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1.
Horm Metab Res ; 53(9): 575-587, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34496408

RESUMO

Global warming and the rising prevalence of obesity are well described challenges of current mankind. Most recently, the COVID-19 pandemic arose as a new challenge. We here attempt to delineate their relationship with each other from our perspective. Global greenhouse gas emissions from the burning of fossil fuels have exponentially increased since 1950. The main contributors to such greenhouse gas emissions are manufacturing and construction, transport, residential, commercial, agriculture, and land use change and forestry, combined with an increasing global population growth from 1 billion in 1800 to 7.8 billion in 2020 along with rising obesity rates since the 1980s. The current Covid-19 pandemic has caused some decline in greenhouse gas emissions by limiting mobility globally via repetitive lockdowns. Following multiple lockdowns, there was further increase in obesity in wealthier populations, malnutrition from hunger in poor populations and death from severe infection with Covid-19 and its virus variants. There is a bidirectional relationship between adiposity and global warming. With rising atmospheric air temperatures, people typically will have less adaptive thermogenesis and become less physically active, while they are producing a higher carbon footprint. To reduce obesity rates, one should be willing to learn more about the environmental impact, how to minimize consumption of energy generating carbon dioxide and other greenhouse gas emissions, and to reduce food waste. Diets lower in meat such as a Mediterranean diet, have been estimated to reduce greenhouse gas emissions by 72%, land use by 58%, and energy consumption by 52%.


Assuntos
Mudança Climática , Obesidade/etiologia , Agricultura/economia , Agricultura/tendências , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/patologia , Mudança Climática/história , Comorbidade , Disruptores Endócrinos/toxicidade , Meio Ambiente , Exposição Ambiental/história , Exposição Ambiental/estatística & dados numéricos , Gases de Efeito Estufa/toxicidade , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Obesidade/epidemiologia , Obesidade/metabolismo , Pandemias , Fatores de Risco
2.
Environ Int ; 156: 106747, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34425642

RESUMO

BACKGROUND: Toxicology studies have identified pregnancy as a window of susceptibility for endocrine disrupting chemicals (EDCs) and cardiometabolic indices in women. No study in humans, however, has examined EDC mixtures and cardiometabolic indices during pregnancy. METHODS: We used the Health Outcomes and Measures of the Environment (HOME) Study to examine whether bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFAS), and phthalates are associated with blood pressure, glucose, and lipids in 388 pregnant women. We measured PBDEs and PFAS in serum at 16 weeks gestation, while BPA and phthalate metabolites were quantified in urine at 16 and 26 weeks gestation. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate covariate-adjusted associations of individual EDCs and their mixtures with cardiometabolic indices during pregnancy. RESULTS: A 10-fold increase in BDE-28 was associated with a 13.1 mg/dL increase in glucose (95% Confidence Interval [CI] 2.9, 23.2) in linear regression. The BKMR model also identified BDE-28 as having a positive association with glucose. BDE-28, BDE-47, and BDE-99 were positively associated with total cholesterol in both single- and multi-pollutant models, whereas a suggestive negative association was noted with BDE-153. Mono-n-butyl phthalate (MBP) (ß = -7.9 mg/dL, 95% CI -12.9, -3.0) and monobenzyl phthalate (MBzP) (ß = -6.3 mg/dL, 95% CI -10.6, -2.0) were both associated with significant decreases in cholesterol in linear regression, but only MBzP was identified as an important contributor in the BKMR model. CONCLUSION: Overall, we observed positive associations between PBDEs with glucose and cholesterol levels during pregnancy, while negative associations were found between some phthalate biomarkers and cholesterol. No relationship was noted for BPA or PFAS with cardiometabolic indices during pregnancy across both models.


Assuntos
Doenças Cardiovasculares , Disruptores Endócrinos , Poluentes Ambientais , Teorema de Bayes , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Feminino , Idade Gestacional , Humanos , Gravidez
3.
Environ Pollut ; 285: 117464, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34380212

RESUMO

Anthropogenic environmental change poses a special threat to species in which genetic sex determination can be overwritten by the thermal and chemical environment. Endocrine disrupting chemicals as well as extreme temperatures can induce sex reversal in such species, with potentially wide-ranging consequences for fitness, demography, population viability and evolution. Despite accumulating evidence suggesting that chemical and thermal effects may interact in ecological contexts, little is known about their combined effects on sex reversal. Here we assessed the simultaneous effects of high temperature (female-to-male sex-reversing agent) and 17α-ethinylestradiol (EE2), a widespread xenoestrogen (male-to-female sex-reversing agent), on sexual development and fitness-related traits in agile frogs (Rana dalmatina). We exposed tadpoles to a six-days heat wave (30 °C) and/or an ecologically relevant concentration of EE2 (30 ng/L) in one of three consecutive larval periods, and diagnosed sex reversals two months after metamorphosis using species-specific markers for genetic sexing. We found that high temperature induced female-to-male sex reversal, decreased survival, delayed metamorphosis, decreased body mass at metamorphosis, and increased the proportion of animals that had no fat bodies, while EE2 had no effect on these traits. Simultaneous exposure to heat and EE2 had non-additive effects on juvenile body mass, which were dependent on treatment timing and further complicated by a negative effect of sex reversal on body mass. These results show that environmentally relevant exposure to EE2 does not diminish the female-to-male sex-reversing effects of high temperature. Instead, our findings on growth suggest that climate change and chemical pollution may have complex consequences for individual fitness and population persistence in species with environment-sensitive sex determination.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , Animais , Anuros , Mudança Climática , Disruptores Endócrinos/toxicidade , Etinilestradiol , Feminino , Masculino , Temperatura , Poluentes Químicos da Água/toxicidade
4.
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
5.
Artigo em Inglês | MEDLINE | ID: mdl-34444624

RESUMO

Endocrine-disrupting chemicals (EDCs) are found in food and various other substances, including pesticides and plastics. EDCs are easily absorbed into the body and have the ability to mimic or block hormone function. The radioligand binding assay based on the estrogen receptors binding affinity is widely used to detect estrogenic EDCs but is limited to radioactive substances and requires specific conditions. As an alternative, we developed a human cell-based dimerization assay for detecting EDC-mediated ER-alpha (ERα) dimerization using bioluminescence resonance energy transfer (BRET). The resultant novel BRET-based on the ERα dimerization assay was used to identify the binding affinity of 17ß-estradiol (E2), 17α-estradiol, corticosterone, diethylhexyl phthalate, bisphenol A, and 4-nonylphenol with ERα by measuring the corresponding BRET signals. Consequently, the BRET signals from five chemicals except corticosterone showed a dose-dependent sigmoidal curve for ERα, and these chemicals were suggested as positive chemicals for ERα. In contrast, corticosterone, which induced a BRET signal comparable to that of the vehicle control, was suggested as a negative chemical for ERα. Therefore, these results were consistent with the results of the existing binding assay for ERα and suggested that a novel BRET system can provide information about EDCs-mediated dimerization to ERα.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Dimerização , Disruptores Endócrinos/toxicidade , Transferência de Energia , Humanos , Receptores de Estrogênio/metabolismo
6.
Ecotoxicol Environ Saf ; 221: 112449, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34214916

RESUMO

Dimethoxyethyl phthalate (DMEP) is an environmental endocrine disruptor. However, research into the underlying mechanisms of DMEP mitochondrial toxicity is still in its infancy. We therefore expect to understand whether DMEP induced mitochondrial damage in HepG2 cells and the associated signaling pathways. DMEP (0.125, 0.25, 0.5, 1 and 2 mM) exposure for 48 h induced a notable increment in reactive oxygen species (ROS), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate transaminase (AST) and 8-hydroxydeoxyguanosine (8-OHdG) in hepG2 cells, resulting in cellular oxidative stress. Low doses of DMEP upregulated nuclear factor E2-related factor 2 (Nrf2) and downstream protein haeme oxygenase-1 (HO-1) levels and high doses down-regulated their levels. Nrf2 levels increased after ROS scavenging by N-acetyl-L-cysteine (NAC), which indicated that the Nrf2 pathway may be affected by oxidative stress. We also found that DMEP decreased ATP content, mitochondrial copy number (mtDNA), translocase of the outer membrane subunit 20 (TOM20) expression, mitochondria-encoded genes CO1, CO2, CO3, ATP6, ATP8 expression, inhibited mitochondrial biogenesis pathway, down-regulated sirtuin 1(SIRT1), PPAR gamma co-activator 1 alpha (PGC-1α), Nuclear respiratory factor 1(Nrf1), Mitochondrial transcription factor A (TFAM) content and activated PINK1/Parkin autophagy pathway. DMEP also activated the mitochondrial apoptotic pathway, causing cytochrome c cytoplasmic translocation and caspase 3 cleavage. What's more, DMEP activated the Nuclear factor-κB (NF-κB) pathway and levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were significantly upregulated, causing an inflammatory response. In summary, DMEP can cause inflammatory response and oxidative stress in HepG2 cells, inhibited the Nrf2 pathway and mitochondrial biogenesis, and induced autophagy and apoptosis. And oxidative stress at least partially affected the Nrf2 pathway and mitochondrial biogenesis SIRT1/PGC-1α pathway.


Assuntos
Disruptores Endócrinos/toxicidade , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ácidos Ftálicos/toxicidade , Sirtuína 1/metabolismo , Células Hep G2 , Humanos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
Sci Total Environ ; 794: 148489, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34217092

RESUMO

In the present study we evaluated cytotoxic and genotoxic activities of endocrine disrupting compounds (EDCs), including dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), and nonylphenol (NP), which have been previously identified in effluents from two paper mills with different paper production technologies (virgin or recycled fibres). Moreover, we evaluated genotoxic activity of the effluents from these two paper mills and compared it to the activity of artificial complex mixtures consisting of the seven EDCs at concentrations detected in corresponding paper mill effluents. None of the EDCs was genotoxic in Salmonella typhimurium (SOS/umuC assay), while all induced DNA damage in human hepatocellular carcinoma (HepG2) cells (comet assay). After 4 h of exposure genotoxic effects were determined at concentrations ≥ 1 µg/L for BBP and DEHP, ≥10 µg/L for DMP, DEP, DBP, and BPA, and ≥100 µg/L for NP, while after 24 h of exposure DNA damage occurred at ≥10 µg/L for DBP, BPA and NP, and ≥100 µg/L for DMP, DEP, BBP and DEHP. The effluents and corresponding artificial mixtures of EDCs from paper mill that uses virgin fibres did not induce DNA damage in HepG2 cells, while the effluents and corresponding artificial mixtures for the paper mill that uses recycled fibres were genotoxic. Genotoxic activity of effluents was significantly higher compared to corresponding artificial mixtures suggesting the presence of further unknown compounds contributing to the effect. Wastewater monitoring based on chemical analysis is limited to determination of targeted compounds and does not take into account possible interactions between chemicals in mixtures. Therefore, it alone cannot provide an adequate information on potential toxic effects required for the assessment of genotoxic activity of real environmental samples and their potential threats to the environment and human health.


Assuntos
Disruptores Endócrinos , Ácidos Ftálicos , Compostos Benzidrílicos/análise , Ensaio Cometa , Dano ao DNA , Dibutilftalato , Disruptores Endócrinos/análise , Disruptores Endócrinos/toxicidade , Humanos , Águas Residuárias
8.
Toxicol Appl Pharmacol ; 426: 115639, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256052

RESUMO

Polychlorinated biphenyls (PCBs) are endocrine disrupting chemicals with documented, though mechanistically ill-defined, reproductive toxicity. The toxicity of dioxin-like PCBs, such as PCB126, is mediated via the aryl hydrocarbon receptor (AHR) in non-ovarian tissues. The goal of this study was to examine the uterine and ovarian effects of PCB126 and test the hypothesis that the AHR is required for PCB126-induced reproductive toxicity. Female Holzman-Sprague Dawley wild type (n = 14; WT) and Ahr knock out (n = 11; AHR-/-) rats received a single intraperitoneal injection of either corn oil vehicle (5 ml/kg: WT_O and AHR-/-_O) or PCB126 (1.63 mg/kg in corn oil: WT_PCB and AHR-/-_PCB) at four weeks of age. The estrous cycle was synchronized and ovary and uterus were collected 28 days after exposure. In WT rats, PCB126 exposure reduced (P < 0.05) body and ovary weight, uterine gland number, uterine area, progesterone, 17ß-estradiol and anti-Müllerian hormone level, secondary and antral follicle and corpora lutea number but follicle stimulating hormone level increased (P < 0.05). In AHR-/- rats, PCB126 exposure increased (P ≤ 0.05) circulating luteinizing hormone level. Ovarian or uterine mRNA abundance of biotransformation, and inflammation genes were altered (P < 0.05) in WT rats due to PCB126 exposure. In AHR-/- rats, the transcriptional effects of PCB126 were restricted to reductions (P < 0.05) in three inflammatory genes. These findings support a functional role for AHR in the female reproductive tract, illustrate AHR's requirement in PCB126-induced reprotoxicity, and highlight the potential risk of dioxin-like compounds on female reproduction.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Disruptores Endócrinos/toxicidade , Bifenilos Policlorados/toxicidade , Receptores de Hidrocarboneto Arílico/deficiência , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biotransformação/genética , Peso Corporal/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/sangue , Tamanho do Órgão/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores de Hidrocarboneto Arílico/genética , Reprodução/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia
9.
Environ Int ; 156: 106751, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34271427

RESUMO

Endocrine disrupting compounds (EDCs) are a persistent threat to humans and wildlife due to their ability to interfere with endocrine signaling pathways. Inspired by previous work to improve chemical hazard identification through the use of toxicogenomics data, we developed a genomic-oriented data space for profiling the molecular activity of EDCs in an in silico manner, and for creating predictive models that identify and prioritize EDCs. Predictive models of EDCs, derived from gene expression data from rats (in vivo and in vitro primary hepatocytes) and humans (in vitro primary hepatocytes and HepG2), achieve testing accuracy greater than 90%. Negative test sets indicate that known safer chemicals are not predicted as EDCs. The rat in vivo-based classifiers achieve accuracy greater than 75% when tested for invitro to in vivoextrapolation. This study reveals key metabolic pathways and genes affected by EDCs together with a set of predictive models that utilize these pathways to prioritize EDCs in dose/time dependent manner and to predict EDCevokedmetabolic diseases.


Assuntos
Disruptores Endócrinos , Toxicogenética , Animais , Simulação por Computador , Disruptores Endócrinos/toxicidade , Expressão Gênica , Ratos
10.
Artigo em Inglês | MEDLINE | ID: mdl-34202247

RESUMO

Several available studies have already analyzed the systemic effects of endocrine-disrupting chemicals (EDCs) on fertile woman and neonatal outcomes, but little is still known in humans about the precise mechanisms of interference of these compounds with the endometrial receptivity. There is consistent evidence that continuous and prolonged exposure to EDCs is a risk factor for reduced fertility and fecundity in women. Preliminary studies on mammalian models provide robust evidence about this issue and could help gynecologists worldwide to prevent long term injury caused by EDCs on human fertility. In this systematic review, we aimed to systematically summarize all available data about EDC effects on blastocyst endometrial implantation. We performed a systematic review using PubMed®/MEDLINE® to summarize all in vivo studies, carried out on mice models, analyzing the molecular consequences of the prolonged exposure of EDC on the implantation process. 34 studies carried out on mouse models were included. Primary effects of EDC were a reduction of the number of implantation sites and pregnancy rates, particularly after BPA and phthalate exposure. Furthermore, the endometrial expression of estrogen (ER) and progesterone receptors (PR), as well as their activation pathways, is compromised after EDC exposure. Finally, the expression of the primary endometrial markers of receptivity (such as MUC1, HOXA10, Inn and E-cadherin) after EDC contact was analyzed. In conclusion EDC deeply affect blastocyst implantation in mouse model. Several players of the implantation mechanism are strongly influenced by the exposure to different categories of EDC.


Assuntos
Disruptores Endócrinos , Animais , Implantação do Embrião , Disruptores Endócrinos/toxicidade , Endométrio , Feminino , Fertilidade , Humanos , Camundongos , Receptores de Progesterona
11.
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
12.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202188

RESUMO

Various natural compounds have been successfully tested for preventing or counteracting the toxic effects of exposure to heavy metals. In this study, we analyzed the effects of cadmium chloride (CdCl2) on immortalized, non-tumorigenic thyroid cells Nthy-ori-3-1. We investigated the molecular mechanism underlying its toxic action as well as the potential protective effect of quercetin against CdCl2-induced damage. CdCl2 suppressed cell growth in a dose- and time-dependent manner (IC50 value ~10 µM) associated with a decrease in levels of phospho-ERK. In addition, CdCl2 elicited an increase in reactive oxygen species (ROS) production and lipid peroxidation. A significant increase in GRP78, an endoplasmic reticulum (ER) stress-related protein, was also observed. Supplementation of quercetin counteracted the growth-inhibiting action of CdCl2 by recovering ERK protein phosphorylation levels, attenuating ROS overproduction, decreasing MDA content and reducing the expression of GRP78 in cells exposed to CdCl2. Thus, in addition to revealing the molecular effects involved in cadmium-induced toxicity, the present study demonstrated, for the first time, a protective effect of quercetin against cadmium-induced damages to normal thyroid cells.


Assuntos
Cádmio/toxicidade , Disruptores Endócrinos/toxicidade , Substâncias Protetoras/farmacologia , Quercetina/farmacologia , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cloreto de Cádmio/toxicidade , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Glândula Tireoide/metabolismo
13.
Toxicology ; 459: 152860, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280466

RESUMO

Di-n-butyl phthalate (DBP) is considered as a potential modifier of puberty. However, different results indicate that DBP plays an accelerated, delayed, or neutral role in the initiation of puberty. Furthermore, whether the effect of DBP on puberty will disrupt the function of reproductive system in the adults is still ambiguous. Therefore, we aimed to investigate the effect of maternal exposure to DBP on the onset of puberty in male offspring mice and the subsequent changes in the development of reproductive system. Here, pregnant mice were treated with 0 (control), 50, 250, or 500 mg/kg/day DBP in 1 mL/kg corn oil administered daily by oral gavage from gestation day (GD) 12.5 to parturition. Compared with the control group, the 50 mg/kg/day DBP group accelerated puberty onset and testicular development were quite remarkable in male offspring mice during early puberty. Furthermore, in 22-day male offspring mice, 50 mg/kg/day DBP induced increased levels of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone in serum, and promoted the expression of steroidogenesis-related genes in the testes. Testicular Leydig cells (LCs) were isolated from the testes of 3-week-old mice and treated with 0 (control), 0.1, 1 mM monobutyl phthalate (MBP, the active metabolite of DBP) for 24 h. Consistent with the in vivo results, the expression of steroidogenesis-related genes and testosterone production were increased in LCs following exposure to 0.1 mM MBP. In adulthood, testes of the male offspring mice exposed to all doses of DBP exhibited adverse morphology compared with the control group. These results demonstrated that maternal exposure to 50 mg/kg/day DBP induced earlier puberty and precocious development of the testis, and eventually damaged the reproductive system in the later life.


Assuntos
Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Maturidade Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Animais , Barreira Hematotesticular/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/análise , Hormônios Esteroides Gonadais/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos BALB C , Ácidos Ftálicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Espermatogênese/efeitos dos fármacos , Esteroides/biossíntese
14.
Sci Total Environ ; 796: 148901, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34265613

RESUMO

The endocrine disrupting chemicals (EDCs) have been at the forefront of environmental issues for over 20 years and are a principle factor considered in every ecological risk assessment, but this kind of risk assessment faces difficulties. The expense, time cost of in vivo tests, and lack of toxicity data are key limiting factors for the ability to conduct ecological risk assessments of EDCs to aquatic species. In this study, a machine learning model named the support vector machine (SVM) was used to predict the reproductive toxicity of EDCs, and the performance of the models was evaluated. The results showed that the SVM model provided more accurate toxicity prediction data compared with the interspecies correlation estimation (ICE) model developed by previous study to predict the reproductive toxicity. The application of the predicted toxicity data was an important supplement to the observed data for the ecological risk assessment of EDCs in the Yangtze River, where estrogens and phenolic compounds have been found at some sampling sites in the middle and lower reaches. The results showed that the ecological risk of estrone, 17ß-estradiol, and ethinyl estradiol were significant. This study revealed the application potential of machine learning models for the prediction of reproductive toxicity effects of EDCs. This can provide reliable alternative toxicity data for the ecological risk assessments of EDCs.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , China , Disruptores Endócrinos/análise , Disruptores Endócrinos/toxicidade , Monitoramento Ambiental , Aprendizado de Máquina , Medição de Risco , Rios , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
15.
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
16.
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
17.
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
18.
Environ Res ; 200: 111345, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34087190

RESUMO

Everyday use chemicals have been demonstrated to be endocrine disruptors. Since normal thyroid function during pregnancy is transcendental for the neurodevelopment of the offspring, knowledge of endocrine disrupting chemicals (EDC) is of main importance. The aim of our study is to recognize and describe EDC actions in pregnant women and focus on neurodevelopmental processes that can lead to neurotransmitter imbalance and cognitive impairment, and the possible clinical outcomes in the newborn and child. We searched PubMed databases for animal studies and clinical trials evaluating chemicals recognized as thyroid disruptors -perchlorate, phthalates, bisphenol A-, as well as chemicals with potential thyroid disruption activity -parabens, pesticides and persistent organic pollutants, on thyroid hormones (THs) levels and their bioavailability during pregnancy, and the outcome in newborns, infants and children. We also exhibit evidence from worldwide cohort studies to this regard. The publications reviewed show: 1) known endocrine disruptors have an association with hormonal thyroid levels, where an effect of increase or decrease in TH concentrations has been reported depending on the chemical exposed 2) associations between TH, EDCs and neurocognitive disorders have been addressed, such as ADHD, though no conclusive impact on potential related disorders as autism has been established, 3) perchlorate has demonstrated effects on thyroid levels on iodine uptake. In conclusion, detrimental risks and long-term consequences after in-utero exposure to EDCs are being reported in several cohort studies and further research must be conducted to establish a well-known cause-effect association.


Assuntos
Disruptores Endócrinos , Poluentes Ambientais , Praguicidas , Animais , Disruptores Endócrinos/toxicidade , Exposição Ambiental , Poluentes Ambientais/toxicidade , Feminino , Humanos , Recém-Nascido , Parabenos , Gravidez , Hormônios Tireóideos
19.
Environ Res ; 200: 111386, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34087191

RESUMO

BACKGROUND: Improved understanding of how prenatal exposure to environmental mixtures influences birth weight or other adverse outcomes is essential in protecting child health. OBJECTIVE: We illustrate a novel exposure continuum mapping (ECM) framework that combines the self-organizing map (SOM) algorithm with generalized additive modeling (GAM) in order to integrate spatially-correlated learning into the study mixtures of environmental chemicals. We demonstrate our method using biomarker data on chemical mixtures collected from a diverse mother-child cohort. METHODS: We obtained biomarker concentrations for 16 prevalent endocrine disrupting chemicals (EDCs) collected in the first-trimester from a large, ethnically/racially diverse cohort of healthy pregnant women (n = 604) during 2009-2012. This included 4 organochlorine pesticides (OCPs), 4 polybrominated diphenyl ethers (PBDEs), 4 polychlorinated biphenyls (PCBs), and 4 perfluoroalkyl substances (PFAS). We applied a two-stage exposure continuum mapping (ECM) approach to investigate the combined impact of the EDCs on birth weight. First, we analyzed our EDC data with SOM in order to reduce the dimensionality of our exposure matrix into a two-dimensional grid (i.e., map) where nodes depict the types of EDC mixture profiles observed within our data. We define this map as the 'exposure continuum map', as the gridded surface reflects a continuous sequence of exposure profiles where adjacent nodes are composed of similar mixtures and profiles at more distal nodes are more distinct. Lastly, we used GAM to estimate a joint-dose response based on the coordinates of our ECM in order to capture the relationship between participant location on the ECM and infant birth weight after adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index (BMI), education, serum cotinine, total plasma lipids, and infant sex. Single chemical regression models were applied to facilitate comparison. RESULTS: We found that an ECM with 36 mixture profiles retained 70% of the total variation in the exposure data. Frequency analysis showed that the most common profiles included relatively low concentrations for most EDCs (~10%) and that profiles with relatively higher concentrations (for single or multiple EDCs) tended to be rarer (~1%) but more distinct. Estimation of a joint-dose response function revealed that lower birth weights mapped to locations where profile compositions were dominated by relatively high PBDEs and select OCPs. Higher birth weights mapped to locations where profiles consisted of higher PCBs. These findings agreed well with results from single chemical models. CONCLUSIONS: Findings from our study revealed a wide range of prenatal exposure scenarios and found that combinations exhibiting higher levels of PBDEs were associated with lower birth weight and combinations with higher levels of PCBs and PFAS were associated with increased birth weight. Our ECM approach provides a promising framework for supporting studies of other exposure mixtures.


Assuntos
Disruptores Endócrinos , Poluentes Ambientais , Efeitos Tardios da Exposição Pré-Natal , Peso ao Nascer , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Feminino , Humanos , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
20.
Chemosphere ; 282: 131013, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34090004

RESUMO

We have previously shown that adult male mice exposure to low doses of di(2-ethylhexyl)phthalate (DEHP) alters neural function and behaviour. Whether such exposure also affects the integrity and function of the blood-brain barrier (BBB) remained to be explored. The impact of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on the BBB integrity and surrounding parenchyma was studied in male mice. Two-month-old C57BL/6J males were orally exposed for 6 weeks to DEHP alone (5, and 50 µg/kg/day) or to DEHP (5 µg/kg/day) in an environmental phthalate mixture. BBB permeability, glial activation and neuroinflammation were investigated in the hypothalamic medial preoptic area (mPOA) and hippocampus involved, respectively on the reproductive and cognitive functions. Exposure to DEHP alone or in a phthalate mixture increased BBB permeability and affected the endothelial accessory tight junction protein zona occludens-1 and caveolae protein Cav-1 in the mPOA and the hippocampal CA1 and CA3 areas. This was associated with an inflammatory profile including astrocyte activation accompanied by enhanced expression of inducible nitric oxide synthase in the mPOA, and a microglial activation in the mPOA and the hippocampal CA1 and CA3 areas. The protein levels of the inflammatory molecule cyclooxygenase-2 were increased in activated microglial cells of the exposed mPOA. None of the major effects induced by DEHP alone or in a mixture was detected in the hippocampal dendate gyrus. The data highlight that environmental exposure to endocrine disruptors such as phthalates, could represent a risk factor for the cerebrovascular function.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Ácidos Ftálicos , Animais , Barreira Hematoencefálica , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Exposição Ambiental , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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