RESUMO
Bisphenol A (BPA) is an industrial pollutant that can cause immune impairment. Selenium acts as an antioxidant, as selenium deficiency often accompanies oxidative stress, resulting in organ damage. This study is the first to demonstrate that BPA and/or selenium deficiency induce pyroptosis and ferroptosis-mediated thymic injury in chicken and chicken lymphoma cell (MDCC-MSB-1) via oxidative stress-induced endoplasmic reticulum (ER) stress. We established a broiler chicken model of BPA and/or selenium deficiency exposure and collected thymus samples as research subjects after 42 days. The results demonstrated that BPA or selenium deficiency led to a decrease in antioxidant enzyme activities (T-AOC, CAT, and GSH-Px), accumulation of peroxides (H2O2 and MDA), significant upregulation of ER stress-related markers (GRP78, IER 1, PERK, EIF-2α, ATF4, and CHOP), a significant increase in iron ion levels, significant upregulation of pyroptosis-related gene (NLRP3, ASC, Caspase1, GSDMD, IL-18 and IL-1ß), significantly increase ferroptosis-related genes (TFRC, COX2) and downregulate GPX4, HO-1, FTH, NADPH. In vitro experiments conducted in MDCC-MSB-1 cells confirmed the results, demonstrating that the addition of antioxidant (NAC), ER stress inhibitor (TUDCA) and pyroptosis inhibitor (Vx765) alleviated oxidative stress, endoplasmic reticulum stress, pyroptosis, and ferroptosis. Overall, this study concludes that the combined effects of oxidative stress and ER stress mediate pyroptosis and ferroptosis in chicken thymus induced by BPA exposure and selenium deficiency.
Assuntos
Compostos Benzidrílicos , Galinhas , Estresse do Retículo Endoplasmático , Ferroptose , Fenóis , Piroptose , Espécies Reativas de Oxigênio , Selênio , Animais , Compostos Benzidrílicos/toxicidade , Ferroptose/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Selênio/deficiência , Fenóis/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Timo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Bisphenol compounds (BPs) have various industrial uses and can enter the environment through various sources. To evaluate the ecotoxicity of BPs and identify potential gene candidates involved in the plant toxicity, Arabidopsis thaliana was exposed to bisphenol A (BPA), BPB, BPE, BPF, and BPS at 1, 3, 10 mg/L for a duration of 14 days, and their growth status were monitored. At day 14, roots and leaves were collected for internal BPs exposure concentration detection, RNA-seq (only roots), and morphological observations. As shown in the results, exposure to BPs significantly disturbed root elongation, exhibiting a trend of stimulation at low concentration and inhibition at high concentration. Additionally, BPs exhibited pronounced generation of reactive oxygen species, while none of the pollutants caused significant changes in root morphology. Internal exposure concentration analysis indicated that BPs tended to accumulate in the roots, with BPS exhibiting the highest level of accumulation. The results of RNA-seq indicated that the shared 211 differently expressed genes (DEGs) of these 5 exposure groups were enriched in defense response, generation of precursor metabolites, response to organic substance, response to oxygen-containing, response to hormone, oxidation-reduction process and so on. Regarding unique DEGs in each group, BPS was mainly associated with the redox pathway, BPB primarily influenced seed germination, and BPA, BPE and BPF were primarily involved in metabolic signaling pathways. Our results provide new insights for BPs induced adverse effects on Arabidopsis thaliana and suggest that the ecological risks associated with BPA alternatives cannot be ignored.
Assuntos
Arabidopsis , Compostos Benzidrílicos , Oxirredução , Fenóis , Raízes de Plantas , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , RNA-Seq , Análise de Sequência de RNA , Poluentes do Solo/toxicidadeRESUMO
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: Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, with its pathogenesis and progression influenced by myriad factors. Among them, the pervasive organic synthetic compound, bisphenol A (BPA), previously linked with various adverse health effects, has been speculated to play a role. This study endeavors to elucidate the complex interplay between BPA, the immune microenvironment of HCC, and the broader molecular landscape of this malignancy. METHODS: A comprehensive analysis was undertaken using data procured from both The Cancer Genome Atlas and the Comparative Toxicogenomics Database. Rigorous differential expression analyses were executed, supplemented by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. In addition, single-sample gene set enrichment analysis, gene set enrichment analysis and gene set variation analysis were employed to reveal potential molecular links and insights. Immune infiltration patterns were delineated, and a series of in vitro experiments on HCC cells were conducted to directly assess the impact of BPA exposure. RESULTS: Our findings unveiled a diverse array of active immune cells and functions within HCC. Distinct correlations emerged between high-immune-related scores, established markers of the tumor microenvironment and the expression of immune checkpoint genes. A significant discovery was the identification of key genes simultaneously associated with immune-related pathways and BPA exposure. Leveraging these genes, a prognostic model was crafted, offering predictive insights into HCC patient outcomes. Intriguingly, in vitro studies suggested that BPA exposure could promote proliferation in HCC cells. CONCLUSION: This research underscores the multifaceted nature of HCC's immune microenvironment and sheds light on BPA's potential modulatory effects therein. The constructed prognostic model, if validated further, could serve as a robust tool for risk stratification in HCC, potentially guiding therapeutic strategies. Furthermore, the implications of the findings for immunotherapy are profound, suggesting new avenues for enhancing treatment efficacy. As the battle against HCC continues, understanding of environmental modulators like BPA becomes increasingly pivotal.
Assuntos
Compostos Benzidrílicos , Carcinoma Hepatocelular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Fenóis , Microambiente Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Compostos Benzidrílicos/efeitos adversos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Fenóis/efeitos adversos , Fenóis/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genéticaRESUMO
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
Our capability to predict the impact of exposure to chemical mixtures on environmental and human health is limited in comparison to the advances on the chemical characterization of the exposome. Current approaches, such as new approach methodologies, rely on the characterization of the chemicals and the available toxicological knowledge of individual compounds. In this study, we show a new methodological approach for the assessment of chemical mixtures based on a proteome-wide identification of the protein targets and revealing the relevance of new targets based on their role in the cellular function. We applied a proteome integral solubility alteration assay to identify 24 protein targets from a chemical mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin, alpha-endosulfan, and bisphenol A among the HepG2 soluble proteome, and validated the chemical mixture-target interaction orthogonally. To define the range of interactive capability of the new targets, the data from intrinsic properties of the targets were retrieved. Introducing the target properties as criteria for a multi-criteria decision-making analysis called the analytical hierarchy process, the prioritization of targets was based on their involvement in multiple pathways. This methodological approach that we present here opens a more realistic and achievable scenario to address the impact of complex and uncharacterized chemical mixtures in biological systems.
Assuntos
Proteoma , Proteoma/metabolismo , Humanos , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Fenóis/análise , Células Hep G2 , Dibenzodioxinas Policloradas/toxicidade , Dibenzodioxinas Policloradas/análise , Poluentes Ambientais/toxicidadeRESUMO
Exposures to complex environmental chemical mixtures during pregnancy reach and target the feto-placental unit. This study investigates the influence of environmental chemical mixtures on placental bioenergetics. Recognizing the essential role of the epidermal growth factor receptor (EGFR) in placental development and its role in stimulating glycolysis and mitochondrial respiration in trophoblast cells, we explored the effects of chemicals known to disrupt EGFR signaling on cellular energy production. Human primary cytotrophoblasts (hCTBs) and a first-trimester extravillous trophoblast cell line (HTR-8/SVneo) were exposed to a mixture of EGFR-interfering chemicals, including atrazine, bisphenol S, niclosamide, PCB-126, PCB-153, and trans-nonachlor. An RNA sequencing approach revealed that the mixture altered the transcriptional signature of genes involved in cellular energetics. Next, the impact of the mixture on cellular bioenergetics was evaluated using a combination of mitochondrial and glycolytic stress tests, ATP production, glucose consumption, lactate synthesis, and super-resolution imaging. The chemical mixture did not alter basal oxygen consumption but diminished the maximum respiratory capacity in a dose-dependent manner, indicating a disruption of mitochondrial function. The respiratory capacity and ATP production were increased by EGF, while the Chem-Mix reduced both EGF- and non-EGF-mediated oxygen consumption rate in hCTBs. A similar pattern was observed in the glycolytic medium acidification, with EGF increasing the acidification, and the Chem-Mix blocking EGF-induced glycolytic acidification. Furthermore, direct stochastic optical reconstruction microscopy (dSTORM) imaging demonstrated that the Chem-Mix led to a reduction of the mitochondrial network architecture, with findings supported by a decrease in the abundance of OPA1, a mitochondrial membrane GTPase involved in mitochondrial fusion. In conclusion, we demonstrated that a mixture of EGFR-disrupting chemicals alters mitochondrial remodeling, resulting in disturbed cellular bioenergetics, reducing the capacity of human cytotrophoblast cells to generate energy. Future studies should investigate the mechanism by which mitochondrial dynamics are disrupted and the pathological significance of these findings.
Assuntos
Metabolismo Energético , Receptores ErbB , Mitocôndrias , Trofoblastos , Humanos , Receptores ErbB/metabolismo , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Fenóis/toxicidade , Feminino , Bifenilos Policlorados/toxicidade , Atrazina/toxicidade , Gravidez , Compostos Benzidrílicos/toxicidade , Linhagem Celular , Poluentes Ambientais/toxicidade , SulfonasRESUMO
Halogenated bisphenol A (BPA) derivatives are produced during disinfection treatment of drinking water or are synthesized as flame retardants (TCBPA or TBBPA). BPA is considered as an endocrine disruptor especially on human follicle-stimulating hormone receptor (FSHR). Using a global experimental approach, we assessed the effect of halogenated BPA derivatives on FSHR activity and estimated the risk of halogenated BPA derivatives to the reproductive health of exposed populations. For the first time, we show that FSHR binds halogenated BPA derivatives, at 10 nM, a concentration lower than those requires to modulate the activity of nuclear receptors and/or steroidogenesis enzymes. Indeed, bioluminescence assays show that FSHR response is lowered up to 42.36 % in the presence of BPA, up to 32.79 % by chlorinated BPA derivatives and up to 27.04 % by brominated BPA derivatives, at non-cytotoxic concentrations and without modification of basal receptor activity. Moreover, molecular docking, molecular dynamics simulations, and site-directed mutagenesis experiments demonstrate that the halogenated BPA derivatives bind the FSHR transmembrane domain reducing the signal transduction efficiency which lowers the cellular cAMP production and in fine disrupts the physiological effect of FSH. The potential reproductive health risk of exposed individuals was estimated by comparing urinary concentrations (through a collection of human biomonitoring data) with the lowest effective concentrations derived from in vitro cell assays. Our results suggest a potentially high concern for the risk of inhibition of the FSHR pathway. This global approach based on FSHR activity could enable the rapid characterization of the toxicity of halogenated BPA derivatives (or other compounds) and assess the associated risk of exposure to these halogenated BPA derivatives.
Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Simulação de Acoplamento Molecular , Fenóis , Receptores do FSH , Humanos , Fenóis/toxicidade , Fenóis/química , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Receptores do FSH/metabolismo , Medição de Risco , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/química , Halogenação , Células HEK293 , Simulação de Dinâmica MolecularRESUMO
The synthetic phenolic antioxidant 2,4-di-tert-butylphenol (2,4-DTBP) is an emergent contaminant and can disrupt the delicate balance of aquatic ecosystems. This study aimed to investigate 2,4-DTBP-induced hepatotoxicity in common carp and the underlying mechanisms involved. Sixty common carp were divided into four groups and exposed to 0â¯mg/L, 0.01â¯mg/L, 0.1â¯mg/L or 1â¯mg/L 2,4-DTBP for 30 days. Here, we first demonstrated that 2,4-DTBP exposure caused liver damage, manifested as hepatocyte nuclear pyknosis, inflammatory cell infiltration and apoptosis. Moreover, 2,4-DTBP exposure induced hepatic reactive oxygen species (ROS) overload and disrupted antioxidant capacity, as indicated by the reduced activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). In addition, transmission electron microscopy revealed that 2,4-DTBP exposure induced autophagosome accumulation in the liver of common carp. Western blot analysis further revealed that 2,4-DTBP exposure significantly decreased the protein levels of mTOR and increased the LC3II/LC3I ratio. Furthermore, 2,4-DTBP exposure inhibited lysozyme (LZM) and alkaline phosphatase (AKP) activity; decreased immunoglobulin M (IgM), complement 3 (C3), and complement 4 (C4) levels in the serum; increased the mRNA levels of proinflammatory cytokines (NF-κB, TNF-α, IL-1ß and IL-6); and increased the mRNA levels of three types of proliferator-activated receptors (PPARs) (α, ß/δ and γ). Molecular docking revealed that 2,4-DTBP directly binds to the internal active pocket of PPARs. Overall, we concluded that 2,4-DTBP exposure in aquatic systems could induce hepatotoxicity in common carp by regulating autophagy and controlling inflammatory responses. The present study provides new insights into the hepatotoxicity mechanism induced by 2,4-DTBP in aquatic organisms and furthers our understanding of the effects of 2,4-DTBP on public health and ecotoxicology.
Assuntos
Antioxidantes , Autofagia , Carpas , Fígado , NF-kappa B , Fenóis , Poluentes Químicos da Água , Animais , Autofagia/efeitos dos fármacos , NF-kappa B/metabolismo , Poluentes Químicos da Água/toxicidade , Fenóis/toxicidade , Antioxidantes/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: According to the Institute of Environmental Sciences, endocrine-disrupting chemicals (EDCs) are "natural or human-made chemicals that may mimic, block, or interfere with the body's hormones, associated with a wide array of health issues", mainly in the endocrine system. Recent studies have discussed the potential contribution of EDCs as risk factors leading to diabetes mellitus type 1 (T1DM), through various cellular and molecular pathways. PURPOSE: The purpose of this study was to investigate the correlation between the EDCs and the development of T1DM. METHODOLOGY: Thus, a 5-year systematic review was conducted to bring light to this research question. Using the meta-analysis and systematic review guideline protocol, a PRISMA flow diagram was constructed and, using the keywords (diabetes mellitus type 1) AND (endocrine-disrupting chemicals) in the databases PubMed, Scopus and ScienceDirect, the relevant data was collected and extracted into tables. Quality assessment tools were employed to evaluate the quality of the content of each article retrieved. RESULTS: Based on the data collected and extracted from both human and animal studies, an association was found between T1DM and certain EDCs, such as bisphenol A (BPA), bisphenol S (BPS), persistent organic pollutants (POPs), phthalates and dioxins. Moreover, based on the quality assessments performed, using the Newcastle-Ottawa Scale and ARRIVE quality assessment tool, the articles were considered of high quality and thus eligible to justify the correlation of the EDCs and the development of T1DM. CONCLUSION: Based on the above study, the correlation can be justified; however, additional studies can be made focusing mainly on humans to understand further the pathophysiologic mechanism involved in this association.
Assuntos
Diabetes Mellitus Tipo 1 , Disruptores Endócrinos , Fenóis , Humanos , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/toxicidade , Diabetes Mellitus Tipo 1/induzido quimicamente , Fenóis/toxicidade , Fenóis/efeitos adversos , Animais , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/efeitos adversos , Poluentes Orgânicos Persistentes/efeitos adversos , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/efeitos adversos , Exposição Ambiental/efeitos adversos , SulfonasRESUMO
Background: Bisphenol A (BPA), a characteristic endocrine disruptor, is a substance that seriously interferes with the human endocrine system and causes reproductive disorders and developmental abnormalities. However, its toxic effects on the gut-liver-hormone axis are still unclear. Method: Male and female rats were exposed to BPA (300 mg/kg) by oral gavage for 60 consecutive days. H&E staining was used for histopathological evaluation, and the serum biochemical indexes were determined using an automatic analyzer. The 16S rRNA gene sequencing was used to detect the intestinal microbial diversity, and the GC-MS was used to analyze the contents of short-chain fatty acids (SCFAs) in colon contents. UPLC-QTOF MS was used to analyze the related metabolites. The ELISA method was used to assess the levels of serum inflammatory factors. Results: Histopathological analysis indicated that the liver, heart, and testis were affected by BPA. There was a significant effect on alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) in the male-BPA group (P < 0.05), and globulin (GLB), indirect bilirubin (IBIL), alkaline phosphatase (ALP), ALT, TG, TC, high-density lipoprotein (HDL), and creatinine (Cr) in the female-BPA group (P < 0.05). Metagenomics (16S rRNA gene sequencing) analysis indicated that BPA reduced the diversity and changed the composition of gut microbiota in rats significantly. Compared with the control and blank groups, the contents of caproic acid, isobutyric acid, isovaleric acid, and propanoic acid in the colon contents decreased in the male-BPA group (P < 0.05), and caproic acid, isobutyric acid, isovaleric acid, and valeric acid in the colon contents decreased in the female-BPA group (P < 0.05). Metabolomic analysis of the serum indicated that BPA could regulate bile acid levels, especially ursodeoxycholic acid (UDCA) and its conjugated forms. The contents of amino acids, hormones, and lipids were also significantly affected after exposure to BPA. The increase in interleukin-6 (IL-6), interleukin-23 (IL-23), and transforming growth factor-ß (TGF-ß) in the serum of the male-BPA group suggests that BPA exposure affects the immune system. Conclusion: BPA exposure will cause toxicity to rats via disrupting the gut-liver-hormone axis.
Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Microbioma Gastrointestinal , Fígado , Fenóis , Animais , Fenóis/toxicidade , Masculino , Feminino , Ratos , Microbioma Gastrointestinal/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Disruptores Endócrinos/toxicidade , Ratos Sprague-Dawley , Hormônios/sangueRESUMO
A common industrial chemical known as bisphenol A (BPA) has been linked to endocrine disruption and can interfere with hormonal signaling pathways in humans and animals. This comprehensive review aims to explore the detrimental consequences of BPA on reproductive organ performance and apoptosis induction, shedding light on the emerging body of evidence from laboratory animal studies. Historically, most studies investigating the connection between BPA and reproductive tissue function have mainly leaned on laboratory animal models. These studies have provided crucial insights into the harmful effects of BPA on several facets of reproduction. This review consolidates an increasing literature that correlates exposure to BPA in the environment with a negative impact on human health. It also integrates findings from laboratory studies conducted on diverse species, collectively bolstering the mounting evidence that environmental BPA exposure can be detrimental to both humans and animals, particularly to reproductive health. Furthermore, this article explores the fundamental processes by which BPA triggers cell death and apoptosis in testicular cells. By elucidating these mechanisms, this review aids a deeper understanding of the complex interactions between BPA and reproductive tissues.
Assuntos
Apoptose , Compostos Benzidrílicos , Fenóis , Testículo , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Humanos , Masculino , Animais , Apoptose/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/patologia , Disruptores Endócrinos/toxicidadeRESUMO
Bisphenol A (BPA) is one of the most prevalent endocrine disrupting chemicals (EDCs) and there is widespread concern about the adverse effects of EDCs on human health. However, the exact mechanism of these toxicities has still not been fully deciphered. Additionally, studies have reported the toxicological effects at far low doses to the generally considered no-observed-adverse-effect level (NOAEL) dose. The present study investigates the effects of a sub-acute (28 days) exposure to BPA (10, 50 and 100 mg/kg/day) in adult male mice on various hormones levels, sperm motility, sperm count, functional integrity of sperm plasma membrane, testicular histological changes, oxidative stress markers and DNA damage. The key proteome signatures were quantified by LC-MS/MS analysis using Orbitrap Fusion Lumos Tribrid Mass Spectrometer equipped with nano-LC Easy-nLC 1200. Data suggest that the BPA exposure in all doses (below/above NOAEL dose) have greatly impacted the hormone levels, sperm parameters (sperm count, motility and membrane integrity) and testicular histology. Mass spectrometry-based proteomics data suggested for 1352 differentially expressed proteins (DEPs; 368 upregulated, 984 downregulated) affecting biological process, cellular component, and molecular functions. Specifically searched male reproductive function related proteins suggested a complex network where 46 potential proteins regulating spermatogenesis, sperm structure, activity and membrane integrity while tackling oxidative stress responses were downregulated. These potential biomarkers could shed some more light on our current understanding of the reproductive toxicological effects of BPA and may lead to exploration of novel interventions strategies against these targets for male infertility.
Assuntos
Compostos Benzidrílicos , Fenóis , Proteômica , Testículo , Masculino , Animais , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Camundongos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Proteoma/metabolismo , Proteoma/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Saúde Reprodutiva , Estresse Oxidativo/efeitos dos fármacosRESUMO
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
Bisphenols (BPs) are recognized as endocrine disrupting compounds and have garnered increasing attention due to their widespread utilization. However, the varying biological toxicities and underlying mechanisms of BPs with different functional groups remain unknown. In the present study, the toxic effects of four BPs (BPA, BPS, BPAF, and TBBPA) on a photosynthetic microalgae Chromochloris zofingiensis were compared. Results showed that halogen-containing BPs exhibited higher cellular uptake, leading to more severe oxidative stress, lower photosynthetic efficiency, and greater accumulation of starch and lipids. Specifically, TBBPA with bromine groups showed a greater toxicity than BPAF with fluorine groups, possibly due to the incomplete debromination in C. zofingiensis. Transcriptomic analysis revealed that halogen-containing BPs triggered greater number of differentially expressed genes (DEGs), and only 64 common DEGs were found among different BPs, indicating that the effects of BPs with different functional groups varied greatly. Genes involved in endocytosis, peroxisomes, and endoplasmic reticulum protein processing pathways were mostly upregulated across different BPs, while photosynthesis-related genes showed varied expression, possibly due to their distinct functional groups. Additionally, SIN3A, ZFP36L, CHMP, and ATF2 emerged as potential key regulatory genes. Overall, this study thoroughly explained how functional groups impact the toxicity and biodegradation of BPs in C. zofingiensis.
Assuntos
Biodegradação Ambiental , Fenóis , Fenóis/toxicidade , Fenóis/metabolismo , Fotossíntese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Microalgas/efeitos dos fármacos , Microalgas/metabolismo , Clorófitas/metabolismo , Clorófitas/efeitos dos fármacos , Clorófitas/genética , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/metabolismo , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/metabolismo , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/metabolismoRESUMO
The present study provides information on the effects of BPA on ROS production-related phenomena in the chlorophytes Ulva rigida and U. intestinalis, and on the mechanism they establish against BPA toxicity, at environmentally relevant concentrations (0.1-3 µg L-1). Up-regulated H2O2 generation seems to be a key factor causing oxidative damage. Interspecific differences, in terms of the mechanism and the temporal response to BPA toxicity were observed. BPA effects on U. rigida were more intense and appeared earlier (on 1D at 0.1 µg L-1) compared to U. intestinalis and mostly after 7D (LOEC: 0.3 µg L-1, Terminal time, Tt: 7D). In U. rigida, on 1-5D, the 'mosaic' type effect patterns ('models' 3A/3B) with 'unaffected' and 'affected' areas (dark content, positive H2DCF-DA staining signal/H2O2 production and chlorophyll autofluorescence signal loss) indicated a time-dependent manner. After 7D, only U. rigida cells with dark content formed aggregates, showing positive H2O2 production ('model' 4) or in some cells oxidative damages triggering retrograde signaling in the neighboring 'unaffected' areas ('model' 5). H2O2 overproduction (CTCF ratio) in U. rigida, on 1D at the lowest concentration and after 7D at 0.3-1/3 µg L-1, respectively, seems to stimulate (poly)phenolic production, in a dose- and time-dependent manner. U. intestinalis did not display severe BPA impact (i.e., 'models' 4, 5) at any exposures, although at a later time indicated a lower LOEC (0.1 µg L-1, Tt: 9D) than that in U. rigida. In U. intestinalis, H2O2 production does not appear to stimulate high (poly)phenolic amounts.
Assuntos
Peróxido de Hidrogênio , Alga Marinha , Ulva , Ulva/efeitos dos fármacos , Fenóis/toxicidade , Regulação para Cima , Compostos Benzidrílicos/toxicidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
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
Plastics are widespread pollutants found in atmospheric, terrestrial and aquatic ecosystems due to their extensive usage and environmental persistence. Plastic additives, that are intentionally added to achieve specific functionality in plastics, leach into the environment upon plastic degradation and pose considerable risk to ecological and human health. Limited knowledge concerning the presence of plastic additives throughout plastic life cycle has hindered their effective regulation, thereby posing risks to product safety. In this study, we leveraged the adverse outcome pathway (AOP) framework to understand the mechanisms underlying plastic additives-induced toxicities. We first identified an exhaustive list of 6470 plastic additives from chemicals documented in plastics. Next, we leveraged heterogenous toxicogenomics and biological endpoints data from five exposome-relevant resources, and identified associations between 1287 plastic additives and 322 complete and high quality AOPs within AOP-Wiki. Based on these plastic additive-AOP associations, we constructed a stressor-centric AOP network, wherein the stressors are categorized into ten priority use sectors and AOPs are linked to 27 disease categories. We visualized the plastic additives-AOP network for each of the 1287 plastic additives and made them available in a dedicated website: https://cb.imsc.res.in/saopadditives/ . Finally, we showed the utility of the constructed plastic additives-AOP network by identifying highly relevant AOPs associated with benzo[a]pyrene (B[a]P), bisphenol A (BPA), and bis(2-ethylhexyl) phthalate (DEHP) and thereafter, explored the associated toxicity pathways in humans and aquatic species. Overall, the constructed plastic additives-AOP network will assist regulatory risk assessment of plastic additives, thereby contributing towards a toxic-free circular economy for plastics.
Assuntos
Rotas de Resultados Adversos , Plásticos , Toxicogenética , Plásticos/toxicidade , Humanos , Toxicogenética/métodos , Medição de Risco , Poluentes Ambientais/toxicidade , Animais , Fenóis/toxicidade , Compostos BenzidrílicosRESUMO
Bisphenol A (BPA) is widely applied in plastic products, which will produce immunotoxicity to organisms after spilling in the environment, and become a kind of endocrine disruptor. Selenium (Se) is an essential trace element and plays an important role in maintaining redox homeostasis and immune function. BPA exposure and Se deficiency often occur together in livestock and poultry farming, however, studies on the effects of joint exposure on chicken immunotoxins have not been reported. Therefore, this study established a chicken spleen and MDCC-MSB1 cell model under the combined effects of BPA exposure or/and Se deficiency. Transcriptomic analysis showed that BPA exposure and/or Se deficiency induced differential enrichment of positive regulatory pathways such as NLRP3 inflammatory complex assembly, inflammatory response and cellular oxidative stress response. In the -Se+BPA group, pathological damage was significantly increased, Se content decreased, BPA accumulation, oxidative stress and pyroptosis. Meanwhile, the roles and mechanisms of oxidative stress and pyroptosis in BPA exposure or/and Se deficiency-induced splenic tissue injury were investigated by using IF and qRT-PCR methods. The results showed that joint BPA exposure with Se deficiency resulted in more significant changes in the above outcomes than 1 of them. The oxidative stress inhibitor NAC effectually reduced Se deficiency and BPA-induced oxidative stress and pyroptosis, further suggests that oxidative stress mediated Se deficiency or/and BPA-induced pyroptosis. This study revealed that BPA exposure and Se deficiency induced spleen pyroptosis in chickens via the ROS/NLRP3 pathway. These results provide the theoretical basis for the toxicity of BPA in poultry and enrich the toxicological mechanism of combined exposure of Se deficiency and environmental toxins.
Assuntos
Compostos Benzidrílicos , Galinhas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenóis , Piroptose , Espécies Reativas de Oxigênio , Selênio , Baço , Animais , Compostos Benzidrílicos/toxicidade , Baço/efeitos dos fármacos , Baço/metabolismo , Selênio/deficiência , Fenóis/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Espécies Reativas de Oxigênio/metabolismo , Piroptose/efeitos dos fármacos , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Estresse Oxidativo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Doenças das Aves Domésticas/induzido quimicamenteRESUMO
Past studies have observed that BHPF induces multi-organ toxicity, however, whether it induces damage to male reproductive system and the specific mechanism remains unclear. In the present study, male mice were given 0, 2, 10 or 50â¯mg/kg/day of BHPF by gavage for 35 days to observe its effect on reproductive organ and sperm quality. The results indicated that BHPF decreased sperm count and sperm motility in a dose-dependent manner. Besides, our results demonstrated that BHPF triggered the proliferation inhibition and cell death of germ cells in vivo and in vitro. Also, BHPF reduced the expression of function markers for germ cells, Sertoli cells, and Leydig cells, indicating its damage to function of testis cells. Simultaneously, testicular microenvironment was found to be altered by BHPF, as presented with declined testosterone level and decreased expression of local microenvironment regulators. Overall, our findings indicated the detrimental effects of BHPF on male reproductive function in mice, suggesting testicular function and local microenvironment disturbance as mechanism underlying testicular damage.