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1.
Chem Biol Interact ; 347: 109616, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34363818

RESUMO

The reproductive toxicity of endocrine-disrupting chemicals has become a matter of great concern. However, the potential toxicological mechanism of typical environmental estrogens, bisphenol A (BPA) and genistein (GEN), on adult ovary remains ambiguous. In this study, we used laying hens as the experimental model and aimed to clarify the effect of long-term exposure to safe reference doses of BPA and GEN on adult ovary. Results demonstrated that 1/10 no-observable-adverse effect-level dose (1/10 NOAEL, 500 µg/kg body weight [bw]/day) of BPA significantly reduced the production performance and caused the degeneration of follicles and stromal cells and the increase of atretic follicles. Moreover, 1/10 NOAEL dose of BPA undermined the redox homeostasis of the ovary through activating Keap1 and suppressing the Nrf2-signaling pathway (Nrf2, NQO1, and HO-1). On the contrary, GEN (20, 40 mg/kg bw/day) dramatically improved the antioxidant capacity of the ovary by regulating the Nrf2-Keap1 pathway, enhancing the activities of antioxidant-related enzymes (CAT, GSH-Px, and T-SOD), and inhibiting the excessive accumulation of lipid peroxidation products (MDA). Parallel in vitro studies confirmed that the differential role of BPA and GEN on ovarian redox balance was directly mediated by Nrf2-Keap1 antioxidant system. And GEN could ameliorate BPA-induced oxidative stress. Importantly, our research found that exposure to BPA and GEN altered estrogen receptor alpha (ERα) expression in the ovary. And the use of specific ERα agonist/antagonist confirmed that BPA and GEN have opposite regulatory effects on the Nrf2-Keap1 pathway by targeting ERα.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Genisteína/toxicidade , Ovário/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Galinhas , Receptor alfa de Estrogênio/metabolismo , Feminino , Homeostase/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ovário/metabolismo , Ovário/patologia
2.
Environ Sci Technol ; 55(14): 10001-10011, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34241998

RESUMO

Bisphenol (BP) compounds are endocrine-disrupting organic pollutants. BPs may increase the messenger RNA (mRNA) transcripts of nuclear receptors (NRs) regulating the expression of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes. Their impact on the genotoxicity of metabolically activated carcinogens, however, remains unknown. In this study, effects of the bisphenols A, F, S, and AF on the expression of the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor, and individual xenobiotic-metabolizing CYP enzymes in a human hepatoma (HepG2) cell line were investigated, along with in silico binding studies of BPs to each receptor. The results indicated that each BP at 1 to 100 nM concentrations increased the mRNA transcripts and protein levels of AhR, PXR, CYP1A1, 1A2, 1B1, 2E1, and 3A4. The predicted affinities of the BPs for binding AhR were comparable to those of potent agonists. Pretreatment of HepG2 cells with each BP potentiated the induction of micronuclei by benzo[a]pyrene, aflatoxin B1, benzene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; this effect was abolished/reduced by inhibitors of NRs and/or CYPs. Our study suggests that BPs at human exposure levels may aggravate chromosome damage by several impactful carcinogens in human cells by inducing relevant CYP enzymes, mostly via NR modulation.


Assuntos
Carcinógenos/toxicidade , Fenóis/toxicidade , Cromossomos , Sistema Enzimático do Citocromo P-450/genética , Células Hep G2 , Humanos , Receptor de Pregnano X , Receptores de Hidrocarboneto Arílico/genética , Xenobióticos
3.
Nat Genet ; 53(8): 1233-1242, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326545

RESUMO

The agouti viable yellow (Avy) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. Avy expressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.


Assuntos
Metilação de DNA , Disruptores Endócrinos/toxicidade , Obesidade/genética , Retroelementos , Animais , Compostos Benzidrílicos/toxicidade , Metilação de DNA/efeitos dos fármacos , Dieta/efeitos adversos , Epigênese Genética , Feminino , Ferredoxina-NADP Redutase/genética , Ácido Fólico/genética , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/genética , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Obesidade/etiologia , Fenóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal
5.
J Environ Manage ; 296: 113226, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34252852

RESUMO

Endocrine-disrupting chemicals (EDCs) are primarily studied regarding endocrine-mediated effects in mammals and fish. However, EDCs can cause toxicity by mechanisms outside the endocrine system, and, as they are released continuously into soils, they may pose risks to terrestrial organisms. In this work, the plant Allium cepa and the earthworm Eisenia foetida were used as test systems to evaluate the toxicity and cyto-/geno-toxicity of three environmental phenols known as EDCs (Bisphenol A - BPA, Octylphenol - OP, Nonylphenol - NP). The tested phenols were evaluated in environmentally relevant concentrations (µg/L) and in single forms and mixture. BPA, OP, and NP did not inhibit the seed germination and root development in A. cepa in their single forms and mixture. However, all single forms of the tested phenols caused cellular and DNA damages in A. cepa, and although these effects persist in the mixtures, the effects were verified at lower levels. These phenols caused acute toxicity to E. foetida after 48 h of exposure and at both conditions evaluated (single forms and mixture); however, unlike A. cepa, in earthworms, mixtures and single forms presented the same level of effects, indicating that interspecies physiological different might influence the mixture toxicity. In summary, our results suggest that BPA, OP, and NP are toxicants to earthworm and cyto-/geno-toxicants to monocotyledonous plants at low concentrations. However, interaction among these phenols reduces the magnitude of their individual effects (antagonistic effect) in the plant test system. Therefore, this study draws attention to the need to raise knowledge about the ecotoxicity of phenolic compounds to help predict their ecological risks and protect non-target terrestrial species.


Assuntos
Disruptores Endócrinos , Oligoquetos , Poluentes Químicos da Água , Animais , Compostos Benzidrílicos/análise , Compostos Benzidrílicos/toxicidade , Ecossistema , Disruptores Endócrinos/análise , Monitoramento Ambiental , Peixes , Fenóis/análise , Fenóis/toxicidade , Poluentes Químicos da Água/análise
6.
Toxicol Appl Pharmacol ; 426: 115641, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242568

RESUMO

Bisphenol-A (BPA) is an environmental endocrine disruptor and impairs learning and memory. However, the direct evidence for BPA exposure affecting neural circuits has been limited. In this study, a virus tracing assay has been established to explore the brain's neural circuits. Thy1-Cre mice were used to investigate the effects of BPA on the neural projection of glutamatergic pyramidal neurons in hippocampal CA1 based on Thy1 promoter. These transgenic mice were orally exposed to BPA (0, 0.5 mg/kg/day) from postnatal day (PND) 0 to PND60 and then subjected to behavioral tests. Morris water maze(MWM)and Barnes maze's showed that the spatial memory was seriously impaired in BPA exposed Thy1-Cre mice. Virus tracing assay indicated that CA1 pyramidal neurons mainly received neural inputs from hippocampal CA3, entorhinal cortex (EC), and medial septum (MS). The analysis showed that BPA reduced the number of RV+ neurons in CA3 and EC but not MS. The immunohistochemistry experiment displayed that BPA decreased the percentage of CaMKIIRV+ cells in CA3 and EC. The results demonstrated that the synaptic connection of upstream glutamatergic neurons and CA1 pyramidal cells was weakened by BPA exposure. These point to potentially detrimental effects of BPA exposure on the excitatory neural circuit of CA3-CA1 and EC-CA1 in memory formation. Thus, our findings revealed that the decrease in excitatory neural circuits of CA3-CA1 and EC-CA1 contribute to the BPA-induced spatial memory deficits in Thy1-Cre mice.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Fenóis/toxicidade , Memória Espacial/efeitos dos fármacos , Animais , Feminino , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Sinapses/efeitos dos fármacos
7.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209270

RESUMO

Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. The aim of this study was designed as an animal experiment to explore the effects of RBE on the serum biochemistry, and fat deposits in the offspring rats exposed to bisphenol A (BPA), along with the growth and decline of gut microbiota. We constructed an animal model of perinatal Bisphenol A (BPA) exposure to observe the effects of RBE supplementation on obesity, blood lipids, and intestinal microbiota in female offspring rats. Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. RBE supplementation reduced the weight gain and lipid accumulation caused by BPA, optimised the levels of blood lipids, significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio, and increased and decreased the abundance of S24-7 and Lactobacillus, respectively. The analysis of faecal short-chain fatty acid (SCFA) levels revealed that BPA exposure increased the faecal concentration of acetate, which could be reduced via RBE supplementation. However, the faecal concentrations of propionate and butyrate were not only significantly lower than that of acetate, but also did not significantly change in response to BPA exposure or RBE supplementation. Hence, RBE can suppress BPA-induced obesity in female offspring rats, and it demonstrates excellent modulatory activity on intestinal microbiota, with potential applications in perinatological research.


Assuntos
Compostos Benzidrílicos/toxicidade , Ácido Butírico/farmacologia , Obesidade , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Resveratrol/farmacologia , Animais , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Nutrients ; 13(6)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201166

RESUMO

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.


Assuntos
Compostos Benzidrílicos/toxicidade , Feto/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Compostos Benzidrílicos/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Feto/efeitos dos fármacos , Inflamação/patologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Fenóis/química , Gravidez , Ratos Sprague-Dawley
9.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205666

RESUMO

Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents a hazard in prenatal life because of its presence in tissues and fluids during pregnancy. Our recent study in rats fed with BPA showed a placental increase in glucose type 1 transporter (GLUT-1), suggesting a higher uptake of glucose. However, the role of BPA on GLUT transporters in pregnant women with metabolic dysfunction has not yet been investigated. In this study, placental tissue from 26 overweight (OW) women and 32 age-matched normal weight (NW) pregnant women were examined for expression of GLUT1 and GLUT4. Placental explants from OW and NW mothers were exposed to BPA 1 nM and 1 µM and tested for GLUTs expression. The data showed a different response of placental explants to BPA in GLUT1 expression with an increase in NW mothers and a decrease in OW ones. GLUT4 expression was lower in the explants from OW than NW mothers, while no difference was showed between OW and NW in placental biopsies for any of the transporters.


Assuntos
Compostos Benzidrílicos/toxicidade , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Sobrepeso/complicações , Fenóis/toxicidade , Placenta/efeitos dos fármacos , Complicações na Gravidez/induzido quimicamente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Sobrepeso/metabolismo , Placenta/metabolismo , Gravidez , Complicações na Gravidez/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-34208913

RESUMO

Bisphenol A is an extremely high-volume chemical widely used in polycarbonate plastics, the linings of food and beverage tins, and shopping receipts. Canadians are ubiquitously exposed to bisphenol A and research shows that exposure at environmentally relevant doses causes endocrine disruption. Recent risk assessments and exposure estimates by the European Food Safety Authority have guided increased restrictions around the use of bisphenol A and established a lower tolerable daily intake, while the CLARITY-BPA program in the United States identified several adverse effects below this exposure level. Within the context of bisphenol toxicity and international regulation, this paper describes the need for revised bisphenol A risk assessments in Canada. Completed in 2008, the most recent bisphenol A risk assessment conducted by Health Canada does not include risks from alternative bisphenols or non-dietary exposure. It also does not account for the additive effects caused by simultaneous exposure to multiple endocrine-disrupting chemicals.


Assuntos
Compostos Benzidrílicos , Disruptores Endócrinos , Compostos Benzidrílicos/análise , Compostos Benzidrílicos/toxicidade , Canadá , Disruptores Endócrinos/toxicidade , Fenóis/análise , Fenóis/toxicidade
11.
Ecotoxicol Environ Saf ; 221: 112450, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186417

RESUMO

Bisphenol A (BPA) is a widely distributed environmental endocrine disruptor. The accumulation of BPA has been proved that produce various toxic effects both on human and animals. However, the strategies to reduce the damage of BPA on the body and related mechanisms remain to be studied. Coenzyme Q10 (CoQ10), as a powerful antioxidant, is ubiquitous in many eukaryotic cells, which can improve the integrity of lysosomal membrane, lysosomal degradation function and promote autophagy. Here, we examined the ability of CoQ10 to alleviate oxidative stress and apoptosis in BPA-induced damages in C2C12 cells, and how to alleviate it. Our results showed that BPA treatment significantly reduced cell viability, increased the number of cell apoptosis and ROS production, decreased mitochondrial membrane potential, and inhibited the gene expression of mitochondria biogenesis. Moreover, we demonstrated that exposure to BPA increased expression levels of autophagy protein (LC3-II, p62), inhibited autophagy flux, and disrupted the acidic pH environment of lysosomes. Importantly, CoQ10 supplementation effectively restored these abnormalities caused by BPA. CoQ10 significantly decreased the apoptotic incidence and ROS levels, improved mitochondrial membrane potential. Moreover, CoQ10 improved lysosome function and enhanced autophagy flux. Taken together, our results indicate that CoQ10 supplementation is a feasible and effective way to promote the level of autophagy by improving lysosomal function, thereby reducing the apoptosis caused by BPA accumulation. This study aims to provide evidence for the role of CoQ10 in repairing BPA-induced cell damage in clinical practice.


Assuntos
Antioxidantes/toxicidade , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Ubiquinona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular , Lisossomos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/farmacologia
12.
Toxicol Appl Pharmacol ; 426: 115634, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174261

RESUMO

While Bisphenol A (BPA) has been a requisite plastic additive, as an endocrine disruptor it has been associated with adverse health effects including ovarian disorders. Following implemented restrictions on BPA usage, it is replaced by alternative bisphenols, biological effects of which have not been adequately investigated. Our study examined effects of bisphenols AF (BPAF) and S (BPS), on the human ovarian granulosa cell line COV434, and compared them with BPA, with the focus on cell viability (10-9-10-4 M) and angiogenesis-related factors (10-9-10-5 M), relevant for both the follicle development and ovarian pathologies: vascular endothelial growth factor A (VEGF-A), platelet-derived growth factor AA (PDGF-AA), and matrix metalloproteinase 9 (MMP-9). Each bisphenol impaired cell viability and increased generation of intracellular reactive oxygen species at the highest concentration (10-4 M). While VEGF-A production in BPAF-treated groups did not differ from the control, all doses of BPS and BPA caused a marked reduction in VEGF-A output. Nevertheless, the alterations in VEGF-A production were not caused by the impact on VEGFA gene expression since there were no indications of VEGFA downregulation in the presence of either BPS or BPA. Interestingly, we observed a similar pattern of PDGF-AA output reduction in BPS- and BPA-treated groups to that of VEGF-A production. BPAF and BPS (10-5 M) increased MMP9 expression, however, this effect was not reflected by the increase in MMP-9 production. The results obtained demonstrate that the novel bisphenol analogs are not inert with respect to the ovarian cells, and their effects might contribute to dysregulation of granulosa cells functions.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Células da Granulosa/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células da Granulosa/metabolismo , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica , Fator de Crescimento Derivado de Plaquetas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
Environ Pollut ; 285: 117472, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34082367

RESUMO

Bisphenol A (BPA) is a high-production-volume monomer for the manufacture of a wide variety of polycarbonate plastics and resins. Evidence suggests BPA can induce carcinogenesis, reproductive toxicity, abnormal inflammatory or immune response, and developmental disorders of the brain or nervous system. However, whether BPA affects the very same basic molecular processes in all the in vivo and in vitro systems employed to exert its molecular mechanisms of toxicity remains to be clarified. In this study, we collected multi-source global transcriptomics datasets for BPA-exposed organisms and cells, and evaluated the adverse effects of BPA by using data integration and gene functional enrichment analyses. We found that BPA may affect basic cellular processes, such as cell growth, survival, proliferation, differentiation, and apoptosis, independent of species and specific in vivo or in vitro systems. Mechanistically, BPA could regulate cell-extra cellular matrix interactions via challenging TGF-beta signaling pathways. Furthermore, we compared our in vitro BPA-dependent mouse embryoid body (EB) global differentiation transcriptomics with all the other datasets. We verified the EB-based toxicological system could recapitulate several in vivo and other in vitro findings very efficiently, and in a less time- and resource-consuming fashion. Taken together, this study emphasizes the utility of meta-analyses to understand common molecular mechanisms of toxicity of synthetic chemicals.


Assuntos
Compostos Benzidrílicos , Transcriptoma , Animais , Compostos Benzidrílicos/toxicidade , Camundongos , Fenóis/toxicidade , Fator de Crescimento Transformador beta/genética
14.
Toxicol Lett ; 350: 30-39, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34147605

RESUMO

Bisphenol F (BPF) is a member of endocrine disrupting chemicals (EDCs). As a substitute of bisphenol A (BPA), BPF is widely used in various consumer products, leading to an increased risk of people's exposure. However, there are few studies on the immunotoxicity and mechanism of BPF. This study aimed to investigate the effect of BPF on the secretion of pro-inflammatory cytokines by macrophages and explore its mechanism. In our study, RAW264.7 macrophages were treated with different concentrations of BPF (0, 5, 10 and 20 µM) for 24 h. The results showed that the secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1ß) and the production of lactate were increased in a dose-dependent manner. BPFalso led to the activation of the PI3K-AKT signaling pathway. After pretreatment with glycolysis inhibitor (2-DG) and exposure to BPF (20 µM), the secretion of pro-inflammatory cytokines induced by BPF was inhibited. PI3K inhibitor (LY294002) and estrogen receptor (ER) antagonist (ICI 182,780) could also inhibit the above effects induced by BPF (20 µM). In conclusion, our results suggested that BPF can enhance glycolysis through ER mediated PI3K-AKT signaling pathway, and the enhanced glycolysis further promoted the secretion of pro-inflammatory cytokines. Our research provides basic data for future studies on bisphenol exposure and immunotoxicity.


Assuntos
Compostos Benzidrílicos/toxicidade , Citocinas/metabolismo , Glicólise/efeitos dos fármacos , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Fenóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Compostos Benzidrílicos/metabolismo , Células Cultivadas/efeitos dos fármacos , Humanos , Imunotoxinas/metabolismo , Fenóis/metabolismo
15.
Environ Int ; 156: 106697, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34147998

RESUMO

BACKGROUND: Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. OBJECTIVES: To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. METHODS: We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother-child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5-5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). RESULTS: The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: -0.42, 3.81) and 1.17 points (95 %CI: -0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. DISCUSSION: Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.


Assuntos
Poluentes Ambientais , Ácidos Ftálicos , Criança , Comportamento Infantil , Exposição Ambiental , Feminino , Humanos , Masculino , Relações Mãe-Filho , Fenóis/toxicidade , Ácidos Ftálicos/toxicidade , Gravidez
16.
Environ Pollut ; 286: 117567, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126515

RESUMO

Heart development requires a precise temporal regulation of gene expression in cardiomyoblasts. Therefore, the transcriptional changes in differentiating cells can lead to congenital heart diseases. Although the genetic mutations underlie most of these alterations, exposure to environmental contaminants, such as bisphenol A (BPA), has been recently considered as a risk factor as well. In this study we investigated the genotoxic and epigenotoxic effects of BPA throughout cardiomyocyte differentiation. H9c2 cells (rat myoblasts) were exposed to 10 and 30 µM BPA before and during the last two days of cardiac-driven differentiation. Then, we have analysed the phenotypic and molecular modifications (at transcriptional, genetic and epigenetic level). The results showed that treated myoblasts developed a skeletal muscle cell-like phenotype. The transcriptional changes induced by BPA in genes codifying proteins involved in heart differentiation and function depend on the window of exposure to BPA. The exposure before differentiation repressed the expression of heart transcription factors (Hand2 and Gata4), whereas exposure during differentiation reduced the expression of cardiac-specific genes (Tnnt2, Myom2, Sln, and Atp2a1). Additionally, significant effects were observed regarding DNA damage and histone acetylation levels after the two periods of BPA exposure: in cells exposed to the toxicant the percentage of DNA repair foci (formed by the co-localization of γH2AX and 53BP1) increased in a dose-dependent manner, whereas the treatment with the toxicant triggered a decrease in the epigenetic marks H3K9ac and H3K27ac. Our in vitro results reveal that BPA seriously interferes with the process of cardiomyocyte differentiation, which could be related to the reported in vivo effects of this toxicant on cardiogenesis.


Assuntos
Compostos Benzidrílicos , Epigênese Genética , Animais , Compostos Benzidrílicos/toxicidade , Diferenciação Celular , Fenóis/toxicidade , Ratos
17.
Chemosphere ; 282: 130994, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34102488

RESUMO

Studies have shown that there were associations between endocrine disrupting chemicals (EDCs) and anxiety. Nonylphenol (NP) is an EDC with weak estrogen activity. This study aimed to clarify whether subchronic exposure of NP at environmental concentrations induces anxiety-like behavior, and effects of NP on the regulators (NMDAR2B, PSD-95, Synapsin1) expressions of synaptic plasticity in vivo and in vitro experiments. In vivo, 40 male SD rats were randomly divided into 4 groups (each with 10 rats): low dose (0.4 mg/kg/day, L-NP), middle-dose (4 mg/kg/day, M - NP), high-dose (40 mg/kg/day, H-NP) and corn oil (Control) groups. In vitro, HT22 cells were divided into a control group (Control), NP group (NP, 20 µM), glutamine acid receptor inhibitor group (MK-801, 10 µM) and MK-801 + NP group. The concentration of NP in the hippocampus rised with the increase of NP exposure concentration in the treatment groups (F = 7.542, P = 0.001). Compared with the control group, the residence time in the dark box after NP exposure had extended (F = 117.927, P < 0.01). The duration (F = 112.054, P < 0.01) and the number of times (F = 13.514, P < 0.01) to enter the closed arm in the NP exposure group significantly increased. There were more neurons degeneration and nuclear shrinkage in the M - and H- NP groups, while the average number of shrinked neurons increased with the increasing dose of NP exposure. The protein expressions of PSD-95 (F = 97.723, P < 0.01), Synapsin1 (F = 41.797, P < 0.01) and NMDAR2B (F = 3.440, P = 0.036) in the NP group were lower than those of the control. Simultaneously, the expressions of PSD-95, Synapsin1 and NMDAR2B in the hippocampus were down-regulated; the mRNA expression of PSD-95 (F = 19.950, P < 0.01), Synapsin1 (F = 3.498, P = 0.035) and NMDAR2B (F = 9.293, P < 0.01) genes in the hippocampus decreased in the M - and H-NP groups. In vitro, the trend of the fluorescence intensity expressed by PSD-95 (F = 2.606, P = 0.124) and Synapsin1 (F = 20.573, P < 0.01) among the groups was: MK-801 + NP group < MK-801 < NP group. The protein expressions of PSD-95 (F = 5.699, P = 0.022), Synapsin1 (F = 10.820, P = 0.003) and NMDAR2B (F = 6.041, P = 0.019) were down-regulated. These results suggested that subchronic exposure to environmental concentrations of NP induced anxiety, and reduced the protein and/or mRNA expressions of regulators of synaptic plasticity (PSD-95, Synapsin1, NMDAR2B).


Assuntos
Ansiedade , Fenóis , Animais , Ansiedade/induzido quimicamente , Masculino , Plasticidade Neuronal , Fenóis/toxicidade , Ratos , Ratos Sprague-Dawley
18.
J Biochem Mol Toxicol ; 35(8): e22820, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34075651

RESUMO

Bisphenol S (BPS) is an organic chemical that has been used as a substitute for bisphenol A (BPA) in making polycarbonate plastics, epoxy resins, thermal receipt papers, and currency bills, as BPA has been reported to have dreadful effects on the living system. From this view point, the present study investigates whether BPS has the same or rather more toxic effects like BPA or not. Limited studies were carried out on the effect of BPS on fish. The hepatic antioxidant enzymes such as superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase (GPx), along with the nonenzymatic antioxidant, glutathione, in a freshwater fish, Labeo rohita, were selected as biomarkers. The results revealed that the sublethal exposure of BPS significantly influenced the activities of these biomarkers. Lipid peroxidation (LPO) products such as malondialdehyde and conjugate diene levels were also altered by the exposure. The alteration in the levels of antioxidants and LPO products after BPS exposure clearly showed that the fish experienced oxidative stress. Furthermore, the current study showed that BPS is a pollutant with oxidative potential by disrupting the antioxidant enzymes.


Assuntos
Cyprinidae/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Xenobióticos/toxicidade , Animais
19.
Environ Toxicol ; 36(9): 1932-1943, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34165232

RESUMO

Obesity is closely linked with metabolic diseases, while life and prenatal exposure to endocrine-disrupting chemicals has been implicated in the development of obesity. Magnesium lithospermate B (MLB), an active compound of Salvia miltiorrhiza (Danshen), has beneficial effects on insulin resistance and metabolic abnormalities in diet-induced obese rodents. Since exposure to endocrine-disrupting chemical Bisphenol A (BPA) during pregnancy mimics the effects of high fat diet-induced alterations of glucose and lipid metabolism in adult male offspring, the effects of daily MLB supplementation for 4 weeks on metabolic abnormalities in rats weaning from prenatal BPA-exposed dams were investigated. BPA-exposed rats developed obesity and adiposity concurrent with hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and elevation of circulating glucagon and free fatty acids. Increased hepatic fatty acid synthesis and decreased fatty acid ß-oxidation, activation of adipocytic adipogenesis, maturation, and lipogenesis, as well as reduction of muscular glucose uptake were demonstrated in BPA-exposed rats. The aforementioned alterations were improved by MLB supplementation. Additionally, MLB displayed negative effects on glucocorticoid receptor action and inflammation, and promoted lipolysis and thermogenesis in the adipose tissues. In conclusion, our findings suggest that MLB may be a potential therapeutic compound against metabolic diseases, including maternal exposure-induced metabolic abnormalities.


Assuntos
Compostos Benzidrílicos , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos/toxicidade , Suplementos Nutricionais , Medicamentos de Ervas Chinesas , Feminino , Masculino , Fenóis/toxicidade , Gravidez , Ratos
20.
Toxicology ; 458: 152830, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34097993

RESUMO

Previous studies have suggested that bisphenol A (BPA) has a toxic effect on bone development; however, its pathological mechanism has not been fully elucidated. In the present study, pregnant Wistar rats were intragastrically administered BPA (10 µg/kg per day) during gestational days 14-21. Then, bone tissues were obtained from neonatal rats on postnatal day 1 for histological analysis, and the bone mass of adult rat offspring was analyzed by micro-CT at postnatal week 10. Furthermore, osteoprogenitors from neonatal rats were obtained and treated with various concentrations of BPA in vitro to clarify the associated mechanism. In vivo, we found that prenatal BPA exposure reduced body weight and body length in female neonatal rats but not in male neonatal rats. Meanwhile, BPA exposure during pregnancy delayed bone development and reduced bone mass only in female rat offspring. Moreover, BPA exposure during pregnancy inhibited osteogenic function and downregulated the transforming growth factor ß (TGF ß) signaling pathway in the bone tissue of female neonatal rats. Our in vitro findings further indicated that various concentrations of BPA suppressed the osteogenic function of osteoprogenitors by downregulating the TGFß signaling pathway. Meanwhile, BPA downregulated H3K9ac and expression levels of TGFß via the ERß/HDAC5 signaling pathway. Collectively, this research revealed that prenatal BPA exposure impairs bone development and bone mass accumulation in female rat offspring, which was attributed to inhibitory osteogenic function via the ERß/HDAC5/TGFß signaling pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/anatomia & histologia , Disruptores Endócrinos/toxicidade , Receptor beta de Estrogênio/efeitos dos fármacos , Histona Desacetilases/efeitos dos fármacos , Fenóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Células-Tronco/efeitos dos fármacos , Microtomografia por Raio-X
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