Assuntos
Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/toxicidade , Exposição Ambiental/efeitos adversos , Disruptores Endócrinos/administração & dosagem , Humanos , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/metabolismo , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Fatores de TempoRESUMO
Endocrine-disrupting compounds as pesticides affect the hormonal balance, and this can result in several diseases. Therefore, the analysis of representative hormones with acetamiprid (AC) and azoxystrobin (AZ) was a good strategy for the investigation of the endocrine-disrupting activity of pesticides. Hence, a sensitive and rapid analytical method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. The method was validated for the analysis of AC, AZ, estriol, estrone, progesterone, and testosterone in the serum, testis, and liver of rats. The correlation between the residues of pesticides and the disturbance of the endocrine system was evaluated. The different mass parameters, mobile phase types, analytical columns, injection volumes, and extraction solvents were compared to get the lowest limit of detection of the studied compounds. The detection limits of AC, AZ, estriol, estrone, progesterone, and testosterone were 0.05, 0.05, 1.0, 10, and 1.0 ng/ml, respectively. The method developed was applied to evaluate the changes in these hormones induced by the duration of exposure to AC and AZ in rat testis and serum. The hormones level in rat serum and testis had a significant decrease as they were oral gavage treated with different high concentrations of studied pesticides. Both pesticides were distributed in the body of rats by the multi-compartment model (liver, testis, and serum).
Assuntos
Disruptores Endócrinos/toxicidade , Hormônios Esteroides Gonadais/análise , Neonicotinoides/toxicidade , Pirimidinas/toxicidade , Estrobilurinas/toxicidade , Animais , Calibragem , Cromatografia Líquida/métodos , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/análise , Disruptores Endócrinos/farmacocinética , Estriol/análise , Estrona/análise , Limite de Detecção , Masculino , Neonicotinoides/administração & dosagem , Neonicotinoides/análise , Neonicotinoides/farmacocinética , Praguicidas/toxicidade , Pirimidinas/administração & dosagem , Pirimidinas/análise , Pirimidinas/farmacocinética , Ratos Wistar , Reprodutibilidade dos Testes , Estrobilurinas/administração & dosagem , Estrobilurinas/análise , Estrobilurinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Testosterona/análise , Distribuição TecidualRESUMO
Cyclic siloxane octamethylcyclotetrasiloxane (D4) has raised concerns as an endocrine-disrupting chemical (EDC). D4 is widely used in detergent products, cosmetics, and personal care products. Recently, robust toxicological data for D4 has been reported, but the adverse effects of D4 on brain development are unknown. Here, pregnant mice on gestational day 9.5 were treated daily with D4 to postnatal day 28, and the offspring mice were studied. The prenatal D4-treated mice exhibited cognitive dysfunction, limited memory, and motor learning defect. Moreover, prenatal D4 exposure reduced the proliferation of neuronal progenitors in the offspring mouse brain. Next, the mechanisms through which D4 regulated the cell cycle were investigated. Aberrant gene expression, such as cyclin-dependent kinases CDK6 and cyclin-dependent kinase inhibitor p27, were found in the prenatal D4-treated mice. Furthermore, the estrogen receptors ERa and ERb were increased in the brain of prenatal D4-treated mice. Overall, these findings suggest that D4 exerts estrogen activity that affects the cell cycle progression of neuronal progenitor cells during neurodevelopment, which may be associated with cognitive deficits in offspring.
Assuntos
Disruptores Endócrinos/toxicidade , Células-Tronco Neurais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Siloxanas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proliferação de Células , Cognição/efeitos dos fármacos , Disruptores Endócrinos/administração & dosagem , Feminino , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Atividade Motora/efeitos dos fármacos , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/patologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Fatores de Transcrição SOXB1/genética , Siloxanas/administração & dosagem , Comportamento SocialRESUMO
Triclosan (TCS) is a phenolic compound with broad-spectrum antimicrobial action that has been incorporated into a variety of personal care products and other industry segments such as toys, textiles, and plastics. Due to its widespread use, TCS and its derivatives have been detected in several environmental compartments, with potential bioaccumulation and persistence. Indeed, some studies have demonstrated that TCS may act as a potential endocrine disruptor for the reproductive system. In the current study, we are reporting on the results obtained for male rats after a two-generation reproduction toxicity study conducted with TCS. Female and male Wistar rats were treated daily by gavage with TCS at doses of 0.8, 2.4, and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) before mating and then throughout mating, until weaning F2 generations, respectively. TCS exposure decreased sperm viability and motility of F1 rats at the dose of 2.4 mg/kg. The effects of TCS on sperm quality may be related to the exposure window, which includes the programming of reproductive cells that occurs during fetal/neonatal development.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Disruptores Endócrinos/administração & dosagem , Reprodução/efeitos dos fármacos , Comportamento Sexual/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Triclosan/administração & dosagem , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Wistar , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Testosterona/sangueRESUMO
Thifluzamide is widely used fungicide and frequently detected in aquatic system. In this study, the toxicity of fungicide thifluzamide to non-targeted aquatic organisms was investigated for neuroendocrine disruption potentials. Here, zebrafish embryos were exposed to a series of concentrations of thifluzamide for 6 days. The results showed that both the development of embryos/larvae and the behavior of hatched larvae were significantly affected by thifluzamide. Importantly, the decreased activity of acetylcholinesterase (AchE) and the increased contents of neurotransmitters such as serotonin (5-HT) and norepinephrine (NE), along with transcriptional changes of nervous system related genes were observed following 4 days exposure to thifluzamide. Besides, the decreased contents of triiodothyronine (T3) and thyroxine (T4) in whole body, as well as significant expression alteration in hypothalamic-pituitary-thyroid (HPT) axis associated genes were discovered in zebrafish embryos after 4 days of exposure to thifluzamide. Our results clearly demonstrated that zebrafish embryos exposed to thifluzamide could disrupt neuroendocrine, compromise behavior and induce developmental abnormality, suggesting impact of this fungicide on developmental programming in zebrafish.
Assuntos
Anilidas/toxicidade , Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Tiazóis/toxicidade , Acetilcolinesterase/metabolismo , Anilidas/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Embrião não Mamífero/efeitos dos fármacos , Disruptores Endócrinos/administração & dosagem , Fungicidas Industriais/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Larva/efeitos dos fármacos , Norepinefrina/metabolismo , Serotonina/metabolismo , Tiazóis/administração & dosagem , Hormônios Tireóideos/metabolismo , Peixe-ZebraRESUMO
Triadimefon is a broad-spectrum antifungal agent, which is widely used in agriculture to control mold and fungal infections. It is considered an endocrine disruptor. Whether triadimefon exposure can inhibit the development of fetal adrenal glands and the underlying mechanism remain unclear. Thirty-two pregnant female Sprague-Dawley rats were randomly divided into four groups. Dams were gavaged triadimefon (0, 25, 50, and 100 mg/kg/day) daily for 10 days from gestational day (GD) 12 to GD 21. Triadimefon significantly reduced the thickness of the zona fasciculata of male fetuses at 100 mg/kg, although it did not change the thickness of the zona glomerulosa. It significantly reduced the serum aldosterone levels of male fetuses at a dose of 100 mg/kg, and significantly reduced serum corticosterone and adrenocorticotropic hormone levels at doses of 50 and 100 mg/kg. Triadimefon significantly down-regulated the expression of Agtr1, Mc2r, Star, Cyp11b1, Cyp11b2, Igf1, Nr5a1, Sod2, Gpx1, and Cat, but did not affect the mRNA levels of Scarb1, Cyp11a1, Cyp21, Hsd3b1, and Hsd11b2. Triadimefon markedly reduced AT1R, CYP11B2, IGF1, NR5A1, and MC2R protein levels. Triadimefon significantly reduced the phosphorylation of AKT1 and ERK1/2 at 100 mg/kg without affecting the phosphorylation of AKT2. In contrast, it significantly increased AMPK phosphorylation at 100 mg/kg. In conclusion, exposure to triadimefon during gestation inhibits the development of fetal adrenal cortex in male fetuses. This inhibition is possibly due to the reduction of several proteins required for the synthesis of steroid hormones, and may be involved in changes in antioxidant contents and the phosphorylation of AKT1, ERK1/2, and AMPK.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Exposição Materna/efeitos adversos , Triazóis/toxicidade , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/embriologia , Glândulas Suprarrenais/embriologia , Animais , Antioxidantes/metabolismo , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/toxicidade , Feminino , Fungicidas Industriais/administração & dosagem , Masculino , Fosforilação/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Triazóis/administração & dosagemRESUMO
The aim of this work was to determine whether chronic exposure to nonylphenol (NP), a representative substance of environmental endocrine disruptors (EEDs), at environmental concentration would have toxic effects on thyroid function and thyroid hyperplasia disease. Two hundred SPF Sprague-Dawley rats were divided into five groups (n = 40 per group): blank control group (corn oil), low-dose NP exposure group (0.4 mg/kg/d), medium-dose NP exposure group (4 mg/kg/d), high-dose NP exposure group (40 mg/kg/d), and estradiol control group (E2: 30 µg/kg/d). The rats were treated by gavage for 34 weeks, which were sampled twice (17 weeks and 34 weeks respectively). NP accumulation in the thyroid tissue (F = 52.93, P < 0.001) and serum (F = 5.54, P = 0.00) continuously increased in a significant dose-effect relationship. After NP exposure, the serum FT3 levels exhibited a dose-dependent increasing trend (F = 4.68, P = 0.01), while the serum FT4 level showed an opposite trend (F = 3.93, P= 0.01). Compared with the control group, hyperechoic areas (i.e., calcification points) were observed in the high-dose group. Follicular epithelial stratification was extremely severe, the monolayer cubic epithelial cells became flat, and the area of single follicles was even smaller in the high-dose group. In the high-dose NP group, there were numerous mitochondria that were severely swollen. The rough endoplasmic reticulum was abundant, with obvious expansion and vesiculation. The relative expression of ERα (F = 5.29, P = 0.00), ERß (F = 10.17, P = 0.00), TRα (F = 7.71, P = 0.00), TRß (F = 3.52.17, P = 0.02) and HMGB1 (F = 10.16, P = 0.01) proteins in the thyroid tissue in each NP exposure group was increased compared with the control group, and the relative expression of proteins increased if the exposure time was prolonged under the same exposure dose. Chronic exposure to NP at environmental concentration could have toxic effects on thyroid function, and induce thyroid hyperplasia disease in male rats.
Assuntos
Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Células Epiteliais da Tireoide/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Retículo Endoplasmático/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Masculino , Fenóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Células Epiteliais da Tireoide/citologia , Glândula Tireoide/patologia , Fatores de TempoRESUMO
OBJECTIVE: Bisphenol A (BPA) and nonylphenol (NP) are widely distributed endocrine-disrupting compounds. We aimed to estimate the combined toxicity of BPA and NP at a clinically safe dose (100 µg/kg) in rats. MATERIALS AND METHODS: Liver and kidney functions were evaluated by detecting the relevant indicators. Hematoxylin and Eosin (HE) staining was performed to examine the injury in the tissue. TUNEL assay and Western blot were used to detect cell apoptosis and expressions of target factors, respectively. RESULTS: The body weight of rats in the BPA + NP group was lighter than that in the BPA or NP group. BPA or NP weakened liver function through increasing levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), cholesterol (CHOL), triglyceride TG, globulin (GLOB), treponemiapallidum (TP), and total bilirubin (TBIL). BPA and NP could induce kidney damage by elevating the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). Moreover, the malondialdehyde (MDA) content was increased, whereas the activities of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX), glutathione sulfotransferase (GSH-ST), catalase (CAT), and peroxidase (POD) were reduced in those groups exposed to BPA or NP. HE staining exhibited injuries of the liver and kidney. Furthermore, the apoptosis of liver and kidney cells was enhanced by exposure to BPA or NP. Additionally, the expressions of CYP2D6, CYP1A1, and CYP2E1 were triggered by the treatment of BPA or NP. The combined effect of BPA and NP seemed to be antagonistic at a low dose. CONCLUSION: BPA and NP may have potential interactions.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Compostos Benzidrílicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Poluentes Ocupacionais do Ar/toxicidade , Animais , Compostos Benzidrílicos/administração & dosagem , Interações Medicamentosas/fisiologia , Disruptores Endócrinos/administração & dosagem , Estrogênios não Esteroides/administração & dosagem , Estrogênios não Esteroides/toxicidade , Fenóis/administração & dosagem , Ratos , Ratos WistarRESUMO
Amphibian endocrine systems interact with each other during normal development. Interference with one of the endocrine systems may influence others. We studied the effect of a thyroid inhibitor (ethylenethiourea [ETU]) on metamorphosis and ovary development of three species, Sphaerotheca pashchima, Indosylvirana caesari, and Euphlyctis cyanophlyctis with different larval durations. We treated the tadpoles of these species with 50, 100, and 200 mg/L concentrations of ETU and studied their larval duration, size at metamorphosis, and ovary development. The results revealed that ETU affects metamorphosis, depending on the species and concentration. ETU delayed metamorphosis of E. cyanophlyctis tadpoles and did not affect metamorphosis in S. pashchima tadpoles. Lower concentrations of ETU stimulated metamorphosis in I. caesari tadpoles while high concentration delayed metamorphosis. In the tadpoles (E. cyanophlyctis) treated with higher concentrations of ETU, ovary development was advanced with an increased size of the diplotene oocytes. Oocyte size was smaller in the tadpoles (of I. caesari) treated with lower concentrations of ETU. These results demonstrated that the tadpoles of these species show different responses to the thyroid inhibitor, possibly due to the differences in the larval duration and sensitivity. Inhibition or acceleration of metamorphosis did not interfere in the ovary development of E. cyanophlyctis and I. caesari. These results will be useful in understanding the impact of endocrine disruptors on the interaction between thyroid and sex steroid hormones.
Assuntos
Anuros/crescimento & desenvolvimento , Etilenotioureia/toxicidade , Larva/efeitos dos fármacos , Metamorfose Biológica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/toxicidade , Etilenotioureia/administração & dosagem , Feminino , Ovário/crescimento & desenvolvimentoRESUMO
Dichlorodiphenyltrichloroethane (DDT) is the most widespread, persistent pollutant and endocrine disruptor on the planet. Although DDT has been found to block androgen receptors, the effects of its low-dose exposure in different periods of ontogeny on the male reproductive system remain unclear. We evaluate sex steroid hormone production in the pubertal period and after maturation in male Wistar rats exposed to low doses of o,p'-DDT, either during prenatal and postnatal development or postnatal development alone. Prenatally and postnatally exposed rats exhibit lower testosterone production and increased estradiol and estriol serum levels after maturation, associated with the delayed growth of gonads. Postnatally exposed rats demonstrate accelerated growth of gonads and higher testosterone production in the pubertal period. In contrast to the previous group, they do not present raised estradiol production. All of the exposed animals exhibit a reduced conversion of progesterone to 17OH-progesterone after sexual maturation, which indicates putative attenuation of sex steroid production. Thus, the study reveals age-dependent outcomes of low-dose exposure to DDT. Prenatal onset of exposure results in the later onset of androgen production and the enhanced conversion of androgens to estrogens after puberty, while postnatal exposure induces the earlier onset of androgen secretion.
Assuntos
Androgênios/biossíntese , DDT/farmacologia , Disruptores Endócrinos/farmacologia , Exposição Ambiental/efeitos adversos , Estrogênios/biossíntese , Animais , DDT/administração & dosagem , Disruptores Endócrinos/administração & dosagem , Feminino , Genitália Masculina/efeitos dos fármacos , Genitália Masculina/metabolismo , Hormônios Esteroides Gonadais/biossíntese , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Masculino , RatosRESUMO
This article presents the outcomes of higher-tier repeated-dose toxicity studies and developmental and reproductive toxicity (DART) studies using Wistar rats requested for methyl paraben and propyl paraben under the European Union chemicals legislation. All studies revealed no-observed adverse effects (NOAELs) at 1000 mg/kg body weight/day. These findings (absence of effects) were then used to interpolate the hazard profile for ethyl paraben, further considering available data for butyl paraben. The underlying read-across hypothesis (all shorter-chained linear n-alkyl parabens are a 'category' based on very high structural similarity and are transformed to a common compound) was confirmed by similarity calculations and comparative in vivo toxicokinetics screening studies for methyl paraben, ethyl paraben, propyl paraben and butyl paraben. All four parabens were rapidly taken up systemically following oral gavage administration to rats, metabolised to p-hydroxybenzoic acid, and rapidly eliminated (parabens within one hour; p-hydroxybenzoic acid within 4-8 h). Accordingly, for ethyl paraben, the NOAELs for repeated-dose toxicity and DART were interpolated to be 1000 mg/kg body weight/day. Finally, all evidence was evaluated to address concerns expressed in the literature that parabens might be endocrine disruptors. This evaluation showed that the higher-tier studies do not provide any indication for any endocrine disrupting property. This is the first time that a comprehensive dataset from higher-tier in vivo studies following internationally agreed test protocols has become available for shorter-chained linear n-alkyl parabens. Consistently, the dataset shows that these parabens are devoid of repeated-dose toxicity and do not possess any DART or endocrine disrupting properties.
Assuntos
Disruptores Endócrinos/toxicidade , Parabenos/toxicidade , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/química , Feminino , Masculino , Nível de Efeito Adverso não Observado , Parabenos/administração & dosagem , Parabenos/química , Ratos , Ratos Wistar , Fatores de Tempo , ToxicocinéticaRESUMO
BACKGROUND: Prenatal exposure to environmental chemicals has been associated with Autism Spectrum Disorder (ASD) symptoms in some, but not all, studies, but most research has not accounted for other childhood behavior problems. OBJECTIVES: To evaluate the specific associations of prenatal phthalate exposures with ASD symptoms in children (ages 3-6) accounting for other behavior problems, and to assess sex differences in these associations. METHODS: We measured phthalate metabolites in prenatal urine samples. Mothers completed the Social Responsiveness Scale-2nd edition (SRS-2) to assess child ASD symptoms and the Child Behavior Checklist (CBCL) to assess general behavior problems. We assessed associations of the sum of di-(2-ethylhexyl) phthalate metabolites, monobutyl phthalate, mono-isobutyl phthalate, and monoethyl phthalate (mEP) with ASD symptoms, adjusting for other behavior problems, using linear regression models (n=77). RESULTS: Most associations were null, and the sample size limited power to detect associations, particularly in the stratified analyses. After adjusting for internalizing and externalizing problems from the CBCL, ASD symptoms increased for each doubling of prenatal mEP concentration among boys only. CONCLUSIONS: Further investigation of maternal prenatal urinary phthalate metabolite concentrations and ASD symptoms while adjusting for other behavioral problems is warranted.
Assuntos
Transtorno do Espectro Autista/etiologia , Disruptores Endócrinos/toxicidade , Ácidos Ftálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Criança , Transtornos do Comportamento Infantil/etiologia , Pré-Escolar , Estudos de Coortes , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/urina , Feminino , Humanos , Modelos Lineares , Masculino , Michigan , Ácidos Ftálicos/administração & dosagem , Ácidos Ftálicos/urina , Gravidez , Efeitos Tardios da Exposição Pré-Natal/urina , Fatores de Risco , Adulto JovemRESUMO
Diabetes is one of the World's most concerning health problems and millions of patients are using anti-diabetic drugs (ADDs) in order to control blood glucose. The in vitro H295R steroidogenesis assay was implemented to investigate endocrine effects of three ADDs, metformin (MET), glimepiride (GLIM), sitagliptin (SIT) and the cholesterol-lowering drug simvastatin (SIM) individually and in three binary mixtures. Steroid hormones were analyzed using LC-MS/MS. Mixture effects were assessed by applying the Concentration Addition (CA) model. All tested drugs and binary mixtures interrupted the H295R steroidogenesis with different potency. The effects of MET:GLIM on the steroidogenesis were overall similar to the steroidogenic profile of GLIM, however effects were less pronounced. The binary mixture of MET:SIT showed overall minor effects on steroid production and only at very high concentrations. The SIM:SIT mixture showed inhibition downstream from cholesterol, which was attributed to the effects of SIM. The CA model partly predicted the effect of MET:SIT on some steroids but significantly overestimated the effects of MET:GLIM and SIM:SIT. Thus, the applicability of the CA model was limited and cocktail effects appeared to be intermediate responses of individual drugs, rather than additive. The complexity of dynamic pathways such as steroidogenesis appears to significantly reduce the use of the CA model. In conclusion, more dynamic models are needed to predict mixture effects in complex systems.
Assuntos
Disruptores Endócrinos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Sinvastatina/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Esteroides/biossíntese , Compostos de Sulfonilureia/administração & dosagem , Administração Oral , Linhagem Celular , Cromatografia Líquida , Interações Medicamentosas , Humanos , Espectrometria de Massas em TandemRESUMO
Male reproductive function and health are largely dependent on the testes, which are strictly regulated by their major cell components, i. e., Sertoli, Leydig, and germ cells. Sertoli cells perform a crucial phagocytic function in addition to supporting the development of germ cells. Leydig cells produce hormones essential for male reproductive function, and germ cell quality is a key parameter for male fertility assessment. However, these cells have been identified as primary targets of endocrine disruptors, including bisphenols. Bisphenols are a category of man-made organic chemicals used to manufacture plastics, epoxy resins, and personal care products such as lipsticks, face makeup, and nail lacquers. Despite long-term uncertainty regarding their safety, bisphenols are still being used worldwide, especially bisphenol A. While considerable attention has been paid to the effects of bisphenols on health, current bisphenol-related reproductive health cases indicate that greater attention should be given to these chemicals. Bisphenols, especially bisphenol A, F, and S, have been reported to elicit various effects on testicular cells, including apoptosis, DNA damage, disruption of intercommunication among cells, mitochondrial damage, disruption of tight junctions, and arrest of proliferation, which threaten male reproductive health. In addition, bisphenols are xenoestrogens, which alter organs and cells functions via agonistic or antagonistic interplay with hormone receptors. In this review, we provide in utero, in vivo, and in vitro evidence that currently available brands of bisphenols impair male reproductive health through their action on testicular cells.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Disruptores Endócrinos/administração & dosagem , Infertilidade Masculina/induzido quimicamente , Fenóis/administração & dosagem , Saúde Reprodutiva , Testículo/efeitos dos fármacos , Animais , Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Humanos , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Fenóis/efeitos adversos , Células de Sertoli/efeitos dos fármacos , Espermatogênese/efeitos dos fármacosRESUMO
Numerous chemicals derived from human activity are now disseminated in the environment where their exert estrogenic endocrine disrupting effects, and therefore represent major health concerns. The present study explored whether Methoxychlor (MXC), an insecticide with xenoestrogens activities, given during the perinatal period (from gestational day 11 to postnatal day 8) and at an environmentally dose [20 µg/kg (body weight)/day], would affect reproductive physiology and sexual behavior of the offspring in mice. While MXC exposure did not induce any differences in the weight gain of animals from birth to 4 months of age, a clear difference (although in opposite direction according to the sexes) was observed on the anogenital distance between intact and exposed animals. A similar effect was also observed on preputial separation and vaginal opening, which reflects, respectively, in males and females, puberty occurrence. The advanced puberty observed in females was associated with an enhanced expression of kisspeptin cells in the anteroventral periventricular region of the medial preoptic area. Exposure to MXC did not induce in adult females changes in the estrous cycle or in the weight of the female reproductive tract. By contrast, males showed reduced weight of the epididymis and seminiferous vesicles associated with reduced testosterone levels and seminiferous tubule diameter. We also showed that both males and females showed deficits in mate preference tests. As a whole, our results show that MXC impacts reproductive outcomes.
Assuntos
Disruptores Endócrinos/administração & dosagem , Inseticidas/administração & dosagem , Metoxicloro/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Reprodução/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Kisspeptinas/metabolismo , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Maturidade Sexual/efeitos dos fármacosRESUMO
Dibutyl phthalate (DBP) is recognized as an environmental endocrine disruptor that has been detected in fetal and postnatal samples. Recent evidence found that in utero DBP exposure was associated with an increase of adipose tissue weight and serum lipids in offspring, but the precise mechanism is unknown. Here we aimed to study the effects of in utero DBP exposure on obesity in offspring and examine possible mechanisms. SPF C57BL/6J pregnant mice were gavaged with either DBP (5 mg /kg/day) or corn oil, from gestational day 12 until postnatal day 7. After the offspring were weaned, the mice were fed a standard diet for 21 weeks, and in the last 2 weeks 20 mice were selected for TUDCA treatment. Intrauterine exposure to low-dose DBP promoted obesity in offspring, with evidence of glucose and lipid metabolic disorders and a decreased metabolic rate. Compared to controls, the DBP exposed mice had lower expression of UCP1 and significantly higher expression of Bip and Chop, known markers of endoplasmic reticulum (ER) stress. However, TUDCA treatment of DBP exposed mice returned these parameters nearly to the levels of the controls, with increased expression of UCP1, lower expression of Bip and Chop and ameliorated obesity. Intrauterine exposure of mice to low-dose DBP appears to promote obesity in offspring by inhibiting UCP1 via ER stress, a process that was largely reversed by treatment with TUDCA.
Assuntos
Dibutilftalato/administração & dosagem , Disruptores Endócrinos/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Obesidade/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Proteína Desacopladora 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Dibutilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Feminino , Camundongos , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
This study was conducted to determine the endocrine-disrupting effects of phthalate esters (PAEs) on the glucocorticoid receptor (GR) signaling. Potential (anti)glucocorticoid activities of six typical PAEs including di (2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), diethyl phthalate (DEP) and dimethyl phthalate (DMP) were evaluated on human GR using cell viability assessment, reporter gene expression analysis, mRNA analysis, and molecular docking and simulation. For all tested chemicals, co-treatment of DEHP and DINP with dexamethasone (DEX) exhibited a synergistic effect on GR transactivity in the reporter assays. Such co-treatment also synergistically enhanced DEX-induced upregulation of GR mediated gene (PEPCK, FAS and MKP-1) mRNA expression in HepG2 cells and A549 cells. Molecular docking and dynamics simulations showed that hydrophobic interactions may stabilize the binding between molecules and GR. In summary, DEHP and DINP may be involved in synergistic effects via human GR, which highlight the potential endocrine-disrupting activities of PAEs as contaminants.
Assuntos
Dexametasona/toxicidade , Disruptores Endócrinos/toxicidade , Ácidos Ftálicos/toxicidade , Receptores de Glucocorticoides/metabolismo , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Disruptores Endócrinos/administração & dosagem , Genes Reporter , Células HeLa , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácidos Ftálicos/administração & dosagem , Plasmídeos , Ligação Proteica , Receptores de Glucocorticoides/genética , Regulação para CimaRESUMO
Bisphenol (BP) A, a known food contaminant, is a possible risk factor in the epidemic of non-communicable diseases (NCD) including food intolerance and inflammatory bowel diseases (IBD). Regulatory restrictions regarding BPA usage led to BPA removal and replacement by poorly described substitutes, like BPS or BPF (few data on occurrence in food and human samples and biological effect). Oral tolerance protocol to ovalbumin (OVA) in WT mice and Il10-/- mice prone to IBD were used respectively to address immune responses towards food and microbial luminal antigens following BP oral exposure. Both mice models were orally exposed for five weeks to BPA, BPS or BPF at 0.5, 5 and 50 µg/kg of body weight (bw)/day (d). Oral exposure to BPs at low doses (0.5 and 5 µg/kg bw/d) impaired oral tolerance as indicated by higher humoral and pro-inflammatory cellular responses in OVA-tolerized mice. However, only BPF exacerbate colitis in Il10-/- prone mice associated with a defect of fecal IgA and increased secretion of TNF-α in colon. These findings provide a unique comparative study on effects of adult oral exposure to BPs on immune responses and its consequences on NCD related to intestinal luminal antigen development.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Colite/induzido quimicamente , Disruptores Endócrinos/administração & dosagem , Intolerância Alimentar/induzido quimicamente , Imunidade Humoral/efeitos dos fármacos , Fenóis/administração & dosagem , Administração Oral , Animais , Compostos Benzidrílicos/toxicidade , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Feminino , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem , Fenóis/toxicidadeRESUMO
Zinc (Zn) plays an important role in maintaining the process of spermatogenesis and reproductive health. Bisphenol A (BPA), an endocrine disrupting chemical is known to be a reproductive toxicant in different animal models. The present study was designed to study the effect of two of the utmost determinative factors (Zn deficient condition and influence of toxicant BPA) on germ cell growth and overall male reproductive health in the testis, epididymis, and sperm using (a) biochemical, (b) antioxidant, (c) cellular damage, (d) apoptosis, and (e) protein expression measurements. Rats were divided into Control (normal feed and water), BPA (100 mg/kg/d), zinc deficient diet (ZDD; fed with ZDD), and BPA + ZDD for 8 weeks. Body and organ weights, sperm motility and counts, and sperm head morphology were evaluated. The histology of testes, epididymides, and prostate was investigated. Testicular deoxyribonucleic acid (DNA) damage was evaluated by Halo and Comet assay, apoptosis of sperm and testes were quantified by TUNEL assay. Serum protein electrophoretic patterns and testicular protein expressions such as Nrf-2, catalase, PCNA, and Keap1 were analyzed by Western blot analysis. The results showed that BPA significantly increased the testicular, epididymal, and prostrate toxicity in dietary Zn deficient condition due to testicular hypozincemia, hypogonadism, increased cellular and DNA damage, apoptosis, as well as perturbations in protein expression.
Assuntos
Compostos Benzidrílicos/toxicidade , Dieta , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Testículo/efeitos dos fármacos , Zinco/administração & dosagem , Animais , Compostos Benzidrílicos/administração & dosagem , Proteínas Sanguíneas/metabolismo , Peso Corporal/efeitos dos fármacos , DNA/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Masculino , Tamanho do Órgão/efeitos dos fármacos , Fenóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Espermatozoides/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Zinco/metabolismoRESUMO
OBJECTIVES: Bisphenol A (BPA) has been reported that among other male reproductive dys-functions, it can cause marked estrogenic effects including alteration in serum hormones as well as testicular lesions in exposed animals. This work sought to study the role of gallic acid (GA), a known antioxidant, on the BPA-induced testicular oxidative stress in adult male Wistar rats using serum hormone analysis, histopathology, and biochemical assays. METHODS: Adult male rats were divided into four groups (n=10) including control (0.2 ml of corn oil), GA (20 mg/kg/day), BPA (10 mg/kg/day), BPA+GA (BPA, 10 mg/kg/day + GA, 20 mg/kg/day). All medications were given by oral gavage for 45 consecutive days. The body and testicular weights were measured. Blood and organ samples were collected for the serum hormonal assay: testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL), and tissue biochemistry analysis: superoxide dismutase (SOD), reduced glutathione (GSH), glutathione-S-transferase (GST), malondialdehyde (MDA), hydrogen peroxide (H2O2), respectively. RESULTS: The BPA-treated rats showed significant reduction in the gonadosomatic index. BPA also caused significant decrease in the levels of the serum testosterone and prolactin. Furthermore, BPA induced testicular oxidative stress by decreasing the activities of antioxidant enzymes and increasing reactive oxygen species. However, co-treatment with GA protected against these alterations. CONCLUSION: Findings from the present study confirmed the previously reported data and show that the ability of GA, as a potent antioxidant, may protect against BPA-induced alterations in the male reproductive function. Hence, GA protects against testicular oxidative stress in adult male Wistar rats following chronic exposure to BPA.