RESUMO
Neonicotinoids are the most widely used insecticides in the world. They are synthetic nicotine derivatives that act as nicotinic acetylcholine receptor agonists. Although parent neonicotinoids have low affinity for the mammalian nicotinic acetylcholine receptor, they can be activated in the environment and the body to positively charged metabolites with high affinity for the mammalian nicotinic acetylcholine receptor. Imidacloprid, the most popular neonicotinoid, and its bioactive metabolite desnitro-imidacloprid differentially interfere with ovarian antral follicle physiology in vitro, but their effects on ovarian nicotinic acetylcholine receptor subunit expression are unknown. Furthermore, ovarian nicotinic acetylcholine receptor subtypes have yet to be characterized in the ovary. Thus, this work tested the hypothesis that ovarian follicles express nicotinic acetylcholine receptors and their expression is differentially modulated by imidacloprid and desnitro-imidacloprid in vitro. We used polymerase chain reaction, RNA in situ hybridization, and immunohistochemistry to identify and localize nicotinic acetylcholine receptor subunits (α2, 4, 5, 6, 7 and ß1, 2, 4) expressed in neonatal ovaries (NO) and antral follicles. Chrnb1 was expressed equally in NO and antral follicles. Chrna2 and Chrnb2 expression was higher in antral follicles compared to NO and Chrna4, Chrna5, Chrna6, Chrna7, and Chrnb4 expression was higher in NO compared to antral follicles. The α subunits were detected throughout the ovary, especially in oocytes and granulosa cells. Imidacloprid and desnitro-imidacloprid dysregulated the expression of multiple nicotinic acetylcholine receptor subunits in NO, but only dysregulated one subunit in antral follicles. These data indicate that mammalian ovaries contain nicotinic acetylcholine receptors, and their susceptibility to imidacloprid and desnitro-imidacloprid exposure varies with the stage of follicle maturity.
Assuntos
Inseticidas , Neonicotinoides , Folículo Ovariano , Receptores Nicotínicos , Feminino , Animais , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/genética , Neonicotinoides/farmacologia , Camundongos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Inseticidas/farmacologia , Nitrocompostos/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismoRESUMO
As a protein kinase inhibitor, cantharidin (CTD) exhibits antitumor activities. However, CTD is highly toxic, thereby limiting clinical applications. Moreover, relatively few studies have investigated CTD-induced reproductive toxicity, thus the underlying mechanism remains unclear. In this study, the toxic effects of CTD on mouse testis were confirmed in vivo and the potential mechanism was predicted by network toxicology (NT) and molecular docking technology. Proteins involved in the signaling pathways and core targets were verified. The results showed that different concentrations of CTD induced weight loss increased the testicular coefficient, and caused obvious pathological damage to testicular cells. The NT results showed that the main targets of CTD-induced testicular injury (TI) included AKT1, Caspase 3, Bcl-2, and Bax. The results of pathway enrichment analysis showed that CTD-induced TI was closely related to apoptosis and the PI3K/AKT and HIF-1 signaling pathways. Molecular docking methods confirmed high affinity between CTD and key targets. Western blot analysis showed that CTD inhibited expression of PI3K, AKT, and the anti-apoptotic protein Bcl-2, while promoting expression of the pro-apoptotic proteins Bax and Caspase 3. These results suggest that CTD-induced TI involves multiple targets and pathways, and the underlying mechanism was associated with inhibition of the apoptosis-related PI3K/AKT signaling pathway.
Assuntos
Cantaridina , Simulação de Acoplamento Molecular , Farmacologia em Rede , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Testículo , Animais , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Cantaridina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
RESEARCH QUESTION: Does dexpanthenol work as an effective therapeutic agent against cyclophosphamide (CYC)-induced premature ovarian failure (POF) in rats? DESIGN: A total of 28 female Wistar Albino rats were randomly divided into four groups (nâ¯=â¯7 per group). The POF and POF plus dexpanthenol groups were intraperitoneally administered CYC at an initial dose of 50 mg/kg, followed by 8 mg/kg for 14 days. The dexpanthenol and POF plus dexpanthenol groups were both intraperitoneally administered dexpanthenol at a dose of 500 mg/kg/day for 15 days. RESULTS: In the group administered CYC, the following was observed: a decrease in the ovarian index; a decrease in the numbers of primordial, primary, secondary and antral follicles; an increase in the number of corpus luteum and atretic follicles; a decrease in proliferation cell nuclear antigen immunoreactivity; a significant reduction in anti-Müllerian hormone and oestradiol levels; and an increase in serum FSH levels compared with controls. Dexpanthenol, on the other hand, reversed these effects. Quantitative reverse transcription polymerase chain reaction analyses showed that dexpanthenol increased Bcl-2, Akt1, mTOR, Nrf2 and HO-1 in CYC-induced ovarian tissues, but decreased Bax, Cas3, Hsp27, Hsp70, and Hsp90. Dexpanthenol treatment has a potential for inhibiting the intrinsic apoptotic pathway and oxidative stress levels in ovarian tissues via the downregulation of the mRNA expression of heat shock proteins and the activation of Nrf2/HO-1 pathways. CONCLUSIONS: Our findings demonstrated that dexpanthenol is an effective agent against POF caused by CYC; however, further experimental and clinical data are needed to use it effectively.
Assuntos
Ciclofosfamida , Ovário , Ácido Pantotênico , Insuficiência Ovariana Primária , Ratos Wistar , Animais , Feminino , Ciclofosfamida/toxicidade , Ciclofosfamida/efeitos adversos , Ácido Pantotênico/análogos & derivados , Ácido Pantotênico/farmacologia , Ovário/efeitos dos fármacos , Ovário/patologia , Insuficiência Ovariana Primária/induzido quimicamente , Ratos , Folículo Ovariano/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Hormônio Foliculoestimulante/sangue , Serina-Treonina Quinases TOR/metabolismo , Hormônio Antimülleriano/sangueRESUMO
Triphenyl phosphate (TPhP) is an organophosphate flame retardant and plasticizer that is added to a wide variety of consumer and industrial products. It is also a ubiquitous environmental pollutant. Exposure to TPhP has been shown to alter gene expression in metabolic and estrogenic signaling pathways in in vitro and in vivo models of a variety of species, and as such, is considered to be an endocrine disrupting chemical. Exposure to endocrine disrupting chemicals is increasingly being associated with changes to the epigenome, especially during embryonic development. The aim of this study was to evaluate whether TPhP exposure in aquatic ecosystems has the ability to alter the epigenome in two immortal cell lines derived from trout (Oncorhynchus mykiss). This study assessed whether 24 h exposure to TPhP resulted in changes to histone modification and DNA methylation profiles in steelhead trout embryonic cells and rainbow trout gill epithelial cells. Results show that several epigenetic modifications on histone H3 and DNA methylation are altered in the embryonic cells following TPhP exposure, but not in the gill epithelial cells. Specifically, histone H3 acetylation, histone H3 mono-methylation and global DNA methylation were found to be reduced. The alterations of these epigenetic modification profiles in the embryonic cells suggest that exposure to TPhP during fetal development may alter gene expression in the developing embryo, likely in metabolic and estrogenic pathways. The impacts to the epigenome determined in this study may even carry multigenerational detrimental effects on human and ecosystem health, which requires further investigation.
Assuntos
Metilação de DNA , Retardadores de Chama , Oncorhynchus mykiss , Organofosfatos , Poluentes Químicos da Água , Animais , Retardadores de Chama/toxicidade , Oncorhynchus mykiss/embriologia , Oncorhynchus mykiss/genética , Metilação de DNA/efeitos dos fármacos , Organofosfatos/toxicidade , Poluentes Químicos da Água/toxicidade , Epigenoma/efeitos dos fármacos , Linhagem Celular , Disruptores Endócrinos/toxicidade , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Epigênese Genética/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Histonas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismoRESUMO
Women comprise approximately 40% of the global workforce, and many women continue to work during pregnancy. Although occupational exposure limit values (OELVs) are intended to protect all workers, many OELVs may have been established without consideration of the unique changes in pregnant workers, and many chemicals lack OELVs altogether. A short educational course was developed to address the informational needs of health professionals who have responsibility to ensure a safe workplace for pregnant employees. The course was designed to raise awareness of the key elements in risk management and their application to the pregnant worker, such as physiological changes of pregnancy that influence susceptibility to exposures; guidance for nonclinical data interpretation; exposure assessment and control strategies; and risk management in practice in a diverse regulatory environment. This paper summarizes the course content and is intended to support informed risk management decision making to protect the health of pregnant workers and their offspring.
RESUMO
Arsenic is an environmental toxicant known to be a carcinogen and endocrine disruptor. Maternal exposure to arsenic has been associated with fetus malformation and reproductive disorders in male offspring. However, it is unclear the extent to which those effects remain during postnatal development and adulthood. Therefore, this study aimed to investigate the long-term effects of prenatal arsenic exposure on reproductive parameters of male offspring at peripubertal and adult periods. Pregnant female Wistar rats were exposed to 0 or 10 mg/L sodium arsenite in drinking water from gestational day 1 (GD 1) until GD 21 and male pups were analyzed at postnatal day 44 (PND 44) and PND 70. We observed that some reproductive parameters were affected differently by arsenic exposure at each age evaluated. The body and reproductive organs weights, as well as testicular and epididymal morphology were strongly affected in peripubertal animals and recovered at adult period. On the other hand, the antioxidant genes expression (SOD1, SOD2, CAT and GSTK1) and the endogenous antioxidant system were affected in the testes and epididymides from both peripubertal and adult rats. Finally, an impairment in daily sperm production and in sperm parameters was observed in adult animals. Taken together, our findings show that prenatal arsenic exposure affected reproductive parameters of peripubertal and adult male rats mainly due to oxidative stress. Collectively, those alterations may be affecting fertility potential of adult animals.
Assuntos
Arsênio , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Ratos , Masculino , Animais , Feminino , Ratos Wistar , Sêmen , Reprodução , TestículoRESUMO
Glyphosate (Gly) is a broad-spectrum herbicide widely used thanks to its high efficiency and low toxicity. However, evidence exists of its toxic effects on non-target organisms. Among these, the animals inhabiting agricultural fields are particularly threatened. Recent studies demonstrated that exposure to Gly markedly affected the morphophysiology of the liver and testis of the Italian field lizard Podarcis siculus. The present study aimed to investigate the effects of the herbicide on the female reproductive system of this lizard in order to have a full picture of Gly-induced reproductive impairment. The animals were exposed to 0.05 and 0.5 µg/kg of pure Gly by gavage for 3 weeks. The results demonstrated that Gly, at both doses tested, profoundly interfered with ovarian function. It induced germ cells' recruitment and altered follicular anatomy by anticipating apoptotic regression of the pyriform cells. It also induced thecal fibrosis and affected oocyte cytoplasm and zona pellucida organizations. At the functional levels, Gly stimulated the synthesis of estrogen receptors, suggesting a serious endocrine-disrupting effect. Overall, the follicular alterations, combined with those found at the level of the seminiferous tubules in males, suggest serious damage to the reproductive fitness of these non-target organisms, which over time could lead to a decline in survival.
Assuntos
Herbicidas , Lagartos , Animais , Masculino , Feminino , Oócitos , Testículo , Herbicidas/toxicidade , Lagartos/fisiologia , GlifosatoRESUMO
There is evidence suggesting the participation of non-coding RNAs in male reproductive dysfunction induced by lead, and the significance of microRNAs has been highlighted recently because of their essential roles in gene regulatory networks. To comprehensively understand the functions of miRNA and the regulatory networks, RNA sequencing was carried out to obtain miRNA expression profiles in mice testes exposed to low dose Pb for 90 days at the onset of puberty. In total, 44 differentially expressed miRNAs with 26 up-regulated and 18 down-regulated were identified between 200 mg/L Pb group and control group (p < 0.05). Enrichment analysis confirmed that the target genes of DE miRNAs might participate in the metabolism of testicular cells. Furthermore, a miRNA-mRNA co-expression network consisting of 19 miRNAs and 106 mRNAs and a competing endogenous RNA network of lncRNA-miRNA-mRNA including 179 genes were established. Finally, the expressions of 4 miRNAs (mmu-miR-451a, mmu-miR-133a-3p, mmu-miR-1a-3p and mmu-miR-486a-3p) and 4 mRNAs (Gramd1b, Tcf7l2, Mov10 and Srcin1) involved in regulatory networks were verified by RT-qPCR. In conclusion, our research might provide targets for the mechanism studies of miRNAs in reproductive toxicity of Pb.
Assuntos
MicroRNAs , RNA Longo não Codificante , Animais , Redes Reguladoras de Genes , Chumbo , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Maturidade Sexual , Testículo/metabolismoRESUMO
The molecular mechanisms of PM2.5 exposure in the male reproductive system, have scarcely been studied. Here, we demonstrate the possible relationship and molecular mechanisms between endoplasmic reticulum stress (ERS), oxidative stress, and reproductive toxicity caused by PM2.5. A "PM2.5 real-time online concentrated animal whole-body exposure system" was employed to expose male Wistar rats to PM2.5 for 12 weeks, which could induce sperm quality decline, apoptosis, inflammation, oxidative stress, ERS, and histopathological damage in the testis. In vitro study on cultured primary testicular spermatogonia and Leydig cells confirmed that treatment with PM2.5 (0-320 µg/mL) for 24 h decreased cell survival rate, increased reactive oxygen species, lactate dehydrogenase and 8-hydroxydeoxyguanosine levels, induced DNA damage, ERS and apoptosis, and inhibit the secretion and synthesis of testosterone in Leydig cells. These results clarified that ERS pathways triggered by oxidative stress could significantly induce CHOP and caspase-12 activation, which are significantly associated with cell apoptosis. However, oxidative stress and ERS inhibitors significantly inhibited the occurrence of these injuries. In conclusion, PM2.5 triggers the ERS pathway and induces DNA damage in rat testicular cells through oxidative stress, ultimately leading to cellular apoptosis. Furthermore, high-concentration intermittent inhalation was more harmful than low-concentration continuous inhalation when the total mass of PM2.5 exposure was the same.
Assuntos
Estresse do Retículo Endoplasmático , Sêmen , 8-Hidroxi-2'-Desoxiguanosina , Animais , Apoptose , Caspase 12/metabolismo , Lactato Desidrogenases/metabolismo , Masculino , Estresse Oxidativo , Material Particulado/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , TestosteronaRESUMO
Statins are 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor drugs that lead to serum-cholesterol-lowering effects. Rosuvastatin, a third-generation statin, has shown better results in reducing cholesterol concentrations when compared to other widely prescribed statins. Recent studies by our group reported that rosuvastatin impairs reproductive function in rats possibly by disrupting the reproductive-endocrine axis. In this study, we evaluated whether rosuvastatin presents estrogenic or antiestrogenic effects, by an in vivo uterotrophic assay in rats, and investigated the direct effect of this drug upon rat uterine tissue contractility both in non-gravid and gravid periods. Rosuvastatin exposure in vivo at doses of 0 (control), 3, and 10 mg/kg/d was not associated with estrogenic or antiestrogenic effects on uterine tissue. However, in vivo (doses of 0, 3, and 10 mg/kg/d) and ex vivo (concentrations of 0, 1, 10, and 100 µg/mL) exposures to this drug were related to alterations in uterine basal contraction pattern. Furthermore, in vivo and ex vivo rosuvastatin exposures potentially modulate the action of uterine contraction inducers carbachol, norepinephrine, and prostaglandin E2. Thus, rosuvastatin can affect uterine physiology not necessarily by an endocrine mechanism related to the estrogen signaling, but possibly by its pleiotropic effects, with indirect tissue and cellular interactions, since in vivo and ex vivo exposures of uterine fragments to rosuvastatin presented different responses in uterine contractile parameters, which require further studies upon the precise mechanism of action of this drug in female reproductive function.
Assuntos
Estrogênios , Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Colesterol , Estrogênios/toxicidade , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Gravidez , Ratos , Ratos Wistar , Rosuvastatina Cálcica/toxicidadeRESUMO
N-methyl pyrrolidone (NMP) is an FDA approved molecule used as an excipient in pharmaceutical industry. Besides having a central role in formulation of drugs, the most important function of any excipient is to guarantee the safety of the medicine during and after its administration. Several studies have shown that exposure to NMP and especially in rats produce a gonadotoxic effect leading to infertility. However, the mechanisms underlying the effect of NMP on male reproduction are unknown. The aim of this study was to assess the reproductive toxicity of NMP in male rats and to elucidate the underlying mechanism. Male Sprague Dawley rats were injected intraperitoneally, twice/ week, at a dose of 108 mg/ 100 g of body weight with NMP. Analysis of reproductive parameters revealed testicular atrophy in NMP treated animals compared to control animals. Germ cell composition within the seminiferous tubules was disturbed and manifested in an increase in number of cells with fragmented DNA. A subsequent decrease in number of spermatocytes and spermatids was observed. Alpha screen assay shows that NMP acts at the concentrations we applied in vivo as a low affinity inhibitor for BRDT (testis specific bromodomain protein). BRDT inhibition is mirrored by a significant decrease in the expression of early stage spermatocyte markers (lmna, aurkc and ccna1), during which BRDT expression predominates. A significant decrease in testosterone levels was also observed. Since NMP interferes with spermatogenesis on various levels, its use in humans must be carefully monitored.
Assuntos
Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/metabolismo , Pirrolidinonas/toxicidade , Espermatogênese/efeitos dos fármacos , Teratogênicos/toxicidade , Animais , Relação Dose-Resposta a Droga , Hormônio Foliculoestimulante/sangue , Masculino , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Espermatogênese/fisiologia , Testosterona/sangueRESUMO
Phthalate esters are synthetic chemicals used in the plastic industry as plasticizers and consumable products. According to United Nations, about 400 million tons of plastic are produced every year. In parallel with increased production, the concerns about its effects on human health have increased because phthalates are endocrine-disrupting compounds. Humans are continuously exposed to phthalates through different routes of exposure. Experimental data have associated the phthalates exposure to adverse effects on development and reproduction in women (e.g., earlier puberty, primary ovarian insufficiency, endometriosis, preterm birth, or in vitro fertilization) and men (e.g., anogenital distance, cryptorchidism, hypospadias, and changes in adult reproductive function) although there is no consensus. Therefore, one question arises: could the increase in infertility be related to phthalates exposure? To answer this question, we aimed to assess the disrupting-effects of phthalates on the human reproductive system. For this, we reviewed the current literature based on epidemiological and experimental data and experimental studies in humans. The phthalate effects were discussed in a separate mode for female and male reproductive systems. In summary, phthalates induce toxicity in the reproductive system and human development. The increased plastic production may be related to the increase in human infertility.
Assuntos
Poluentes Ambientais , Ácidos Ftálicos , Nascimento Prematuro , Adulto , Poluentes Ambientais/toxicidade , Feminino , Genitália , Humanos , Recém-Nascido , Masculino , Ácidos Ftálicos/toxicidadeRESUMO
Natural and synthetic environmental estrogens (EEs), interfering with the physiological functions of the body's estrogens, are widespread and are rising much concern for their possible deleterious effects on human and animal health, in particular on reproduction. In fact, increasing evidence indicate that EEs can be responsible for a variety of disfunctions of the reproductive system especially in females such as premature ovarian insufficiency (POI). Because of their great structural diversity, the modes of action of EEs are controversial. One important way through which EEs exert their effects on reproduction is the induction of apoptosis in the ovary. In general, EEs can exert pro-and anti-apoptotic effects by agonizing or antagonizing numerous estrogen-dependent signaling pathways. In the present work, results concerning apoptotic pathways and diseases induced by representative EEs (such as zearalenone, bisphenol A and di-2-ethylhexyl phthalate), in ovaries throughout development are presented into an integrated network. By reviewing and elaborating these studies, we propose inflammatory factors, centered on the production of tumor necrosis factor (TNF), as a major cause of the induction of apoptosis by EEs in the mammalian ovary. As a consequence, potential strategies to prevent such EE effect are suggested.
Assuntos
Citocinas , Ovário , Animais , Apoptose , Estrogênios/toxicidade , Feminino , Humanos , Transdução de SinaisRESUMO
The current parameters for determining maternal toxicity (e.g. clinical signs, food consumption, body weight development) lack specificity and may underestimate the extent of effects of test compounds on the dams. Previous reports have highlighted the use of plasma metabolomics for an improved and mechanism-based identification of maternal toxicity. To establish metabolite profiles of healthy pregnancies and evaluate the influence of food consumption as a confounding factor, metabolite profiling of rat plasma was performed by gas- and liquid-chromatography-tandem mass spectrometry techniques. Metabolite changes in response to pregnancy, food consumption prior to blood sampling (non-fasting) as well as the interaction of both conditions were studied. In dams, both conditions, non-fasting and pregnancy, had a marked influence on the plasma metabolome and resulted in distinct individual patterns of changed metabolites. Non-fasting was characterized by increased plasma concentrations of amino acids and diet related compounds and lower levels of ketone bodies. The metabolic profile of pregnant rats was characterized by lower amino acids and glucose levels and higher concentrations of plasma fatty acids, triglycerides and hormones, capturing the normal biochemical changes undergone during pregnancy. The establishment of metabolic profiles of pregnant non-fasted rats serves as a baseline to create metabolic fingerprints for prenatal and maternal toxicity studies.
Assuntos
Dieta , Metaboloma/fisiologia , Metabolômica/métodos , Gravidez/metabolismo , Aminoácidos/sangue , Animais , Cromatografia Líquida , Ácidos Graxos/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glucose/metabolismo , Corpos Cetônicos/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Triglicerídeos/sangueRESUMO
Benzoic acid (BA) was administered in the diet to male and female Sprague Dawley Crl:CD(SD) rats in an OECD Test Guideline 443 Extended One-Generation Reproductive Toxicity (EOGRT) study to test for effects that may occur as a result of pre- and postnatal exposure. The study included cohorts of F1 offspring to evaluate potential effects of benzoic acid on reproduction, the developing immune system, and the developing neurological system with the inclusion of learning and memory assessments. Benzoic acid was incorporated in the diet at concentrations of 0, 7,500, 11,500, and 15,000 mg/kg diet (ppm). These concentrations were selected based on the results of preliminary studies, and, based on average food consumption, were intended to supply BA doses of approximately 0, 500, 750, and 1000 mg/kg bw/day. To avoid exceeding these target dose levels, the dietary concentrations were adjusted (based on historical control body weight and food consumption data) to maintain the target mg/kg bw/day dose levels during those life periods when food intake per unit of body weight was increased to support milk production by females (gestation and lactation) and rapid pup growth (post-weaning). In the parental (F0) generation, survival, clinical observations, organ weights, pathology, hematology, serum chemistry, urinalysis, and bile acids were unaffected by BA administration. Reproductive parameters were also unaffected by BA administration. In the F1 generation, survival, growth and developmental landmarks, organ weights, pathology, immunotoxicity assessment, and neurotoxicity and neurobehavioral parameters such as auditory startle response, locomotor activity, learning and memory assessments were unaffected by BA administration, as were clinical pathology (hematology, serum chemistry, urinalysis, bile acids and thyroid hormones) and reproductive performance. Similarly, no adverse effects or systemic toxicity were observed in the F2 generation. Overall, the highest dietary concentration (15,000 ppm), providing a dosage of approximately 1000 mg/kg bw/day, was the NOAEL for benzoic acid in this EOGRT study.
Assuntos
Ácido Benzoico/farmacologia , Conservantes de Alimentos/farmacologia , Genitália/efeitos dos fármacos , Animais , Peso Corporal , Relação Dose-Resposta a Droga , Feminino , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Worldwide demand for petroleum products has resulted in increased oil and gas activities in many countries. Conventional and unconventional oil and gas extraction, production, and transport lead to increased levels of petroleum-derived polycyclic aromatic hydrocarbons (PAHs) in the environment. PAH exposure has profound effects on reproduction by affecting pathways involved in placental trophoblast cell function and impairing normal placental development and function-key contributors to reproductive success. However, other components found in petroleum and wastewaters from oil and gas extraction, including the sulfur-containing heterocyclic aromatic compounds such as dibenzothiophene (DBT) and its alkylated derivatives, may also impact reproductive success. The goal of this study was to examine the effect of exposure to DBT, a compound commonly detected in the environment, and one of its alkylated analogues, 2,4,7-trimethyldibenzothiophene (2,4,7-DBT), on steroidogenic and angiogenic pathways critical for mammalian development in placental trophoblast cells (HTR-8/SVneo cells). 2,4,7-DBT but not DBT increased estradiol output in association with increased tube-like formation (surrogate for angiogenesis). These changes in angiogenesis did not appear to be related to altered expression of the key placental angiogenic gene targets (ANGPTL4, VEGFA, and PGF). Neither compound showed a concentration related effect on progesterone synthesis or its receptor expression. Our results suggest that 2,4,7-DBT can disrupt key pathways important for placental trophoblast function and highlight the importance of determining the impact of exposure to both parent and alkylated compounds. Further, these data suggest that exposure to sulfur-containing heterocyclic aromatic compounds may lead to placental dysfunction and impact reproductive success at environmentally relevant levels.
Assuntos
Placenta/efeitos dos fármacos , Tiofenos/toxicidade , Trofoblastos/efeitos dos fármacos , Alquilação , Proteína 4 Semelhante a Angiopoietina/efeitos dos fármacos , Proteína 4 Semelhante a Angiopoietina/genética , Linhagem Celular , Disruptores Endócrinos/toxicidade , Estradiol/metabolismo , Feminino , Humanos , Indústrias , Neovascularização Fisiológica/efeitos dos fármacos , Petróleo , Gravidez , Prostaglandinas F/metabolismo , Tiofenos/química , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Bisphenol A (BPA) is an organic synthetic compound used in the plastic industry with endocrine disrupting activity. Although it is frequently found in surface waters, few studies have investigated its impact on fish gametogenesis, particularly when associated with natural stressors. In this regard, the present study evaluated BPA toxicity on spermatogenesis in the lambari Astyanax bimaculatus under controlled conditions and its interactive effects with water temperature. Adult specimens were exposed in duplicate to 40 µg/L and 400 µg/L BPA at 23 °C and 28 °C for 21 days; the control group did not receive BPA. Testicular samples were collected and analyzed using different cellular and molecular techniques. The results showed a significant reduction in the gonadosomatic index in the BPA-treated groups at both temperatures. A decrease in the testicular levels of 11-ketotestosterone was observed in the 400 µg/L BPA group at 23 °C, 17ß-estradiol increased significantly in the treated groups at 28 °C, and vitellogenin showed no difference between the treatments. The morphometric analysis of spermatogenesis revealed a significant increase in the proportion of spermatogonia, spermatocytes, and Sertoli cells in the treated groups, with a higher proportion at 23 °C than at 28 °C. Otherwise, the proportion of spermatozoa was significantly lower in the BPA-treated groups, with a greater reduction at 23 °C. In addition, BPA also stimulated spermatogonial proliferation in the treated groups, but apoptosis was significantly increased in spermatids at 23 °C. Testis-ova, cell degeneration, and chromatin alterations in spermatids and Sertoli cells were observed in the germinal epithelium of the BPA-treated groups. The integrated biomarker response (IBR) index revealed that the analyzed endpoints are suitable for assessing estrogenic contamination. Taken together, our results indicate that the interactive effects of BPA and temperature contribute to the impairment of spermatogenesis in A. bimaculatus with more severe effects observed on sperm production at 23 °C than at 28 °C.
RESUMO
The US Department of Defense (DOD) is developing insensitive munitions (IMs) that are resistant to unintended detonation to protect warfighters. To enable material life-cycle analysis for the IM, 1-methyl-3-nitro-1-nitroguanidine (MeNQ), ecotoxicological impacts assessment was required. A previous investigation of MeNQ exposures in Daphnia pulex revealed concentration-responsive decreases in reproduction relative to controls (0 mg/L) across a 174, 346, 709, 1385, and 2286 mg/L exposure range. The present study used those exposures to conduct global transcriptomic expression analyses to establish hypothetical mode(s) of action underlying inhibited reproduction. The number of significantly affected transcripts and the magnitude of fold-change differences relative to controls tended to increase with increasing MeNQ concentration where hierarchical clustering analysis identified separation among the "low" (174 and 346 mg/L) and "high" (709, 1385, and 2286 mg/L) exposures. Vitellogenin is critical to Daphnia reproductive processes and MeNQ exposures significantly decreased transcriptional expression for vitellogenin-1 precursor at the lowest exposure level (174 mg/L) with benchmark dose (BMD) levels closely tracking concentrations that caused inhibited reproduction. Additionally, juvenile hormone-inducible protein, chorion peroxidase, and high choriolytic enzyme transcriptional expression were impacted by MeNQ exposure having potential implications for egg production / maturation and overall fecundity. In concert with these effects on specific genes involved in Daphnia reproductive physiology, MeNQ exposures caused significant enrichment of several canonical-pathways responsible for metabolism of cellular energy substrates where BMD levels for transcriptional expression were observed at ≤100 mg/L. These observations imply possible effects on whole-organism energy budgets that may also incur indirect costs on reproduction.
Assuntos
Anisóis , Daphnia , Animais , Daphnia/genética , Guanidinas , ReproduçãoRESUMO
Panax ginseng, a functional food, has been widely used as an edible nourishment and medicinal supplement. Ginsenoside Rb1 is a major bioactive ingredient of ginseng, which shows very specific anti-apoptosis and anti-oxidant activities. Methylglyoxal (MGO) is one of intermediate products of glucose metabolism, which is absorbed easily from high sugar foods or carbonated beverages. It may involve in a variety of detrimental processes in vivo. However, it has not been fully explored the effects of ginsenoside Rb1 on MGO-induced oocytes damage. This study found that MGO-induced DNA damage and mitochondrial dysfunction result in the failure of porcine oocytes maturation and low in vitro development capacity of parthenogenetic activation (PA) and in vitro fertilization (IVF) embryos. Conversely, Rb1 supplementation recovered the rate of maturation, and improved in vitro development capacity of PA and IVF embryos. Rb1 also provided porcine oocytes a lower level of reactive oxygen species production, higher level of ATP content and mitochondrial membrane potential, and stimulated pluripotency gene expression in blastocysts. The findings of this study reveal ginsenoside Rb1 protects porcine oocyte from the cytotoxicity effects of methylglyoxal and provides novel perspectives for the protection of reproduction system by functional food of ginseng.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Ginsenosídeos/farmacologia , Oócitos/efeitos dos fármacos , Partenogênese/efeitos dos fármacos , Aldeído Pirúvico/toxicidade , Animais , Antioxidantes/metabolismo , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , Dano ao DNA/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Feminino , Fertilização in vitro , Técnicas de Maturação in Vitro de Oócitos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Panax/química , Espécies Reativas de Oxigênio/metabolismo , SuínosRESUMO
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections, and vaccines are needed to treat young children and older adults. One of GSK's candidate vaccines for RSV contains recombinant RSVPreF3 protein maintained in the prefusion conformation. The differences in immune function of young children and older adults potentially require different vaccine approaches. For young children, anti-RSV immunity can be afforded during the first months of life by vaccinating the pregnant mother during the third trimester with unadjuvanted RSVPreF3, which results in protection of the infant due to the transplacental passage of anti-RSV maternal antibodies. For older adults with a waning immune response, the approach is to adjuvant the RSVPreF3 vaccine with AS01 to elicit a more robust immune response.The local and systemic effects of biweekly intramuscular injections of the RSVPreF3 vaccine (unadjuvanted, adjuvanted with AS01, or coadministered with a diphtheria-tetanus-acellular pertussis vaccine) was tested in a repeated dose toxicity study in rabbits. After three intramuscular doses, the only changes observed were those commonly related to a vaccine-elicited inflammatory reaction. Subsequently, the effects of unadjuvanted RSVPreF3 vaccine on female fertility, embryo-fetal, and postnatal development of offspring were evaluated in rats and rabbits. There were no effects on pregnancy, delivery, lactation, or the pre- and postnatal development of offspring.In conclusion, the RSVPreF3 vaccine was well-tolerated locally and systemically and was not associated with any adverse effects on female reproductive function or on the pre- and postnatal growth and development of offspring.