Reproductive toxicology最新文献

Background

Hypertensive disorders of pregnancy (HDP) remain a significant global health burden despite medical advancements. HDP prevalence appears to be rising, leading to increased maternal and fetal complications, mortality, and substantial healthcare costs. The etiology of HDP are complex and multifaceted, influenced by factors like nutrition, obesity, stress, metabolic disorders, and genetics. Emerging evidence suggests environmental pollutants, particularly Per- and polyfluoroalkyl substances (PFAS), may contribute to HDP development.

Objective

This review integrates epidemiological and mechanistic data to explore the intricate relationship between PFAS exposure and HDP.

Epidemiological evidence

Studies show varying degrees of association between PFAS exposure and HDP, with some demonstrating positive correlations, particularly with preeclampsia. Meta-analyses suggest potential fetal sex-specific differences in these associations.

Mechanistic insights

Mechanistically, PFAS exposure appears to disrupt vascular hemodynamics, placental development, and critical processes like angiogenesis and sex steroid regulation. Experimental studies reveal alterations in the renin-angiotensin system, trophoblast invasion, oxidative stress, inflammation, and hormonal dysregulation – all of which contribute to HDP pathogenesis. Elucidating these mechanisms is crucial for developing preventive strategies.

Therapeutic potential

Targeted interventions such as AT2R agonists, caspase inhibitors, and modulation of specific microRNAs show promise in mitigating adverse outcomes associated with PFAS exposure during pregnancy.

Knowledge gaps and future directions

Further research is needed to comprehensively understand the full spectrum of PFAS-induced placental alterations and their long-term implications for maternal and fetal health. This knowledge will be instrumental in developing effective preventive and therapeutic strategies for HDP in a changing environmental landscape.

DNAJA1 is a member of type I DnaJ proteins, which is essential for spermatogenesis and male fertility. However, its expression pattern in the testes and its impact on spermatogenesis remains unclear. Our study aimed to elucidate the mechanism of action of DNAJA1. We employed DNAJA1 knockout mice in this study. Western blotting and immunofluorescence analysis were conducted to determine the protein abundance of DNAJA1 in testes at various developmental stages. Our results revealed that DNAJA1 is predominantly expressed in the testes, and its knockout leads to complete infertility in male mice. We observed that DNAJA1 protein levels increased on postnatal days 14, 21, and 28, peaking on postnatal day 35 in mice. Immunofluorescence staining indicated that DNAJA1 expression varies across different stages of the spermatogenesis cycle. Additionally, DNAJA1 was absent in epididymal sperm. In early- and mid-stage tubules, DNAJA1 protein distribution was co-localized with residual bodies in elongating spermatids. Furthermore, we found that DNAJA1 knockout significantly reduced protein polyubiquitination in the testis. Analysis of the GEO database showed that DNAJA1 levels were significantly decreased in semen samples from subjects with teratozoospermia, asthenozoospermia, and impaired spermatogenesis. Our findings suggest that DNAJA1 is an essential protein for spermatogenesis, and its deletion reduces protein polyubiquitination in the testis, ultimately resulting in infertility and spermatogenesis defects.

Testicular dysplasia significantly impairs male reproductive capacity. This study investigated the expression of Cyclin D1/Nanog and NF-κB/Bax in dysplastic testes of mice using histological staining, Western blotting, and immunohistochemistry. The results showed that Nanog and Bax expression were significantly higher in dysplastic testicular tissue than in normal tissue (P < 0.01). Cyclin D1 protein expression was higher in normal testis tissue than in dysplastic testis (P < 0.01). NF-κB was highly expressed in cryptorchid and normal testis with no significant difference (P > 0.05). Immunolocalization revealed that Nanog, NF-κB, and Bax were expressed in the cytoplasm of Leydig and spermatogenic cells. Cyclin D1 primarily expressed in the nucleus of Sertoli cells. These findings suggest that altered expression of Nanog, Cyclin D1, and Bax may contribute to testicular dysplasia. This study provides a scientific foundation for detecting testicular dysplasia and selecting appropriate animal models, ultimately informing strategies to improve male reproductive health.

The ICH S5(R3) guideline recommends that male rodents in a FEED study are treated for ≥2 weeks before mating, which has frequently been criticized as being too short for the detection of all effects on sperm maturation, mating behavior and male fertility. In a FEED study, males generally continue for ≥5 weeks after the start of cohabitation. This review determines how often a 2-week premating treatment period for males was used in FEED studies of novel drugs approved by the FDA in 2022 and 2023. The male premating treatment duration was specified for 44 drugs. Only 16 % of these had a 2-week male premating treatment period. 52 % of drugs had a 4-week period. No examples were found in the literature of drugs for which male-mediated reproductive toxicity could have been detected using a 4-week, but not a 2-week, premating treatment period. Repeat dose studies in 2 species, with a duration of treatment at least equivalent to that in patients, are generally completed before the FEED study is planned. Providing no effects on male reproductive organs are detected in the repeat dose studies, a 2-week premating treatment period appears sufficient for the detection of effects on male mating performance. If toxic effects on spermatogenesis are detected in the repeat dose studies, a male FEED study serves little regulatory purpose. Even in the absence of effects on mating performance and fertility in the FEED study, a drug-related disruption of spermatogenesis would likely be considered pertinent to the human.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy that is known to be one of the most common reproductive pathologies observed in premenopausal women around the globe and is particularly complex as it affects various endocrine and reproductive metabolic pathways. Endocrine-disrupting chemicals (EDCs) are considered to be environmental toxicants as they have hazardous health effects on the functioning of the human endocrine system. Among various classes of EDCs, bisphenol A (BPA) has been under meticulous investigation due to its ability to alter the endocrine processes. As there is emerging evidence suggesting that BPA-induced mitochondrial homeostasis dysfunction in various pathophysiological conditions, this review aims to provide a detailed review of how various pathways associated with ovarian mitochondrial homeostasis are impaired on BPA exposure and its mirroring effects on the PCOS phenotype. BPA exposure might cause significant damage to the mitochondrial morphology and functions through the generation of reactive oxygen species (ROS) and simultaneously downregulates the total antioxidant capacity, thereby leading to oxidative stress. BPA disrupts the mitochondrial dynamics in human cells by altering the expressions of mitochondrial fission and fusion genes, increases the senescence marker proteins, along with significant alterations in the mTOR/AMPK pathway, upregulates the expression of autophagy mediating factors, and downregulates the autophagic suppressor. Furthermore, an increase in apoptosis of the ovarian granulosa cells indicates impaired folliculogenesis. As all these key features are associated with the pathogenesis of PCOS, this review can provide a better insight into the possible associations between BPA-induced dysregulation of mitochondrial homeostasis and PCOS.

Aquatic ecosystems face significant exposure to endocrine-disrupting chemicals (EDCs), which can mimic, block, or alter the synthesis of endogenous hormones. Bisphenol A (BPA), a widely known EDC, has been phased out from consumer products due to concerns about its potential impacts on human health. In its place, bisphenol S (BPS), an organic compound, has been increasingly used in the production of polycarbonate plastics, epoxy resins, thermal receipt papers, and currency. Vitellogenin (Vtg), a yolk precursor protein synthesized in the liver and present in oviparous fish, particularly males, serves as a pertinent biomarker for studying the effects of estrogenic EDCs on fish. This study aimed to assess the impact of BPS on reproductive parameters and hepatic vitellogenin expression in Channa striatus. The LC50 of BPS was determined to be 128.8 mg/L. Experimental groups included control and BPS-exposed fish, with sub-lethal concentrations of BPS (1 mg/L, 4 mg/L, and 12 mg/L) administered and effects monitored at seven- and twenty-one-day intervals. Significant decreases in gonadosomatic index (GSI), ova diameter, and fecundity were observed in BPS-exposed Channa striatus. Hepatic Vtg mRNA expression was downregulated in female and upregulated in male following BPS exposure. Serum hormone analysis confirmed the estrogenic activity of BPS. These findings underscore BPS's ability as an endocrine disruptor to interfere with hormone synthesis and disrupt spermatogenesis and oogenesis processes in Channa striatus. This research contributes to understanding the endocrine-disrupting effects of BPS on aquatic organisms, highlighting potential ecological implications and the need for continued monitoring and regulatory considerations.

Food-grade titanium dioxide E171 was administered in feed to Sprague Dawley rats in an extended one-generation reproductive toxicity (EOGRT) study (OECD Test 443). The dosed diet (0, 100, 300, or 1000 mg/kg body weight/day) started 10 weeks before mating and continued throughout the study. After weaning, pups were allocated to Cohorts 1 A/1B (to assess reproductive toxicity), 2 A/2B (to assess developmental neurotoxicity), and 3 (to assess developmental immunotoxicity); in addition, Cohort 1B was mated to produce an F₂ generation and satellite F₀ animals were evaluated for colonic aberrant crypt foci (ACF). In F₀ animals, there were no systemic toxicity or reproductive effects, no treatment-related histopathological changes, and no ACF in the colon. Serum estradiol or testosterone concentrations were not changed in F₀ or F₁ animals. No pre-/postnatal developmental changes related to treatment were noted in F₁ animals, and the reproductive performance of F₁ Cohort 1B animals was unaffected. F₂ pups showed no abnormalities in pre- or postnatal development (postnatal days 4–8). No treatment-related developmental neurotoxicity was observed in Cohorts 2 A/2B. Although no treatment-related immunotoxicity was observed in Cohort 3, the positive control did not induce the expected response; this segment of the study will be repeated. Analyses of blood and urine showed negligible systemic absorption of E171 from the gastrointestinal tract upon dietary ingestion. The no observed adverse effect level (NOAEL) for parental systemic toxicity, reproductive toxicity, offspring toxicity, and developmental neurotoxicity was considered 1000 mg/kg body weight/day. For developmental immunotoxicity, a NOAEL was not determined owing to insufficient T-cell-dependent antibody response in the positive control. Our study provides robust data on the reproductive toxicity and preneoplastic potential of E171.

It has been proposed that poor semen quality may have its origins from fetal programming due to environmental factors. We investigated whether maternal coffee consumption during early pregnancy was associated with biomarkers of reproductive health in adult sons in the Fetal Programming of Semen Quality (FEPOS) cohort. In 2017–2019, 1058 young men provided a semen and blood sample and self-measured their testis volume. Daily maternal coffee consumption was reported by the mothers around gestational week 17. We estimated relative percentage differences with 95 % confidence intervals (CI) for semen quality measures, testis volume, and reproductive hormone levels according to maternal coffee consumption during pregnancy. Maternal coffee consumption (yes/no (reference)) was associated with lower semen volume (-7.0 % (95 % CI:-12.9;-0.7)), lower proportion of morphologically normal spermatozoa (-8.3 % (95 % CI:-16.5;0.8)), higher proportion of non-progressive and immotile spermatozoa (4.3 % (95 % CI:-1.5;10.3)), and lower testis volume (-4.8 % (95 % CI:-9.0;-0.4)). No indication of a dose-response association or threshold effects was observed in the categorized and continuous analyses. No associations with reproductive hormone levels were observed in any of the analyses. Overall, the study does not provide obvious indications that maternal coffee consumption in early pregnancy deteriorates male offspring fecundity. While some minor changes were observed, most estimates were small with confidence intervals overlapping the null. Future studies, preferably with greater exposure contrast, are warranted before a conclusion can be drawn as to whether maternal coffee consumption during pregnancy constitutes a risk for reproductive health in adult sons.

Formaldehyde (FA) as a common organic compound has been shown to cause placental dysfunction and fetal defects. The potential benefits of fish oil (FOil) in protecting placental structures are attributed to its antioxidant properties. This study aimed to explore the preventive role of FOil in mitigating the adverse effects of FA in pregnant rats. Thirty pregnant Wistar rats were randomly categorized into five groups of control, sham (Normal saline; Orally and intraperitoneally), FOil (0.5 ml/day; Orally), FA (5 mg/kg/bw; intraperitoneally), FA+FOil. The treatment period was from day 0–20 of pregnancy. On the 20th day of pregnancy, placental morphometric parameters were measured. The histological and histochemical analyses were performed using H&E and PAS staining, respectively. Also, the placenta tissue was analyzed for oxidative stress biomarkers, p-53 protein levels, and the expression of caspase-3 gene. The administration of FA led to a significant decrease in the weight, diameter, and thickness of the placenta, as well as a decrease in the thickness of the decidua layer, junctional and labyrinth zone, and the number of trophoblast giant cells in rat placentas. FA led to a significant increase in placental p-53 protein levels, caspase-3 expression, and oxidative stress biomarkers. Administration of FOil to pregnant rats treated with FA led to a significant decrease in morphometric and histological changes, oxidative stress, and the expression of genes associated with apoptosis. The findings suggest that the administration of FOil to FA-treated pregnant rats can protect placental histopathological changes by enhancing the activity of the antioxidant enzymes.

Bisphenol A (BPA) is a phenolic chemical that has been found to be associated with human health outcomes. It is one of the risk factors for thyroid function. Pregnancy is a vulnerable window for thyroid problems, because of the fluctuations in hormone levels. This review aimed to evaluate the association between BPA exposure and thyroid function during pregnancy. We conducted a comprehensive search of relevant databases, including PubMed, Scopus, Embase, Web of Science, and the Cochrane Library, for original studies published in English that reported data on BPA levels and thyroid-related hormone levels in pregnant women. We used the Newcastle-Ottawa Scale (NOS) to assess the methodological quality of the studies and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method to evaluate the quality of evidence. In total, 11 studies involving 6526 individuals were included in this systematic review. These studies explored fluctuations in thyroid-related hormones, including TSH, TT3, TT4, FT3, and FT4 levels, as well as the TT4/TT3 and FT4/FT3 ratios. The systematic review is to evaluate the evidences between bisphenol A exposure and thyroid-related hormones in pregnant women. We found that BPA exposure in pregnancy might disturb the homeostasis of maternal thyroid-related hormones and suggest an increased risk of hyperthyroidism. Further studies based on the findings are required to explore the underlying mechanisms and determine the potential effects of BPA exposure on thyroid function during pregnancy.