RESUMO
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
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), 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
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), 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
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
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
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
AIM: We reveal the mechanism of action whereby ambient PM2.5 promotes kidney injury. METHODS: Using C57BL/6 mice, the effects of PM2.5 exposure on the acute kidney injury (AKI) were investigated, including renal function changes, expression of inflammatory cytokines, histopathological changes, as well as activation of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3ï¼NLRP3ï¼. The effects of PM2.5 on renal injury after NLRP3 inhibition were explored using NLRP3 inhibitor (MCC950) and NLRP3 knockout mice. The effects of PM2.5 on the inflammatory response of renal macrophages were investigated at the cellular level. RESULTS: PM2.5 exposure could promote kidney injury, NLRP3 activation and inflammatory response in mice. After using MCC950 and NLRP3 knockout mice, the effects of PM2.5 and the kidney injury could be inhibited. The cellular-level results also suggested that MCC950 could inhibit the effects of PM2.5. CONCLUSION: PM2.5 can promote the progression of AKI and aggravate tissue inflammation through NLRP3, which is an important environmental toxicological mechanism of PM2.5.
Assuntos
Injúria Renal Aguda , Inflamação , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Material Particulado , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Material Particulado/toxicidade , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Camundongos , Macrófagos/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Sulfonamidas/toxicidade , Sulfonamidas/farmacologia , Indenos/toxicidade , Poluentes Atmosféricos/toxicidade , Furanos/toxicidade , Sulfonas/toxicidadeRESUMO
The microbial community present in our intestines is pivotal for converting indigestible substances into vital nutrients and signaling molecules such as short-chain fatty acids (SCFAs). These compounds have considerable influence over our immune system and the development of diverse human diseases. However, ingested environmental contaminants, known as xenobiotics, can upset the delicate balance of the microbial gut community and enzymatic processes, consequently affecting the host organism. In our study, we employed an in vitro bioreactor model system based on the simplified human microbiome model (SIHUMIx) to investigate the direct effects of specific xenobiotics, such as perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA) or bisphenol S (BPS) and bisphenol F (BPF), either individually or in combination, on the microbiota. We observed increased SCFA production, particularly acetate and butyrate, with PFAS exposure. Metaproteomics revealed pathway alterations across treatments, including changes in vitamin synthesis and fatty acid metabolism with BPX. This study underscores the necessity of assessing the combined effects of xenobiotics to better safeguard public health. It emphasizes the significance of considering adverse effects on the microbiome in the risk assessment of environmental chemicals.
Assuntos
Compostos Benzidrílicos , Ácidos Graxos Voláteis , Fluorocarbonos , Microbioma Gastrointestinal , Xenobióticos , Humanos , Xenobióticos/toxicidade , Xenobióticos/metabolismo , Fluorocarbonos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Reatores Biológicos , Sulfonas/toxicidade , Poluentes Ambientais/toxicidadeRESUMO
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
Exposure to plastic-derived estrogen-mimicking endocrine-disrupting bisphenols can have a long-lasting effect on bone health. However, gestational exposure to bisphenol A (BPA) and its analogue, bisphenol S (BPS), on offspring's bone mineralization is unclear. The effects of in-utero bisphenol exposure were examined on the offspring's bone parameters. BPA and BPS (0.0, 0.4 µg/kg bw) were administered to pregnant Wistar rats via oral gavage from gestational day 4-21. Maternal exposure to BPA and BPS increased bone mineral content and density in the offspring aged 30 and 90 days (P < 0.05). Plasma analysis revealed that alkaline phosphatase, and Gla-type osteocalcin were significantly elevated in the BPS-exposed offspring (P < 0.05). The expression of BMP1, BMP4, and their signaling mediators SMAD1 mRNAs were decreased in BPS-exposed osteoblast SaOS-2 cells (P < 0.05). The expression of extracellular matrix proteins such as ALPL, COL1A1, DMP1, and FN1 were downregulated (P < 0.05). Bisphenol co-incubation with noggin decreased TGF-ß1 expression, indicating its involvement in bone mineralization. Altered mineralization could be due to dysregulated expression of bone morphogenetic proteins and signalling mediators in the osteoblast cells. Thus, bisphenol exposure during gestation altered growth and bone mineralization in the offspring, possibly by modulating the expression of Smad-dependent BMP/TGF-ß1 signalling mediators.
Assuntos
Compostos Benzidrílicos , Calcificação Fisiológica , Fenóis , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Sulfonas , Animais , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Calcificação Fisiológica/efeitos dos fármacos , Ratos , Sulfonas/toxicidade , Humanos , Proteína Smad1/metabolismo , Proteína Smad1/genética , Fosfatase Alcalina/metabolismo , Fosfatase Alcalina/sangue , Exposição Materna/efeitos adversos , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 4/genética , Osteocalcina/metabolismo , Osteocalcina/genética , Proteína Morfogenética Óssea 1/metabolismo , Proteína Morfogenética Óssea 1/genética , Masculino , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Densidade Óssea/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proteínas de TransporteRESUMO
This study explored the levels, distribution, potential sources, ecological risks and estrogenic activities of 14 bisphenol analogues (BPs) in soil under eight land-use types in the megacity of Chengdu, China. Eleven BPs were detected in the soil samples and the total concentrations ranged from 32.3 to 570 ng/g d.w. Levels of bisphenol BP (BPBP) in the soil (up to 208 ng/g d.w.) only second to the most dominant compound bisphenol A (BPA) were found. Relatively higher Σ14BP accumulation in the soil was observed in the commercial and residential areas (median: 136 ng/g d.w. and 131 ng/g d.w.) compared with agricultural area (median: 67.5 ng/g d.w.). Source identification indicated the role of atmospheric particulate deposition and consecutive anthropogenic activities in BP emission. The ecotoxicity assessment implied that BPA, bisphenol S (BPS), bisphenol F (BPF) and bisphenol PH (BPPH) might pose low to medium risk to the ecosystem due to their extensive use and biological effects. The calculated 17ß-estradiol equivalents of BPs were in the range of 0.501-7.74 pg E2/g d.w, and the estrogenic activities were inferior to those contributed by natural estrogens in the soil.
Assuntos
Compostos Benzidrílicos , Monitoramento Ambiental , Fenóis , Poluentes do Solo , Solo , Fenóis/análise , Poluentes do Solo/análise , China , Compostos Benzidrílicos/análise , Solo/química , Sulfonas/análise , Sulfonas/toxicidade , Agricultura , Medição de Risco , Disruptores Endócrinos/análiseRESUMO
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.
Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Simulação de Acoplamento Molecular , Fenóis , Receptores Androgênicos , Fenóis/toxicidade , Fenóis/química , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Receptores Androgênicos/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/química , Humanos , Simulação por Computador , Sulfonas/toxicidade , Sulfonas/química , Androgênios/químicaRESUMO
Various bisphenols (BPs) have been frequently detected in the aquatic environment and coexist in the form of mixtures with potential huge risks. As we all know, food chain is a media by which BPs mixtures and their mixtures probably enter the organisms at different trophic levels due to their environmental persistence. As a result, the concentrations of BPs and their mixtures may continuously magnify to varying degrees, which can produce higher risks to different levels of organisms, and even human health. However, the related researches about mixtures are few due to the complexity of mixtures. So, the ternary BP mixtures were designed by the uniform design ray method using bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) to investigate their food chain effects including bioconcentration and biomagnification. Here, Chlorella pyrenoidosa (C. pyrenoidosa) and Daphnia magna (D. magna) were selected to construct a food chain. The toxic effects of single BPs and their mixtures were also systematically investigated by the time-dependent microplate toxicity analysis (t-MTA) method. Toxicity interaction within the ternary mixture was analyzed by the concentration addition model (CA) and the deviation from the CA model (dCA). The results show that the C. pyrenoidosa and D. magna had obvious bioconcentration and biomagnification effects on BPs and their mixture. The mixture had the potential to enrich at higher nutrient levels. And BPF had the largest bioconcentration effect (BCF1 = 481.86, BCF2 = 772.02) and biomagnification effect (BMF = 1.6). Three BPs were toxic to C. pyrenoidosa by destroying algal cells and decreasing protein and chlorophyll contents, and their toxicity order was BPF > BPA > BPS. Moreover, their ternary mixture exhibits synergism with time/concentration-dependency. The obtained results are of significant reference value for objectively and accurately assessing the ecological and environmental risks of bisphenol pollutants.
Assuntos
Compostos Benzidrílicos , Daphnia , Cadeia Alimentar , Fenóis , Sulfonas , Poluentes Químicos da Água , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Poluentes Químicos da Água/análise , Animais , Sulfonas/toxicidade , Chlorella/metabolismo , Testes de ToxicidadeRESUMO
Concerns over Bisphenol A (BPA) and its substitute, Bisphenol S (BPS), have led to innovative exploration due to potential adverse health effects. BPS, replacing BPA in some regions to avoid toxic impacts, remains insufficiently studied. Besides this, the organ-on-a-chip technology emerges as a transformative solution in drug discovery and chemiclas toxicity testing, minimizing costs and aligning with ethical standards by reducing reliance on animal models, by integrating diverse tissues and dynamic cell environments enhances precision in predicting organ function. Here, we employ a 3-organ-on-a-chip microfluidic device with skin, intestine, and liver cultures to assess the effects of BPA and BPS via topical and oral administration. Our evaluation focused on gene markers associated with carcinogenicity, systemic toxicity, and endocrine disruption. BPA exhibited expected absorption profiles, causing liver injury and genetic modulation in related pathways. BPS, a safer alternative, induced adverse effects on gene expression, particularly in topical absorption, with distinct absorption patterns. Our findings underscore the urgency of addressing BPA and BPS toxicity concerns, highlighting the crucial role of organ-on-a-chip technology in understanding associated health risks. The study promotes the organ-on-a-chip methodology as a valuable tool for safe drug development and disease treatments, offering a novel liver toxicity screening alternative to traditional animal tests. This contributes to advancing comprehension of the biological effects of these compounds, fostering improved safety assessments in human health.
Assuntos
Compostos Benzidrílicos , Dispositivos Lab-On-A-Chip , Fígado , Fenóis , Pele , Sulfonas , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Sulfonas/toxicidade , Animais , Pele/efeitos dos fármacos , Pele/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Testes de Toxicidade/métodos , Sistemas MicrofisiológicosRESUMO
Bisphenol S (BPS) is an alternative chemical to bisphenol A commonly used in food packaging materials. It raises concerns due to potential adverse effects on human health. However, limited evidence exists regarding reproductive toxicity from BPS exposure, and the mechanism of associated transgenerational toxicity remains unclear. In this study, pregnant SD rats were exposed to two different doses of BPS (0.05 or 20 mg/kg) from GD6 to PND21. The objective was to investigate reproductive and transmissible toxicity induced by BPS, explore endocrine effects, and uncover potential underlying mechanisms in rats. Perinatal exposure to BPS in the F0 generation significantly decreased the rate of body weight, ovarian organ coefficient, and growth and development of the F1 generation. Notably, these changes included abnormal increases in body weight and length, estrous cycle disruption, and embryonic dysplasia in F1. 4D-DIA proteomic and PRM analyses revealed that exposure to 20 mg/kg group significantly altered the expression of proteins, such as Lhcgr and Akr1c3, within the steroid biosynthetic pathway. This led to elevated levels of FSH and LH in the blood. The hypothalamic-pituitary-ovarian (HPO) axis, responsible for promoting fertility through the cyclic secretion of gonadotropins and steroid hormones, was affected. RT-qPCR and Western blot results demonstrated that the expression of GnRH in the hypothalamus was decreased, the GnRHR in the pituitary gland was decreased, and the expression of FSHß and LHß in the pituitary gland was increased. Overall, BPS exposure disrupts the HPO axis, hormone levels, and steroid biosynthesis in the ovaries, affecting offspring development and fertility. This study provides new insights into the potential effects of BPS exposure on the reproductive function of the body and its relevant mechanisms of action.
Assuntos
Disruptores Endócrinos , Fenóis , Ratos Sprague-Dawley , Reprodução , Sulfonas , Animais , Feminino , Fenóis/toxicidade , Ratos , Gravidez , Sulfonas/toxicidade , Reprodução/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Ovário/efeitos dos fármacosRESUMO
Exposure to bisphenol S (BPS) is known to adversely affect neuronal development. As pivotal components of neuronal polarization, axons and dendrites are indispensable structures within neurons, crucial for the maintenance of nervous system function. Here, we investigated the impact of BPS exposure on axonal and dendritic development both in vivo and in vitro. Our results revealed that exposure to BPS during pregnancy and lactation led to a reduction in the complexity, density, and length of axons and dendrites in the prefrontal cortex (PFC) of offspring. Employing RNA sequencing technology to elucidate the underlying mechanisms of axonal and dendritic damage induced by BPS, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted a significant alteration in the oxidative phosphorylation (OXPHOS) pathway, essential for mitochondrial function. Subsequent experiments demonstrate BPS-induced impairment in mitochondrial function, including damaged morphology, decreased adenosine triphosphate (ATP) and superoxide dismutase (SOD) levels, and increased reactive oxygen species and malondialdehyde (MDA). These alterations coincided with the downregulated expression of OXPHOS pathway-related genes (ATP6V1B1, ATP5K, NDUFC1, NDUFC2, NDUFA3, COX6B1) and Myosin 19 (Myo19). Notably, Myo19 overexpression restored the BPS-induced mitochondrial dysfunction by alleviating the inhibition of OXPHOS pathway. Consequently, this amelioration was associated with a reduction in BPS-induced axonal and dendritic injury observed in cultured neurons of the PFC.