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1.
Chemosphere ; 262: 128045, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182117

RESUMO

The vulnerability to environmental insults is heightened at early stages of development. However, the neurotoxic potential of bisphenol A (BPA) and bisphenol S (BPS) at developmental windows remains unclear. To investigate the mechanisms mediating the developmental neurotoxicity, zebrafish embryos were treated with 0.01, 0.03, 0.01, 0.3, 1 µM BPA/BPS. Also, we used Tg(HuC:GFP) zebrafish to investigate whether BPA/BPS could induce neuron development. The reduction in body length, and increased heart rate were significant in 0.3 and 1 µM BPA/BPS groups. The green fluorescence protein (GFP) intensity increased at 72 hpf and 120 hpf in Tg(HuC:GFP) larvae which was consistent with the increased mRNA expression of elval3 following BPS treatments, an indication of the plausible effect of BPS on embryonic neuron development. Additionally, BPA/BPS treatments elicited hyperactivity and reduced static time in zebrafish larvae, suggesting behavioral alterations. Moreover, qRT-PCR results showed that BPA and BPS could interfere with the normal expression of development-related genes vegfa, wnt8a, and mstn1 at the developmental stages. The expression of neurodevelopment-related genes (ngn1, elavl3, gfap, α1-tubulin, mbp, and gap43) were significantly upregulated in BPA and BPS treatments, except for the remarkable downregulation of mbp and gfap elicited by BPA at 48 (0.03 µM) and 120 hpf (0.3 µM) respectively; ngn1 at 48 hpf for 0.1 µM BPS. Overall, our results highlighted that embryonic exposure to low concentrations of BPA/BPS could be deleterious to the central nervous system development and elicit behavioral abnormalities in zebrafish at developmental stages.


Assuntos
Compostos Benzidrílicos/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Embrião não Mamífero/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
2.
Chemosphere ; 262: 128009, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182144

RESUMO

Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of individuals in subsequent generations. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of Bisphenol A (BPA) which is an endocrine disruptor. However, the lack of efficient evaluation of BPS leaves doubts about the relevant substitute of BPA. Few studies of transgenerational inheritance have examined the effects of environmental exposures to endocrine disruptors on the immune system. In this study, we analyzed the transgenerational effects of BPS on intestinal inflammation and its consequence in metabolism. In this study, only F0 pregnant mice were exposed to BPS (1.5 µg/kg bw/day) from gestational day 0 until weaning of offspring. In this work, both F1 and F2 male offspring developed an inflammatory response in the ileum and colon at adulthood after F0 mothers were exposed to BPS; this phenomenon disappeared in F3. This inflammatory response in F1 male offspring is associated with a significant decrease of blood cholesterol without modification of metabolic status. Further, in F3 offspring male, the decrease of gut inflammatory response is associated with a decrease of fat weight and with an increase of blood glucose and cholesterol level. A sex-specific profile is observed in female offspring. We also observed that early life exposure to BPS was associated with strong abnormal intestinal immune status. The study presented here demonstrates that the immune system, like other organ systems, is vulnerable to transgenerational effects caused by environmental exposures.


Assuntos
Citocinas/análise , Disruptores Endócrinos/toxicidade , Intestinos/imunologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sulfonas/toxicidade , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Fezes/química , Feminino , Inflamação , Intestinos/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
3.
Food Chem ; 339: 127813, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916401

RESUMO

Bisphenol S (BPS), a structural analog of Bisphenol A (BPA), has been widely used as a substitute for epoxy resin, food packaging materials, and other products due to the limited application of BPA. Studies in vivo and in vitro have indicated that BPA could induce fat accumulation like an obesogen. The main goal of this study was to investigate the role and mechanism of BPS in lipid metabolism using Caenorhabditis elegans (C. elegans) as a model. Results showed that both the overall fat deposition and the triglyceride level were significantly increased in a non-monotonically increasing trend, and the low dose of BPS (0.01 µM) exhibited a stronger influence. Additionally, BPS enhanced fat synthesis depending on daf-16, fat-5, fat-6 and fat-7, and inhibited fatty acid oxidation via nhr-49 and acs-2. This study further indicate that fat accumulation induced by BPS requires nhr-49, which also mediated the nuclear hormone signaling pathway.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Glucose/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Dieta/efeitos adversos , Gorduras/metabolismo , Ácidos Graxos/metabolismo , Glucose/administração & dosagem , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Triglicerídeos/metabolismo
4.
Ecotoxicol Environ Saf ; 207: 111299, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927158

RESUMO

The analogues of biphenol A (BPA), including bisphenol S (BPS) and bisphenol B (BPB), are commonly used to replace the application of BPA in containers and wrappers of daily life. However, their safeties are questioned due to their similar chemical structure and possible physiological effects as BPA. To investigate the neurotoxic effects of BPA, BPS, and BPB as well as their underlying mechanism, IMR-32 cell line from male and SK-N-SH cell line from female were exposed respectively to BPA, BPS and BPB with concentrations of 1 nM, 10 nM, 100 nM, 1 µM, 10 µM, and 100 µM for 24 h. Additionally, 24 h exposure of BPA combining epigallocatechin gallate (EGCG) (4 µM and 8 µM for IMR-32 and SK-N-SH respectively) were conducted. Results demonstrated that BPs exposure could promote reactive oxygen species production and increase level of malondialdehyde (MDA) while decrease levels of superoxide dismutase (SOD). Intensive study revealed that after exposure to BPA mitochondrial membrane potential (MMP) dropped down and the protein expression levels of Bak-1, Bax, cytochrome c and Caspase-3 were up-regulated but Bcl-2 were down-regulated significantly. Moreover, apoptosis rate was raised and cell activity declined remarkably in the neuroblastoma cells. All the effects induced by BPA could be alleviated by the adding of EGCG, which similar alleviations could be inferred in IMR-32 and SK-N-SH cells induced by BPS and BPB. Furthermore, BPS showed lower neurotoxic effects compared to BPA and BPB. Interestingly, the neurotoxic effects of BPA on IMR-32 cells were significantly higher than those on SK-N-SH cells. In conclusion, the results suggested that BPA, BPS and BPB could induce oxidative stress and apoptosis via mitochondrial pathway in the neuroblastoma cells and male is more susceptible to BPs than female.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Caracteres Sexuais
5.
Chemosphere ; 263: 128304, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33155548

RESUMO

Gap junction intercellular communication (GJIC) is necessary for ovarian function, and it is temporospatially regulated during follicular development and ovulation. At outermost layer of the antral follicle, theca cells provide structural, steroidogenic, and vascular support. Inter- and extra-thecal GJIC is required for intrafollicular trafficking of signaling molecules. Because GJIC can be altered by hormones and endocrine disrupting chemicals (EDCs), we tested if any of five common EDCs (bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), perfluorooctanesulfonic acid (PFOS), and triphenyltin chloride (TPT)) can interfere with theca cell GJIC. Since most chemicals are reported to repress GJIC, we hypothesized that all chemicals tested, within environmentally relevant human exposure concentrations, will inhibit theca cell GJICs. To evaluate this hypothesis, we used a scrape loading/dye transfer assay. BPS, but no other chemical tested, enhanced GJIC in a dose- and time-dependent manner in ovine primary theca cells. A signal-protein inhibitor approach was used to explore the GJIC-modulatory pathways involved. Phospholipase C and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated BPS-induced enhanced GJIC. Human theca cells were used to evaluate translational relevance of these findings. Human primary theca cells had a ∼40% increase in GJIC in response to BPS, which was attenuated with a MAPK inhibitor, suggestive of a conserved mechanism. Upregulation of GJIC could result in hyperplasia of the theca cell layer or prevent ovulation by holding the oocyte in meiotic arrest. Further studies are necessary to understand in vitro to in vivo translatability of these findings on follicle development and fertility outcomes.


Assuntos
Substâncias Perigosas/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Células Tecais/fisiologia , Animais , Compostos Benzidrílicos , Comunicação Celular , Comunicação , Conexina 43/metabolismo , Feminino , Junções Comunicantes/metabolismo , Humanos , Oócitos/metabolismo , Ovinos , Transdução de Sinais , Células Tecais/efeitos dos fármacos , Células Tecais/metabolismo
6.
Bull Environ Contam Toxicol ; 105(4): 565-571, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32918564

RESUMO

Fish consumption from contaminated water-bodies is a serious health issue. This study conducted to reveal the presence of heavy metals and bisphenols in Vembanad lake, an exploiting tourist spot in Kerala, receiving untreated agricultural, domestic, municipal, and industrial effluents. We evaluated aquatic contaminant impact on hepatic stress markers in Etroplus suratensis from fragile Vembanad lake. The significant difference in water physiochemical parameters, the concentration of heavy metals, and bisphenols (BPA and BPS) were studied. Hepatic tissue of E. suratensis inhabited in lake featured with high iron (11.29 ± 0.39 ppm) and BPA (0.02412 ± 0.0031 µg/mL) content along with an increased hepatic stress marker and distorted hepatic structure. The study highlights the presence of high iron and BPA in edible fish. The study recommends monitoring of physiochemical characters of freshwater lakes is essential for better survival of freshwater flora and fauna.


Assuntos
Compostos Benzidrílicos/toxicidade , Ciclídeos , Exposição Ambiental/efeitos adversos , Fígado/efeitos dos fármacos , Metais Pesados/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores , Feminino , Índia , Lagos , Fígado/anatomia & histologia , Fígado/metabolismo , Masculino
7.
Chemosphere ; 257: 127035, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32702804

RESUMO

Human exposure to environmental chemicals might play a role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Bisphenol A (BPA) and bisphenol S (BPS) have been suggested to affect reproductive health. However, the mechanism remains unclear. To explore the association between BPA and BPS exposure and oxidative stress and immune homeostasis, we conducted a cross-sectional study and revealed BPA and BPS levels in relation to these two factors which were supposed to be implicated in miscarriage. 111 URSA patients were recruited and we analyzed urinary BPA and BPS concentrations, oxidative stress biomarkers (8-hydroxydeoxyguanosine and 8-isoprostane) and serum immune balance biomarkers (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, TGF-ß and IFN-γ). Multivariable linear regression models were used to evaluate the correlation between bisphenols exposure and outcome biomarkers. After adjustment for age, BMI, menstrual cycle, and parity history, creatinine-adjusted BPA was significantly associated with increases in 8-isoprostane (ß = 0.74, 95% CI = 0.07, 1.41; p = 0.031) and IFN-γ (ß = 0.18, 95% CI = 0.00, 0.36; p = 0.046). No statistical correlation between BPS and biomarkers of oxidative stress or immune balance was observed when all participants were analyzed. Further analysis revealed that in the subgroup of BPS > limit of detection (0.01 ng/ml), creatinine-adjusted BPS was significantly associated with increases in IL-10 (ß = 0.22, 95% CI = 0.00, 0.45; p = 0.048). Our findings suggested that BPA and BPS exposure might be related to oxidative stress and immune imbalance in URSA patients. Overall, our work might suggest potential pathogenic and aetiological associations among the bisphenols, biomarkers and URSA, which offers hypotheses for further studies.


Assuntos
Aborto Espontâneo/epidemiologia , Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/estatística & dados numéricos , Fenóis/toxicidade , Sulfonas/toxicidade , Adulto , Biomarcadores/sangue , Estudos Transversais , Dinoprosta/análogos & derivados , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Estresse Oxidativo/fisiologia , Gravidez
8.
Chemosphere ; 253: 126707, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32289607

RESUMO

Bisphenol A (BPA) is gradually being replaced by presumably safer analogues such as bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), due to its toxic, endocrine disrupting and possible carcinogenic effects. Although these bisphenols are widely used to produce a variety of everyday household items, the effects of BPA and its analogues on oxidative stress and cellular energy metabolism of the female reproductive system are still poorly understood. The aim of this study was to evaluate the oxidative stress, biomacromolecular damage and changes in calcium ion (Ca2+) levels induced by BPA and its substitutes on KGN cells, which are maintain physiological characteristics of ovarian granulosa cells. We have observed that BPA and BPAF significantly reduced the viability of KGN cells, while BPS and BPF exhibited a slight toxic effect on the cells. The levels of intracellular ROS production and antioxidant capacity were significantly increased and decreased, respectively, in KGN cells after treatment with high concentrations of BPA and its analogues. In addition, we found that the damage to biomacromolecules, which are the main targets of oxidative stress was significantly increased after treatment with BPA, BPS, BPF, and BPAF. The intracellular Ca2+ levels in KGN cells were significantly increased after exposure to high concentrations of BPA and BPAF, respectively. These results suggest that BPA and its analogues may play different roles in regulating the biologic functions of granulosa cells and the process of ovarian follicular development.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Feminino , Células da Granulosa/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos
9.
Chemosphere ; 253: 126643, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278190

RESUMO

Tembotrione is a rather novel pesticide, usually used for post-emergence weed control. Even though its use is rapidly growing, it is not followed by an adequate flow of scientific evidence regarding its toxicity towards non-target organisms. We evaluated the potential of low doses of tembotrione to induce oxidative stress and cytogenetic damage in blood and brain cells of adult male Wistar rats. Parameters of lipid peroxidation, glutathione levels, activities of antioxidant enzymes and primary DNA damage were assessed following 28-day repeated oral exposure to doses comparable with the currently proposed health-based reference values. The results of the alkaline comet assay showed that such low doses of tembotrione have the potency to inflict primary DNA damage in both peripheral blood leukocytes and brain of treated rats, even with only slight changes in the oxidative biomarker levels. The DNA damage in blood and brain cells of Wistar rats significantly increased at all applied doses, suggesting that tembotrione genotoxicity is mainly a result of direct interaction with DNA while the induction of oxidative stress responses contributes to DNA instability in a lesser extent. The findings of the present study call for further research using other sensitive biomarkers of effect and different exposure scenarios.


Assuntos
Cicloexanonas/toxicidade , Dano ao DNA/fisiologia , Herbicidas/toxicidade , Sulfonas/toxicidade , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Ensaio Cometa , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Testes de Toxicidade
10.
Chemosphere ; 252: 126422, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32199162

RESUMO

Prenatal exposure to bisphenol A (BPA) and its analogues can affect fetal growth and development. However, epidemiologic findings were inconsistent and there was a lack of study for BPA analogues. We aimed to examine the associations between prenatal exposure to BPA, bisphenol B (BPB), bisphenol F (BPF), bisphenol S (BPS), and tetrabromobisphenol A (TBBPA) and birth size. 2023 mother-infant pairs were included in this study. The associations between serum bisphenol levels and birth size were analyzed by multivariate linear regression models. After adjusting for covariates, one log10-unit increase in serum BPA was correlated with a 32.10 g (95% CI: -61.10, -3.10) decrease in birth weight for all infants, and the inverse association was only observed in males when stratified analysis by gender. Additionally, higher BPF concentrations were associated with decreasing birth weight (P for trend = 0.031), ponderal index (P for trend = 0.021), and birth weight Z-scores (P for trend = 0.039) in all infants, and the inverse associations were also only observed in males when stratified analysis by gender. Similarly, higher TBBPA levels were also correlated with decreased birth weight (P for trend = 0.023). However, after gender stratification, higher TBBPA concentrations were associated with a decrease in birth weight (P for trend = 0.007), birth length (P for trend = 0.026), and birth weight Z-scores (P for trend = 0.039) in males. Our data suggested an inverse association of prenatal exposure to BPA, BPF, and TBBPA and birth size, which may be more pronounced in male infants.


Assuntos
Peso ao Nascer/efeitos dos fármacos , Poluentes Ambientais/metabolismo , Exposição Materna/estatística & dados numéricos , Fenóis/metabolismo , Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/toxicidade , China/etnologia , Grupos Étnicos , Feminino , Desenvolvimento Fetal , Humanos , Lactente , Recém-Nascido , Masculino , Mães , Fenóis/toxicidade , Bifenil Polibromatos/metabolismo , Bifenil Polibromatos/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etnologia , Sulfonas/metabolismo , Sulfonas/toxicidade
12.
Proc Natl Acad Sci U S A ; 117(9): 4642-4652, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071231

RESUMO

Placental trophoblast cells are potentially at risk from circulating endocrine-disrupting chemicals, such as bisphenol A (BPA). To understand how BPA and the reputedly more inert bisphenol S (BPS) affect the placenta, C57BL6J mouse dams were fed 200 µg/kg body weight BPA or BPS daily for 2 wk and then bred. They continued to receive these chemicals until embryonic day 12.5, whereupon placental samples were collected and compared with unexposed controls. BPA and BPS altered the expression of an identical set of 13 genes. Both exposures led to a decrease in the area occupied by spongiotrophoblast relative to trophoblast giant cells (GCs) within the junctional zone, markedly reduced placental serotonin (5-HT) concentrations, and lowered 5-HT GC immunoreactivity. Concentrations of dopamine and 5-hydroxyindoleacetic acid, the main metabolite of serotonin, were increased. GC dopamine immunoreactivity was increased in BPA- and BPS-exposed placentas. A strong positive correlation between 5-HT+ GCs and reductions in spongiotrophoblast to GC area suggests that this neurotransmitter is essential for maintaining cells within the junctional zone. In contrast, a negative correlation existed between dopamine+ GCs and reductions in spongiotrophoblast to GC area ratio. These outcomes lead to the following conclusions. First, BPS exposure causes almost identical placental effects as BPA. Second, a major target of BPA/BPS is either spongiotrophoblast or GCs within the junctional zone. Third, imbalances in neurotransmitter-positive GCs and an observed decrease in docosahexaenoic acid and estradiol, also occurring in response to BPA/BPS exposure, likely affect the placental-brain axis of the developing mouse fetus.


Assuntos
Compostos Benzidrílicos/toxicidade , Encéfalo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Trofoblastos/efeitos dos fármacos , Animais , Dopamina/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Serotonina/metabolismo , Trofoblastos/metabolismo
13.
Environ Health Perspect ; 128(2): 27008, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32105160

RESUMO

BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor targeting estrogen receptors (ERs), has been implicated in the promotion of breast cancer. Perinatal exposure of BPA could induce longitudinal alteration of DNA hydroxymethylation in imprinted loci of mouse blood cells. To date, no data has been reported on the effects of BPA on DNA hydroxymethylation in breast cells. Therefore, we asked whether BPA can induce DNA hydroxymethylation change in human breast cells. Given that dysregulated epigenetic DNA hydroxymethylation is observed in various cancers, we wondered how DNA hydroxymethylation modulates cancer development, and specifically, whether and how BPA and its analogs promote breast cancer development via DNA hydroxymethylation. OBJECTIVES: We aimed to explore the interplay of the estrogenic activity of bisphenols at environmental exposure dose levels with TET dioxygenase-catalyzed DNA hydroxymethylation and to elucidate their roles in the proliferation of ER+ breast cancer cells as stimulated by environmentally relevant bisphenols. METHODS: Human MCF-7 and T47D cell lines were used as ER-dependent breast cell proliferation models, and the human MDA-MB-231 cell line was used as an ER-independent breast cell model. These cells were treated with BPA or bisphenol S (BPS) to examine BPA/BPS-related proliferation. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and enzyme-linked immunosorbent assays (ELISAs) were used to detect DNA hydroxymethylation. Crispr/Cas9 and RNA interference technologies, quantitative polymerase chain reaction (qPCR), and Western blot analyses were used to evaluate the expression and function of genes. Co-immunoprecipitation (Co-IP), bisulfite sequencing-PCR (BSP), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to identify the interactions of target proteins. RESULTS: We measured higher proliferation in ER+ breast cancer cells treated with BPA or its replacement, BPS, accompanied by an ERα-dependent decrease in genomic DNA hydroxymethylation. The results of our overexpression, knockout, knockdown, and inhibition experiments suggested that TET2-catalyzed DNA hydroxymethylation played a suppressive role in BPA/BPS-stimulated cell proliferation. On the other hand, we observed that TET2 was negatively regulated by the activation of ERα (dimerized and phosphorylated), which was also induced by BPA/BPS binding. Instead of a direct interaction between TET2 and ERα, data of our Co-IP, BSP, and ChIP-qPCR experiments indicated that the activated ERα increased the DNA methyltransferase (DNMT)-mediated promoter methylation of TET2, leading to an inhibition of the TET2 expression and DNA hydroxymethylation. CONCLUSIONS: We identified a new feedback circuit of ERα activation-DNMT-TET2-DNA hydroxymethylation in ER+ breast cancer cells and uncovered a pivotal role of TET2-mediated DNA hydroxymethylation in modulating BPA/BPS-stimulated proliferation. Moreover, to our knowledge, we for the first time established a linkage among chemical exposure, DNA hydroxymethylation, and tumor-associated proliferation. These findings further clarify the estrogenic activity of BPA/BPS and its profound implications for the regulation of epigenetic DNA hydroxymethylation and cell proliferation. https://doi.org/10.1289/EHP5862.


Assuntos
Compostos Benzidrílicos/toxicidade , Dioxigenases/metabolismo , Fenóis/toxicidade , Testes de Toxicidade , Animais , Linhagem Celular Tumoral , Metilação de DNA , Disruptores Endócrinos/toxicidade , Feminino , Humanos , Camundongos , Receptores Estrogênicos , Sulfonas/toxicidade , Espectrometria de Massas em Tandem
14.
Artigo em Inglês | MEDLINE | ID: mdl-32069886

RESUMO

Aim: The aim of this study was to explore associations of urinary concentrations of bisphenols A (BPA), S (BPS), and F (BPF) and of thiobarbituric acid reactive substances (TBARS) with the risk of endometriosis in women of childbearing age. Methods: This case-control study enrolled 124 women between January 2018 and July 2019: 35 women with endometriosis (cases) and 89 women without endometriosis undergoing abdominal surgery for other reasons (controls). Endometriosis was diagnosed (cases) or ruled out (controls) by laparoscopic inspection of the pelvis and the biopsy of suspected lesions (histological diagnosis). Fasting urine samples were collected before surgery to determine concentrations of BPA, BPS, BPF, and TBARS. Associations of bisphenol and TBARS concentrations with endometriosis risk were explored with multivariate logistic and linear regression analyses. Results: After adjustment for urinary creatinine, age, BMI, parity, and residence, endometriosis risk was increased with each 1 log unit of BPA [OR 1.5; 95%CI 1.0-2.3] and Σbisphenols [OR 1.5; 95%CI 0.9-2.3] but was not associated with the presence of BPS and BPF. Classification of the women by tertiles of exposure revealed statistically significant associations between endometriosis risk and the second tertile of exposure to BPA [OR 3.7; 95%CI 1.3-10.3] and Σbisphenols [OR 5.4; 95%CI 1.9-15.6]. In addition, TBARS concentrations showed a close-to-significant relationship with increased endometriosis risk [OR 1.6; 95%CI 1.0-2.8], and classification by TBARS concentration tertile revealed that the association between endometriosis risk and concentrations of BPA [OR 2.0; 95%CI 1.0-4.1] and Σbisphenols [OR 2.2; 95%CI 1.0-4.6] was only statistically significant for women in the highest TBARS tertile (>4.23 µM). Conclusion: Exposure to bisphenols may increase the risk of endometriosis, and oxidative stress may play a crucial role in this association. Further studies are warranted to verify these findings.


Assuntos
Compostos Benzidrílicos , Endometriose , Fenóis , Sulfonas , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/urina , Estudos de Casos e Controles , Endometriose/epidemiologia , Feminino , Humanos , Fenóis/toxicidade , Fenóis/urina , Gravidez , Risco , Sulfonas/toxicidade , Sulfonas/urina
15.
Environ Res ; 183: 108944, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31911000

RESUMO

BACKGROUND: Bisphenols F (BPF) and S (BPS) are bisphenol A (BPA) analogs used as substitutes in consumer products. Despite previous reports of BPA's association with asthma, no studies have examined its structural analogs in relation to asthma and allergy outcomes. OBJECTIVE: To examine the association of urinary BPF, BPS, and BPA with asthma and hay fever in a US representative sample. METHODS: We analyzed data from 3,538 participants aged 12 years or older in the 2013-2016 National Health and Nutrition Examination Survey (NHANES). Children aged 6-11 years (N = 738), who did not have all covariate data available, were analyzed separately. Covariate-adjusted logistic regression was used to assess the association of the exposures with the outcomes. RESULTS: BPF, BPS, and BPA were detected in 57.1%, 88.4%, and 94.8% of the urine samples, respectively. Urinary BPF detection was positively associated with current asthma (odds ratio [OR]: 1.54, 95% confidence interval [CI]: 1.16-2.04) and hay fever (OR: 1.66, 95% CI: 1.12-2.46). Urinary BPS was associated with increased odds of current asthma in men (OR: 1.64, 95% CI: 1.13-2.40) and urinary BPA was associated with increased odds of asthma without hay fever in children aged 6-11 years (OR: 2.65, 95% CI: 1.05-6.68). CONCLUSION: Our nationally-representative findings document that BPF and BPS exposure is common in the US and that exposure to these BPA analogs is associated with asthma and/or hay fever. Our results suggest that BPF and BPS may not be safe alternatives to BPA; however, prospective studies should be conducted to confirm these results.


Assuntos
Asma , Compostos Benzidrílicos , Fenóis , Rinite Alérgica Sazonal , Sulfonas , Asma/epidemiologia , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/urina , Criança , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Fenóis/toxicidade , Fenóis/urina , Estudos Prospectivos , Rinite Alérgica Sazonal/epidemiologia , Sulfonas/toxicidade , Sulfonas/urina
16.
Environ Res ; 182: 109080, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31901629

RESUMO

Exposure to bisphenol A (BPA) and bisphenol S (BPS) has been associated with the development of metabolic disorders, such as obesity, dyslipidemias, and nonalcoholic fatty liver disease. Nonetheless, the associated mechanisms are still not fully understood. BPS is being used with no restrictions to replace BPA, which increases the concern regarding its safety and claims for further investigation on its potential mechanisms of toxicity. The present study aims to access liver molecular disturbances which could be associated with systemic metabolic disorders following exposure to BPA or BPS. Therefore, body weight gain and serum biochemical parameters were measured in male Wistar rats chronically exposed to 50 or 500 µg/kg/day of BPA or BPS, while an extensive evaluation of liver protein expression changes was conducted after exposure to 50 µg/kg/day of both compounds. Exposure to the lowest dose of BPA led to the development of hyperglycemia and hypercholesterolemia, while the BPS lowest dose led to the development of hypertriglyceridemia. Besides, exposure to 500 µg/kg/day of BPS significantly increased body weight gain and LDL-cholesterol levels. Hepatic proteins differentially expressed in BPA and BPS-exposed groups compared to the control group were mostly related to lipid metabolism and synthesis, with upregulation of glucokinase activity-related sequence 1 (1.8-fold in BPA and 2.4-fold in BPS), which is involved in glycerol triglycerides synthesis, and hydroxymethylglutaryl-CoA synthase cytoplasmic (2-fold in BPS), an enzyme involved in mevalonate biosynthesis. Essential mitochondrial proteins of the electron transport chain were upregulated after exposure to both contaminants. Also, BPA and BPS dysregulated expression of liver antioxidant enzymes, which are involved in cellular reactive oxygen species detoxification. Altogether, the results of the present study contribute to expand the scientific understanding of how BPA and BPS lead to the development of metabolic disorders and reinforce the risks associated with exposure to these contaminants.


Assuntos
Compostos Benzidrílicos , Fenóis , Proteômica , Sulfonas , Animais , Compostos Benzidrílicos/toxicidade , Fígado , Masculino , Fenóis/toxicidade , Ratos , Ratos Wistar , Sulfonas/toxicidade
17.
Med Chem ; 16(2): 244-255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30987574

RESUMO

BACKGROUND: Peptic ulcer and urolithiasis are largely due to infection caused by ureaseproducing bacteria. Therefore, the discovery of urease inhibitors is an important area of medicinal chemistry research. OBJECTIVE: The main aim of the work was to identify novel urease inhibitors with no cytotoxicity. METHODS: During the current study, a series of ß-ketosulfones 1-26 was synthesized in two steps and evaluated for their in vitro urease inhibition potential. RESULTS: Out of twenty-six compounds, seventeen have shown good to significant urease inhibitory activity with IC50 values ranging between 49.93-351.46 µM, in comparison to standard thiourea (IC50 = 21 ± 0.11 µM). Moreover, all compounds found to be non-cytotoxic against normal 3T3 cell line. CONCLUSION: This study has identified ß-ketosulfones as novel and non-cytotoxic urease inhibitors.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Urease/antagonistas & inibidores , Animais , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Conformação Proteica , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/toxicidade , Urease/química , Urease/metabolismo
18.
Chemosphere ; 241: 125092, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683443

RESUMO

Environmental pollution is increasingly considered an important factor involved in the obesity incidence. Endocrine disruptors (EDs) are important actors in the concept of DOHaD (Developmental Origins of Health and Disease), where epigenetic mechanisms play crucial roles. Bisphenol A (BPA), a monomer used in the manufacture of plastics and resins is one of the most studied obesogenic endocrine disruptor. Bisphenol S (BPS), a BPA substitute, has the same obesogenic properties, acting at low doses with a sex-specific effect following perinatal exposure. Since the liver is a major organ in regulating body lipid homeostasis, we investigated gene expression and DNA methylation under low-dose BPS exposure. The BPS obesogenic effect was associated with an increase of hepatic triglyceride content. These physiological disturbances were accompanied by genome-wide changes in gene expression (1366 genes significantly modified more than 1.5-fold). Gene ontology analysis revealed alteration of gene cascades involved in protein translation and complement regulation. It was associated with hepatic DNA hypomethylation in autosomes and hypermethylation in sex chromosomes. Although no systematic correlation has been found between gene repression and hypermethylation, several genes related to liver metabolism were either hypermethylated (Acsl4, Gpr40, Cel, Pparδ, Abca6, Ces3a, Sgms2) or hypomethylated (Soga1, Gpihbp1, Nr1d2, Mlxipl, Rps6kb2, Esrrb, Thra, Cidec). In specific cases (Hapln4, ApoA4, Cidec, genes involved in lipid metabolism and liver fibrosis) mRNA upregulation was associated with hypomethylation. In conclusion, we show for the first time wide disruptive physiological effects of low-dose of BPS, which raises the question of its harmlessness as an industrial substitute for BPA.


Assuntos
Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/induzido quimicamente , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/toxicidade , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenóis/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/genética , Sulfonas/administração & dosagem , Testes de Toxicidade
19.
Environ Sci Pollut Res Int ; 27(2): 1800-1807, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31758481

RESUMO

DNA damage in the liver and kidney cells of adult male Wistar rats was studied using the comet assay after a 28-day oral administration of tembotrione at doses of 0.0007, 0.0013 and 0.7 mg/kg b.w./day [AOEL (acceptable operator exposure level), REL (residual exposure level) and 1000× AOEL]. As a descriptor of DNA damage, tail intensity was used. Antioxidant status was assessed by activity of glutathione peroxidase (GPx). Significant DNA damage was recorded in the kidney cells at all three doses as compared to negative control. In parenchymal liver cells, significant DNA damage was observed in AOEL and 1000× AOEL doses, while in non-parenchymal liver cells, only AOEL-treated group was significantly different compared to negative control. In both types of liver cells, REL and 1000× AOEL doses were significantly different from the AOEL dose. No significant changes in GPx activity compared to control were observed at any exposure level. The results of the present study suggest that repeated in vivo exposure to tembotrione led to low-level DNA instability in kidney and liver cells. Exposure to the highest tembotrione dose showed a relatively weak response with the alkaline comet assay. Further research should focus on the effects of this herbicide in other models along with different exposure scenarios.


Assuntos
Cicloexanonas/toxicidade , Dano ao DNA , Herbicidas/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Sulfonas/toxicidade , Administração Oral , Animais , Ensaio Cometa , Rim/patologia , Fígado/patologia , Masculino , Ratos , Ratos Wistar , Testes de Toxicidade Subcrônica
20.
Environ Pollut ; 257: 113639, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31796315

RESUMO

Epidemiological studies have investigated the associations of bisphenol A (BPA) exposure with hypertension risk or blood pressure levels, but findings are inconsistent. Furthermore, the association between its alternatives bisphenol S and F (BPS and BPF) and hypertension risk are not yet known. We conducted a cross-sectional study in 1437 eligible participants without hypertension-related diseases, with complete data about blood pressure levels, hypertension diagnosis, and urinary bisphenols concentrations. Multivariable logistic and linear models were respectively applied to examine the associations of urinary bisphenols concentrations with hypertension risk and blood pressure levels. The dose-response relationship was explored by the restricted cubic spline model. Compared with the reference group of BPA, individuals in the middle and high exposure group had an adjusted odds ratio (OR) of 1.30 and 1.40 for hypertension, had a 3.08 and 2.82 mm Hg higher systolic blood pressure (SBP) levels, respectively, with an inverted "U" shaped dose-response relationship. Compared with the reference group of BPS, individuals in the second and third tertile had an adjusted OR of 1.49 and 1.48 for hypertension, had a 2.61 and 3.89 mm Hg increased levels of SBP, respectively, with a monotonic curve. No significant associations of BPF exposure with hypertension risk or blood pressure levels were found. BPA and BPS exposure were suggested to be associated with increased hypertension risk and blood pressure levels, with different dose-response relationships. Our findings have important implications for public health but require confirmation in prospective studies.


Assuntos
Compostos Benzidrílicos , Pressão Sanguínea , Hipertensão , Fenóis , Sulfonas , Compostos Benzidrílicos/análise , Compostos Benzidrílicos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , China , Estudos Transversais , Humanos , Hipertensão/induzido quimicamente , Fenóis/análise , Fenóis/toxicidade , Estudos Prospectivos , Sulfonas/análise , Sulfonas/toxicidade
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