environments has been observed to have negative impacts on aquatic ecosystems. Research has shown that exposure to BPS can have adverse effects on the health of aquatic animals. This study aimed to explore the mechanism of oxidative stress and endoplasmic reticulum stress induced in freshwater crayfish (Procambarus clarkii) by exposure to BPS (0 µg/L, 1 µg/L, 10 µg/L, and 100 µg/L) for 14 days. The results showed that BPS exposure resulted in elevated levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and severe intestinal histological damage. In addition, oxidative stress can occur in the body by inhibiting the activity of antioxidant enzymes and the expression of related genes. BPS exposure induced a significant increase in the relative mRNA expression levels of inflammatory cytokines (NF-κB and TNF-α) and key unfolded protein response (UPR) related genes (Bip, Ire1, and Xbp1). At the same time, BPS exposure also induced up-regulation of apoptosis genes (Cytc and Casp3), suggesting that UPR and Nrf2-Keap1 signaling pathways may play a protective role in the process of apoptosis and oxidative stress. In conclusion, Our findings present the initial evidence that exposure to environmentally relevant levels of BPS can lead to intestinal injury through various pathways, highlighting concerns about the potential harm at a population level from BPS and other bisphenol analogs.
Assuntos
Astacoidea , Intestinos , Estresse Oxidativo , Fenóis , Sulfonas , Poluentes Químicos da Água , Animais , Astacoidea/efeitos dos fármacos , Astacoidea/genética , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Sulfonas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Malondialdeído/metabolismo , Apoptose/efeitos dos fármacosRESUMO
Recently, there has been increasing concern regarding the emergence of bisphenol S analogues (BPSs) due to their potential toxicity. However, their exposure levels and associated health risks in susceptible populations remain unknown. In our study, we analyzed bisphenol A (BPA), along with 11 common BPA analogues (BPAs), and nine emerging BPSs in urine samples collected from 381 pregnant women in South China. All nine BPSs were first detected in pregnant women's urine. In addition to BPA, two BPAs, three BPSs including Diphenylsulfone (DPS), Bis(phenylsulfonyl)phenol (DBSP) and Bis(3-allyl-4-hydroxyphenyl)sulfone (TGSA), were identified as the predominant bisphenols, with detection frequencies ranging from 53-100 %. BPA still exhibited the highest median concentration at 0.624 ng/mL, followed by DPS (0.169 ng/mL), BPS (0.063 ng/mL) and DBSP (0.023 ng/mL). Importantly, mothers with higher levels of BPA, DBSP, DPS, and TGSA in their urine are statistically more likely to give birth to premature infants with shorter lengths at birth or smaller head circumference (p < 0.05). Although the median exposure to 21 bisphenols did not exceed the tolerable daily intake (TDI) of BPA, it did surpass the recently proposed BPA TDI (0.2 ng/kg bw/day) by a factor ranging from 1.1-99 times. This study signifies the first report unveiling the prevalence of multiple bisphenols, particularly emerging BPSs, in the urine of pregnant women in South China.
Assuntos
Fenóis , Sulfonas , Humanos , Feminino , Fenóis/urina , Fenóis/toxicidade , Gravidez , Sulfonas/toxicidade , China , Adulto , Adulto Jovem , Compostos Benzidrílicos/urina , Exposição Materna/efeitos adversos , Poluentes Ambientais/urina , Poluentes Ambientais/toxicidadeRESUMO
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.
Assuntos
Trifosfato de Adenosina , Encéfalo , Transportador de Glucose Tipo 1 , Fenóis , Peixe-Zebra , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Trifosfato de Adenosina/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Fenóis/toxicidade , Sulfonas/toxicidadeRESUMO
Bisphenol S (BPS), an alternative to bisphenol A (BPA), exerts proliferative effects similar to those of BPA. BPS is a representative endocrine disruptor associated with cancer progression. However, the mechanisms underlying BPS-induced glioblastoma progression are not fully understood. To investigate the effects of BPS on glioblastoma, U-87 MG cancer cell lines were exposed to BPS. The study focused on analyzing the proliferation and migration of U-87 MG cells. Furthermore, the involvement of the enhancer of the zeste homolog 2 (EZH2)-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) pathway was examined. Pharmacological approaches were employed to inhibit EZH2 activity and observe its effects on BPS-induced changes. The results indicated that BPS promoted the proliferation and migration of U-87 MG cells at a concentration of 0.1⯵M. These changes appeared to be linked to the activation of the EZH2-mediated PI3K/AKT/mTOR pathway. Moreover, inhibiting EZH2 activity using pharmacological approaches restored the BPS-mediated induction of proliferation and migration. In conclusion, the results of this study indicated that BPS induces glioblastoma progression through EZH2 upregulation. Therefore, targeting the EZH2-mediated PI3K/AKT/mTOR pathway could be considered a potential therapeutic strategy for the treatment of glioblastoma.
Assuntos
Movimento Celular , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste , Glioblastoma , Fenóis , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Sulfonas , Serina-Treonina Quinases TOR , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/tratamento farmacológico , Fenóis/toxicidade , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Sulfonas/farmacologia , Sulfonas/toxicidade , Progressão da Doença , Disruptores Endócrinos/toxicidade , Fosfatidilinositol 3-Quinase/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
Tire wear particles (TWPs) are considered an important component of microplastic pollution in the marine environment and occur together with a variety of aquatic pollutants, including frequently detected bisphenols. The adverse effects of TWPs or bisphenols on aquatic organisms have been widely reported. However, the combined toxicity of TWPs and bisphenols is still unknown. In this study, the combined toxicity of both pristine (p-) and aged TWPs (a-TWPs) and four bisphenols ((bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF)) to Tigriopus japonicus was evaluated. TWPs increased the toxicity of BPA and BPF but decreased the toxicity of BPAF. For BPS, there was synergistic toxic effect in the presence of p-TWPs, but slightly antagonistic effect was observed in the presence of a-TWPs. This adsorption of BPAF by TWPs resulted in a reduction of its toxicity to the copepod. A-TWPs could release more Zn than p-TWPs, and the released Zn contributed to the synergistic effect of TWPs and BPA or BPF. The aggregation formed by TWPs in certain sizes (e.g., 90-110 µm) could cause intestinal damage and lipid peroxidation in T. japonicus. The synergistic effect of p-TWPs and BPS might be due to the aggregation size of the binary mixture. The results of the current study will be important to understand the combined toxic effect of TWPs and bisphenols and the potential toxic mechanisms of the binary mixture.
Assuntos
Compostos Benzidrílicos , Copépodes , Fenóis , Poluentes Químicos da Água , Fenóis/toxicidade , Animais , Compostos Benzidrílicos/toxicidade , Poluentes Químicos da Água/toxicidade , Copépodes/efeitos dos fármacos , Microplásticos/toxicidade , Borracha/toxicidade , Borracha/química , Sulfonas/toxicidadeRESUMO
Bisphenol A (BPA) has been a substantial additive in plastics until the reports on its adverse effects have led to its restrictions and replacement. Monitoring studies document the increasing occurrence of bisphenol analogs, however, data on their effects and risks is still insufficient. Based on the indications that BPA might contribute to ovarian cancer pathogenesis, we examined effects of the analogs AF (BPAF), S (BPS) and F (BPF) (10-9-10-4 M) on the Caov-3 epithelial cancer cells, including the impact on cell viability, proliferation, oxidative stress, and production and expression of several factors and genes related to ovarian cancer. At environmentally relevant doses, bisphenols did not exert significant effects. At the highest concentration, BPAF caused varied alterations, including decreased cell viability and proliferation, caspase activation, down-regulation of PCNA and BIRC5, elevation of IL8, VEGFA, MYC, PTGS2 and ABCB1 expressions. Only BPA (10-4 M) increased IL-6, IL-8 and VEGFA output by the Caov-3 cells. Each bisphenol induced generation of reactive oxygen species and decreased superoxide dismutase activity at the highest concentration. Although the effects were observed only in the supraphysiological doses, the results indicate that certain bisphenol analogs might affect several ovarian cancer cell characteristics and merit further investigation.
Assuntos
Compostos Benzidrílicos , Proliferação de Células , Sobrevivência Celular , Neoplasias Ovarianas , Fenóis , Humanos , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Feminino , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sulfonas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Survivina/genética , Survivina/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , FluorocarbonosRESUMO
Bisphenols are dangerous endocrine disruptors that pollute the environment. Due to their chemical properties, they are globally used to produce plastics. Structural similarities to oestrogen allow bisphenols to bind to oestrogen receptors and affect internal body systems. Most commonly used in the plastic industry is bisphenol A (BPA), which also has negative effects on the nervous, immune, endocrine, and cardiovascular systems. A popular analogue of BPA-bisphenol S (BPS) also seems to have harmful effects similar to BPA on living organisms. Therefore, with the use of double immunofluorescence labelling, this study aimed to compare the effect of BPA and BPS on the enteric nervous system (ENS) in mouse jejunum. The study showed that both studied toxins impact the number of nerve cells immunoreactive to substance P (SP), galanin (GAL), vasoactive intestinal polypeptide (VIP), the neuronal isoform of nitric oxide synthase (nNOS), and vesicular acetylcholine transporter (VAChT). The observed changes were similar in the case of both tested bisphenols. However, the influence of BPA showed stronger changes in neurochemical coding. The results also showed that long-term exposure to BPS significantly affects the ENS.
Assuntos
Compostos Benzidrílicos , Sistema Nervoso Entérico , Jejuno , Fenóis , Sulfonas , Animais , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Camundongos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Sulfonas/farmacologia , Sulfonas/toxicidade , Substância P/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Masculino , Galanina/metabolismo , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismoRESUMO
Bisphenol A (BPA) is a well-documented endocrine-disrupting chemical widely used in plastic products. In addition to its endocrine-disrupting effects, BPA exhibits immunotoxicity. Many countries have banned BPA because of its adverse effects on human health. In recent years, many chemicals such as bisphenol B (BPB), bisphenol E (BPE), bisphenol S (BPS), and bisphenol fluorene (BHPF) have been used to replace BPA. Because these replacement chemicals have chemical structures similar to that of BPA, they may also harm human health. However, their immunotoxicity and the molecular mechanisms underlying their toxicity remain largely unknown. The aim of this study was to investigate the immunotoxicity of BPA and its replacement chemicals, as well as the underlying mechanisms by exposing primary human lymphocytes to BPA and its replacement chemicals. Our results showed that exposure to BPA and its replacement chemicals altered the interleukin (IL) and cytokine production, such as IL-1b, IL-5, IL-6, IL-8, interferon alfa-2b (IFN-a2B), and tumor necrosis factor alpha (TNF-α), in the lymphocytes. Among these, BPA and BHPF caused a greater inhibition. Using comparative transcriptomic analysis, we further investigated the biological processes and signaling pathways altered by BHPF exposure. Our data highlighted alterations in the immune response, T cell function, and cytokine-cytokine receptor interactions in human lymphocytes through the deregulation of gene clusters. In addition, the results of ingenuity pathway analysis demonstrated the inhibition of T lymphocyte function, including differentiation, movement, and infiltration. Our results, for the first time, delineate the mechanisms underlying the immunotoxicity of BHPF in human lymphocytes.
Assuntos
Compostos Benzidrílicos , Linfócitos , Fenóis , Sulfonas , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Fenóis/toxicidade , Sulfonas/toxicidade , Compostos Benzidrílicos/toxicidade , Citocinas/metabolismo , Células Cultivadas , Disruptores Endócrinos/toxicidadeRESUMO
Bisphenol S (BPS) and Bisphenol F (BPF), the analogues of the legacy endocrine disrupting chemical, Bisphenol A (BPA) are ubiquitous in the environment and present in various consumer goods, and potentially neurotoxic. Here, we studied sex-specific responses of bisphenols on behavioural phenotypes, including their association with pro-inflammatory biomarkers and altered neurotransmitters levels, and the key gut microbial abundances. Neurobehavioural changes, using standard test battery, biochemical and molecular estimations for inflammatory cytokines, neurotransmitters, and oxido-nitrosative stress markers, gene expression analysis using qRT-PCR, H&E based histological investigations, gut permeability assays and Oxford Nanopore-based 16S-rRNA metagenomics sequencing for the gut microbial abundance estimations were performed. Bisphenol(s) exposure induces anxiety and depression-like behaviours, particularly in the male mice, with heightened pro-inflammatory cytokines levels and systemic endotoxemia, altered monoamine neurotransmitters levels/turnovers and hippocampal neuronal degeneration and inflammatory responses in the brain. They also increased gut permeability and altered microbial diversity, particularly in males. Present study provides evidence for sex-specific discrepancies in neurobehavioural phenotypes and gut microbiota, which necessitate a nuanced understanding of sex-dependent responses to bisphenols. The study contributes to ongoing discussions on the multifaceted implications of bisphenols exposure and underscores the need for tailored regulatory measures to mitigate potential health risks associated with them.
Assuntos
Comportamento Animal , Compostos Benzidrílicos , Disruptores Endócrinos , Microbioma Gastrointestinal , Fenóis , Caracteres Sexuais , Sulfonas , Animais , Fenóis/toxicidade , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Feminino , Compostos Benzidrílicos/toxicidade , Sulfonas/toxicidade , Disruptores Endócrinos/toxicidade , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Fenótipo , Camundongos , Camundongos Endogâmicos C57BL , Ansiedade/induzido quimicamente , Depressão/induzido quimicamente , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Neurotransmissores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Bisphenol S (BPS), a substitute for bisphenol A, is widely used in the manufacture of food packaging materials, raising concern over its toxicity. However, evidence is still lacking on whether gut microbiota involved in BPS induced intestinal inflammation in mammals, as well as its underlying mechanism. Using mouse BPS exposure model, we found intestinal inflammation characterized by shortened colon length, crypt distortion, macrophage accumulation and increased apoptosis. As for gut microbiota, 16s rRNA gene amplicon sequencing showed BPS exposure induced gut dysbiosis, including increased pro-inflammatory microbes such as Ileibacterium, and decreased anti-inflammatory genera such as Lactobacillus, Blautia and Romboutsia. Besides, LC-MS/MS-based untargeted metabolomic analysis indicated BPS impaired both bacteria and host metabolism. Additionally, transcriptome analysis of the intestine revealed abnormal gene expression in intestinal mucosal barrier and inflammation. More importantly, treating mice with antibiotics significantly attenuated BPS-induced gut inflammation via the regulation of both bacterial and host metabolites, indicating the role of gut microbiota. Collectively, BPS exposure induces intestinal inflammation via altering gut microbiota in mouse. This study provides the possibility of madecassic acid, an anti-inflammatory metabolite, to prevent BPS-induced intestinal inflammation and also new insights in understanding host-microbiota interaction in BPS toxicity.
Assuntos
Microbioma Gastrointestinal , Fenóis , Sulfonas , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Fenóis/toxicidade , Camundongos , Sulfonas/toxicidade , Inflamação/induzido quimicamente , Camundongos Endogâmicos C57BL , Masculino , Bactérias/efeitos dos fármacos , Bactérias/classificação , Disbiose/induzido quimicamente , Disbiose/microbiologia , RNA Ribossômico 16S/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismoRESUMO
The thyroid disrupting chemicals (TDCs) have raised great concerns due to their adverse impacts on thyroid hormones (THs). In this study, we investigated the thyroid-disrupting effects of bisphenol F (BPF) and bisphenol S (BPS), two major BPA substitutes, on adult zebrafish (Danio rerio). Firstly, anti-transthyretin (TTR) monoclonal antibody (anti-TTR mAb) was prepared and used to establish an indirect ELISA, which had a working range of 15.6â¼1000 ng/mL of a detection limit of 6.1 ng/mL. The immunoassays based on anti-TTR mAb showed that exposure to BPF (10 and 100 µg/L) and BPS (100 µg/L) significantly elevated the levels of TTR protein in the plasma, liver, and brain tissues. Moreover, immunofluorescence showed that 100 µg/L BPF and BPS induced the production of TTR protein in liver and brain tissues. In addition, BPF and BPS increased THs levels and damaged thyroid tissue structure in adult female zebrafish. Especially, 100 µg/L BPF significantly increased T4 and T3 levels by 2.05 and 1.14 times, and induced pathological changes of thyroid follicles. The changes in the expression levels of genes involved in the hypothalamus-pituitary-thyroid (HPT) axis further illustrated that BPF and BPS had significant adverse effects on THs homeostasis and thyroid function in zebrafish. Therefore, TTR immunoassays could be used for the evaluation of thyroid-disrupting effects in fish and BPF exhibited greater disruption than BPS.
Assuntos
Anticorpos Monoclonais , Compostos Benzidrílicos , Disruptores Endócrinos , Fenóis , Sulfonas , Glândula Tireoide , Poluentes Químicos da Água , Peixe-Zebra , Animais , Fenóis/toxicidade , Sulfonas/toxicidade , Glândula Tireoide/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Disruptores Endócrinos/toxicidade , Compostos Benzidrílicos/toxicidade , Anticorpos Monoclonais/toxicidade , Feminino , Fígado/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Hormônios Tireóideos/sangue , ImunoensaioRESUMO
OBJECTIVE: To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERß-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level. METHODS: Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 ß-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 µmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERß and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERß-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits. RESULTS: Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P<0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P<0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P<0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P<0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit. CONCLUSION: Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERß-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.
Assuntos
Células Epiteliais , Receptor beta de Estrogênio , Sistema de Sinalização das MAP Quinases , Ovário , Fenóis , Sulfonas , Humanos , Fenóis/toxicidade , Feminino , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Sulfonas/toxicidade , Linhagem CelularRESUMO
Since the run off of microplastic and plastic additives into the aquatic environment through the disposal of plastic products, we investigated the adverse effects of co-exposure to microplastics and plastic additives on zebrafish embryonic development. To elucidate the combined effects between microplastic mixtures composed of microplastics and plastic additives in zebrafish embryonic development, polystyrene (PS), bisphenol S (BPS), and mono-(2-ethylhexyl) phthalate (MEHP) were chosen as a target contaminant. Based on non-toxic concentration of each contaminant in zebrafish embryos, microplastic mixtures which is consisted of binary and ternary mixed forms were prepared. A strong phenotypic toxicity to zebrafish embryos was observed in the mixtures composed with non-toxic concentration of each contaminant. In particular, the mixture combination with ≤ EC10 values for BPS and MEHP showed a with a strong synergistic effect. Based on phenotypic toxicity to zebrafish embryos, change of transcription levels for target genes related to cell damage and thyroid hormone synthesis were analyzed in the ternary mixtures with low concentrations that were observed non-toxicity. Compared with the control group, cell damage genes linked to the oxidative stress response and thyroid hormone transcription factors were remarkably down-regulated in the ternary mixture-exposed groups, whereas the transcriptional levels of cyp1a1 and p53 were significantly up-regulated in the ternary mixture-exposed groups (P < 0.05). These results demonstrate that even at low concentrations, exposure to microplastic mixtures can cause embryonic damage and developmental malformations in zebrafish, depending on the mixed concentration-combination. Consequently, our findings will provide data to examine the action mode of zebrafish developmental toxicity caused by microplastic mixtures exposure composed with microplastics and plastic additives.
Assuntos
Dietilexilftalato , Embrião não Mamífero , Desenvolvimento Embrionário , Microplásticos , Fenóis , Plásticos , Poluentes Químicos da Água , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Poluentes Químicos da Água/toxicidade , Microplásticos/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Dietilexilftalato/toxicidade , Dietilexilftalato/análogos & derivados , Fenóis/toxicidade , Plásticos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Sulfonas/toxicidade , Poliestirenos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacosRESUMO
Bisphenol A (BPA) is an endocrine disruptor strongly associated with ovarian dysfunction. BPA is being substituted by structurally similar chemicals, such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). However, the toxicity of these analogues in female reproduction remains largely unknown. This study evaluated the effects of BPA and its analogues BPS, BPF, and BPAF on the mitochondrial mass and function, oxidative stress, and their potential to induce apoptosis of human granulosa cells (KGN cells). BPA and its analogues, especially BPA and BPAF, significantly decreased mitochondrial activity and cell viability. The potential of bisphenols to reduce mitochondrial mass and function differed in the following order: BPAF > BPA > BPF > BPS. Flow cytometry revealed that exposure to bisphenols significantly increased mitochondrial ROS levels and increased mitochondrial Ca2+ levels. Thus, bisphenols exposure causes mitochondrial stress in KGN cells. At the same time, bisphenols exposure significantly induced apoptosis. These results thus emphasize the toxicity of these bisphenols to cells. Our study suggests the action mechanism of BPA and its analogues in damage caused to ovarian granulosa cells. Additionally, these novel analogues may be regrettable substitutes, and the biological effects and potential risks of BPA alternatives must be evaluated.
Assuntos
Apoptose , Compostos Benzidrílicos , Células da Granulosa , Mitocôndrias , Fenóis , Espécies Reativas de Oxigênio , Humanos , Fenóis/toxicidade , Fenóis/química , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Feminino , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/química , Sulfonas/toxicidade , Sulfonas/química , Linhagem Celular , Cálcio/metabolismo , FluorocarbonosRESUMO
Interactions between endocrine-disruptor chemicals (EDCs) and androgen receptor (AR) have adverse effects on the endocrine system, leading to human reproductive dysfunction. Bisphenol A (BPA) is an EDC that can damage both the environment and human health. Although numerous BPA analogues have been produced as substitutes for BPA, few studies have evaluated their endocrine-disrupting abilities. We assessed the (anti)-androgenic activities of BPA and its analogues using a yeast-based reporter assay. The BPA analogues tested were bisphenol S (BPS), 4-phenylphenol (4PP), 4,4'-(9-fluorenyliden)-diphenol (BPFL), tetramethyl bisphenol F (TMBPF), and tetramethyl bisphenol A (TMBPA). We also conducted molecular docking and dynamics simulations to assess the interactions of BPA and its analogues with the ligand-binding domain of human AR (AR-LBD). Neither BPA nor its analogues had androgenic activity; however, all except BPFL exerted robust anti-androgenic effects. Consistent with the in vitro results, anti-androgenic analogues of BPA formed hydrogen bonding patterns with key residues that differed from the patterns of endogenous hormones, indicating that the analogues display in inappropriate orientations when interacting with the binding pocket of AR-LBD. Our findings indicate that BPA and its analogues disrupt androgen signaling by interacting with the AR-LBD. Overall, BPA and its analogues display endocrine-disrupting activity, which is mediated by AR.