Reproductive toxicology最新文献

The ECHA's work aims to establish uniform procedures for the authorization or restriction of the use of chemicals in the European Union. Studies conducted in accordance with OECD Guidance Document 443, in which, among others, the evaluation of pituitary and thyroid hormones and fertility under high-dose exposure are used as read-out parameters. Since 2022, ECHA has been compiling such extended one-generation reproductive toxicity (EOGRT) study data and publishing its assessments with regard to design, study conduct and toxicological results. Based on this, since then the authority has made demands on EOGRT study performers that are excessive, sometimes contra productive, may hamper data interpretation and lead neither to an improved validity of the studies nor to better animal welfare. Here, we explicitly address the physiological variability of pituitary hormone values and the interaction of reproductive toxicity with high dose exposure scenarios.

There are still few studies that have investigated the impact of sertraline (SE) on fertility, as well as adjuvant treatments that alleviate its side effects. Thus, the present study aimed to investigate the impact of SE on reproductive and neurobehavior parameters and verify whether the probiotic Lactobacillus rhamnosus alleviates the side effects of SE. After carrying out a dose-response study with SE, experiment II was conducted. Thus, male mice were distributed into four experimental groups (n=8-9/group): control (CO)-received filtered water (vehicle); sertraline group (S)-received 20mg/kg of SE, diluted in the vehicle; probiotic (P)-received the probiotic Lactobacillus rhamnosus (1×10⁹ CFU) diluted in the vehicle; and SP group that received both probiotic and SE. The treatment occurred/lasted for 30 days. At the end of treatment, behavioral aspects were analyzed. After euthanasia, the organs were weighed, the histology of the testis and epididymis were analyzed, and the sperm quality and also natural fertility were verified. Complementarily, in vitro assays were carried out to verify whether sertraline could affect sperm capacitation and embryonic development. The results showed that the SP group, compared to S, did not reduce body weight and seminal gland weight and presented a lower number of resorptions. Notably, the rate of resorption in both the SP and S groups was similar to that of the control group. It was also observed that the S group was less exploratory and more anxious than the SP group. Thus, the present study demonstrated that SE has an impact on the reproductive system and neurobehavior. Therefore, for the first time, we demonstrate that the probiotic can alleviate the side effects of SE.

The European Food Safety Authority (EFSA) conducted a retrospective cumulative dietary risk assessment (CRA) on active substances (AS) and metabolites included in the plant protection products registered in Europe which could provoke craniofacial alterations. Two Cumulative Assessment groups (CAGs) were established: one for alterations due to abnormal skeletal development (CAG-DAC) and one for head soft tissue alterations and brain neural tube defects (CAG-DAH). The probability that each substance is correctly assigned to the specific CAGs (CAG-membership probability) was assessed using weight of evidence and expert knowledge elicitation (EKE) techniques conducted for the six substances identified as risk drivers in each CAG. Four out of the six substances allocated to the CAG-DAC or to the CAG-DAH presented a large interval of uncertainty, with probability of belonging to the attributed CAG between 10 to 70% or 33 to 90%, which makes it difficult to determine if the substances truly belong to the CAG. In the present work the probability ranges of each risk driver were reassigned according to the approximate probability scale recommended in the EFSA guidance on uncertainty analysis. It is proposed that AS with a high probability are to be included in the CAG and those with a low probability removed from the CAG. For compounds with very large probability ranges, uncertainty assessments would have to be redone to reach narrower probability ranges. Finally, whenever recent decisions on reproduction toxicity classifications made by the European Chemical Agency (ECHA) are available, these should be used to conclude on CAG memberships.

Environmental pollutants, especially endocrine-disrupting chemicals (EDCs) like di-ethylhexyl phthalate (DEHP), pose serious threats to human health, with DEHP widely implicated in male reproductive toxicity. However, the complex molecular interactions remain unknown. We employed a network toxicology approach combined with molecular docking analysis to identify potential targets and mechanisms of DEHP's toxic effects. Databases such as ChEMBL, STITCH, OMIM, and GeneCards were utilized to gather data, and Cytoscape software was used to construct protein-protein interaction networks. A total of 51 potential targets were identified, with eight core targets, including PTGS2, CASP3, and ESR1, highlighted for their roles in oxidative stress, apoptosis, and hormonal dysregulation. KEGG pathway enrichment analysis revealed significant associations with pathways in cancer, cytokine-mediated signaling, and the hypothalamic-pituitary-gonadal axis. Additionally, gene expression datasets from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes overlapped with DEHP targets in testicular diseases. Molecular docking results confirmed strong binding affinities between DEHP and the core target proteins, suggesting a robust interaction mechanism. This study underscores the need for further investigation into DEHP's toxic mechanisms and its combined effects with other environmental pollutants, paving the way for comprehensive risk assessments and the development of targeted intervention strategies.

Depression in pregnant women raises concerns about the safety of antidepressants use, particularly its impact on offspring's neurocognition. This study investigates the effects of maternal exposure to vortioxetine (VOX) on the neurocognitive development of rat offspring. Pregnant Wistar rats were administered clinically pertinent doses of VOX, 1 mg/kg/day or 2 mg/kg/day from gestational day 6-21. The dams delivered their offspring naturally and reared until postnatal day (PND) 70. Offspring of both sexes were assessed for postnatal growth by measuring body weight from PND 1-70 weekly and cognitive function using Morris water maze (MWM) test and passive avoidance learning test from PND 49-70. After behavioral assessments, adult rat offspring were sacrificed, and their brains were dissected out for assessment of brain morphology as well as biochemical analysis. The results demonstrated that VOX exposure potentially impaired cognitive performance, evidenced by increased latency in MWM and passive avoidance learning tests. Additionally, it led to decreased body weight, altered brain morphology, and disrupted neurobiochemical profiles. Specifically, VOX 2 mg/kg exposure significantly reduced brain-derived neurotrophic factor (BDNF) expression, increased pro-apoptotic BAX expression, decreased anti-apoptotic Bcl-2 expression, and elevated acetylcholinesterase (AChE) activity in the hippocampus. Lower dose of VOX (1 mg/kg) did not show significant adverse effects on neurocognition, suggesting a dose-dependent impact. No sex specific neurocognitive deficits were observed in current study. These findings indicate that while VOX may offer a safer profile compared to SSRIs, high doses during pregnancy can still result in neurocognitive impairments in offspring.

Di-2-ethylhexyl terephthalate (DEHTP) is a replacement for its structural isomer di-2-ethylhexyl phthalate (DEHP), a known endocrine disrupting chemical and ovarian toxicant. DEHTP is used as a plasticizer in polyvinyl chloride products and its metabolites are increasingly found in biomonitoring studies at levels similar to phthalates. However, little is known about the effects of DEHTP on the ovary. In this research, we tested the hypothesis that DEHTP is an ovarian toxicant and likely endocrine disrupting chemical like its isomer DEHP. The impact of environmentally relevant exposure to DEHTP and/or its metabolite mono-2-ethylhexyl terephthalate (MEHTP) on the mouse ovary was investigated in vivo and in vitro. For the in vivo studies, young adult CD-1 mice were orally dosed with vehicle, 10 µg/kg, 100 µg/kg, or 100 mg/kg of DEHTP for 10 days. For the in vitro studies, isolated untreated ovarian follicles were exposed to vehicle, 0.1, 1, 10, or 100 µg/mL of DEHTP or MEHTP. Follicle counts, hormone levels, and gene expression of steroidogenic enzymes, cell cycle regulators, and apoptosis factors were analyzed. In vivo, DEHTP exposure altered follicle counts compared to control. DEHTP exposure also decreased expression of cell cycle regulators and apoptotic factors compared to control. In vitro, follicle growth was reduced compared to controls, and expression of the cell cycle regulator Cdkn2b was increased. Overall, these results suggest that DEHTP and MEHTP may be ovarian toxicants at low doses and should be subjected to further scrutiny for reproductive toxicity due to their similar structures to phthalates.

Bisphenol A (BPA) is an endocrine-disrupting compound extensively utilized in the production of polycarbonate polymers and epoxy resins that, upon exposure, pose a significant threat to male reproductive health because of its estrogenic properties. Accumulating evidence suggests that BPA exposure disrupts the normal process of spermatogenesis, alters testicular morphology and function, and interferes with testicular steroidogenesis and hormonal signaling. However, the precise mechanism by which BPA affects testicular function remains unclear. In this study, we explored the mechanism underlying BPA-induced testicular abnormalities and evaluated the protective effects of Selenium (Se). Thirty-two adult male albino Wistar rats were divided into four groups, and BPA was administered at 50 mg/kg body weight, with or without Se supplementation, for 30 days. Se supplementation (2.5 mg/kg body weight) was initiated 1 week before BPA administration. BPA administration resulted in alterations in testicular architecture, characterized by basement membrane disintegration in the seminiferous tubules, reduced spermatogenic cell counts, and increased interstitial tubule noncellular space. Furthermore, BPA exposure increased the levels of oxidized phospholipids, lipid peroxides, and hydroxyl radicals and decreased the activities of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. In addition, BPA significantly reduced the activities of 3β- and 17β-hydroxysteroid dehydrogenases, interfering with testicular steroidogenesis. In rats, coadministration of Se and BPA reduced the levels of oxidized phospholipids and increased the activities of antioxidant enzymes, leading to improved testicular function and epididymal sperm parameters, suggesting that Se plays a critical role in alleviating endocrine disruptor-induced testicular dysfunctions in rats.

There is a rising incidence of polycystic ovary syndrome (PCOS) cases worldwide in women of reproductive age due to environmental factors. We evaluated the effect of an environmental estrogen, bisphenol A for its reprotoxicity regarding the induction of PCOS in rats and also assessed its hormonal and metabolic implications. There was 66.6% and 50% disorder, in the estrus cycle at low (50µg/kg) and high (500µg/kg) doses of BPA. While animals treated with the positive control (dehydroepiandrosterone, DHEA at 6mg/100g) caused 100% disorder. Cystic and atretic follicles along with two corpus luteum were found in the low dose group. However, no corpus luteum was found in the high dose group. Furthermore, hyperplasia and hypertrophy were found in the myometrium, endometrium, and luminal epithelium of the uterus of the low dose and DHEA groups. Additionally, 17β estradiol, progesterone, DHEA, androstenedione, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulphate (DHEAS), antimullerian hormone (AMH), ratio of LH/FSH and testosterone/DHT were increased significantly (P < 0.01) in BPA groups. A significantly higher TSH (P < 0.01) indicates hypothyroidism. Furthermore, hyperglycemia, hyperinsulinemia, HOMA-IR, and HOMAβ indicate insulin resistance in the low-dose group. Thus, the low dose of BPA was found to be more potent as compared to the higher dose and defining the hyperandrogenic state. Our study revealed that BPA may not only be a causative factor in the induction of PCOS but also has metabolic implications bearing on its estrogenic nature.