Reproductive toxicology最新文献_第9页

The role of the pentose phosphate pathway in the development of metabolic disorders in the testes during rat intoxication with cypermethrin 戊糖磷酸途径在大鼠氯氰菊酯中毒期间睾丸代谢紊乱发展中的作用

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-25 DOI: 10.1016/j.reprotox.2025.109084

Eugene Chigrinski , Taras Gerunov , Nikita Merzlikin , Liudmila Gerunova , JinLian Hua

Cypermethrin, a synthetic pyrethroid used in crop production, veterinary medicine, and human medicine, poses a risk to human and mammalian health. The reproductive toxicity of synthetic Pyrethroids has not been fully studied, and the purpose of this study was to determine the role of the pentose phosphate pathway in the development of metabolic disorders in rat testicles during cypermethrin intoxication. The experiment was conducted on male rats, and the results showed an increase in the content of lactate, pyruvate, uric acid, inorganic phosphate (Pi) and malondialdehyde (MDA) in testicular tissue after 1–3 days. This indicates a violation of energy metabolism and increased lipid peroxidation processes, which leads to a decrease in glutathione (GSH) levels. The elevated activity of xenobiotic biotransformation systems and antioxidant enzymes exacerbates GSH depletion. Seven days after cypermethrin administration, glucose-6-phosphate dehydrogenase (G6PDH) activity decreases, and GSH deficiency becomes more pronounced. Reduced activity of enzymes of the glutathione redox cycle may be due to a deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) with inhibition of G6PDH. The low efficiency of the pentose phosphate pathway is likely due to a presumed glucose deficiency and excess lipid peroxidation products. The results of our study show that metabolic disorders that occur in the testicles during cypermethrin intoxication can lead to a decrease in the production of sex hormones and inhibition of spermatogenesis. Although sex hormone levels and spermatogenesis parameters were not directly measured in this study, the observed metabolic disruptions are consistent with previously reported impairments in steroidogenesis and spermatogenesis.

氯氰菊酯是一种合成拟除虫菊酯，用于农作物生产、兽药和人类药物，对人类和哺乳动物的健康构成威胁。合成拟除虫菊酯的生殖毒性尚未得到充分的研究，本研究的目的是确定戊糖磷酸途径在氯氰菊酯中毒大鼠睾丸代谢紊乱发展中的作用。对雄性大鼠进行实验，结果显示1-3天后睾丸组织中乳酸、丙酮酸、尿酸、无机磷酸盐（Pi）和丙二醛（MDA）含量增加。这表明能量代谢的破坏和脂质过氧化过程的增加，从而导致谷胱甘肽（GSH）水平的降低。外源生物转化系统和抗氧化酶活性的升高加剧了谷胱甘肽的消耗。施用氯氰菊酯后第7天，葡萄糖-6-磷酸脱氢酶（G6PDH）活性降低，GSH缺乏更加明显。谷胱甘肽氧化还原循环的酶活性降低可能是由于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的缺乏和G6PDH的抑制。戊糖磷酸途径的低效率可能是由于假定的葡萄糖缺乏和过量的脂质过氧化产物。我们的研究结果表明，氯氰菊酯中毒期间睾丸内发生的代谢紊乱可导致性激素产生减少和精子发生抑制。虽然在这项研究中没有直接测量性激素水平和精子发生参数，但观察到的代谢中断与先前报道的类固醇发生和精子发生障碍一致。

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引用次数: 0

Irreversible male infertility from sleep restriction: A dual hit on testicular steroidogenesis and Keap1-Nrf2-mediated antioxidant defense 睡眠不足导致的不可逆男性不育：睾丸类固醇生成和keap1 - nrf2介导的抗氧化防御的双重打击

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-22 DOI: 10.1016/j.reprotox.2025.109083

Keke Chen , Fengyou Luo , Xiling Huang , Kaixing Huang , Xiaoyu Liu , Qiping Hu , Changlong Xu

Background

Chronic sleep restriction (SR) threatens male reproductive health, yet the mechanisms underlying the partial reversibility of the induced damage remain unclear. We hypothesized that this persistent infertility stems from a "dual-hit" mechanism, involving the simultaneous suppression of testicular steroidogenesis and disruption of the Keap1-Nrf2-mediated antioxidant defense system. This study aimed to investigate the interplay between testicular steroidogenesis and antioxidant defense in SR-induced, persistent male infertility.

Methods

Male ICR mice were subjected to SR for 7, 14, or 21 days, followed by a 35-day recovery. We assessed sperm quality (CASA), testicular histology (H&E), apoptosis (TUNEL), serum hormones (ELISA), and the expression of key molecules in testosterone synthesis and Keap1-Nrf2 pathways (qPCR, Western Blot, IF, IHC).

Results

SR caused a time-dependent decline in sperm quality and testicular function, which did not fully recover after a prolonged rest period. Mechanistically, SR induced a dual-pronged assault: it comprehensively inhibited the testosterone synthesis pathway, evidenced by reduced StAR and HSD17B3 expression, and simultaneously disrupted the primary antioxidant defense by impairing the Keap1-Nrf2 pathway. This resulted in sustained oxidative stress, extensive germ cell apoptosis, and a failure to restore testicular homeostasis.

Conclusion

Our findings demonstrate for the first time that the partial irreversibility of SR-induced male infertility arises from a self-perpetuating vicious cycle of steroidogenic impairment and oxidative damage. The persistent dysfunction of both testosterone synthesis and Keap1-Nrf2 signaling pathways provides the molecular basis for this prolonged testicular injury, identifying them as potential therapeutic targets for related reproductive health issues.

慢性睡眠限制（SR）威胁男性生殖健康，但其部分可逆性的机制尚不清楚。我们假设这种持续的不孕症源于“双重打击”机制，包括睾丸类固醇生成的同时抑制和keap1 - nrf2介导的抗氧化防御系统的破坏。本研究旨在探讨sr诱导的持续性男性不育症中睾丸甾体生成与抗氧化防御之间的相互作用。方法小型ICR小鼠分别接受SR治疗7、14、21天，然后恢复35天。我们评估了精子质量（CASA）、睾丸组织学（H&；E）、细胞凋亡（TUNEL）、血清激素（ELISA）以及睾酮合成和Keap1-Nrf2通路关键分子的表达（qPCR、Western Blot、IF、IHC）。结果ssr引起精子质量和睾丸功能的时间依赖性下降，在长时间休息后不能完全恢复。在机制上，SR诱导了双管齐下的攻击：它全面抑制睾酮合成途径，通过降低StAR和HSD17B3表达来证明，同时通过损害Keap1-Nrf2途径破坏初级抗氧化防御。这导致持续的氧化应激、广泛的生殖细胞凋亡和睾丸内稳态恢复失败。结论我们的研究结果首次表明，sr诱导的男性不育症的部分不可逆性源于类固醇损伤和氧化损伤的自我延续的恶性循环。睾酮合成和Keap1-Nrf2信号通路的持续功能障碍为这种长期睾丸损伤提供了分子基础，并将其确定为相关生殖健康问题的潜在治疗靶点。

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引用次数: 0

Allicin attenuates doxorubicin-induced testicular and systemic toxicity in rats via antioxidant and anti-apoptotic mechanisms 大蒜素通过抗氧化和抗凋亡机制减弱阿霉素诱导的大鼠睾丸和全身毒性。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-20 DOI: 10.1016/j.reprotox.2025.109082

Mardin Omer Mohammed , Faraidoon Abdulstar Muhamad , Hiewa Othman Dyary

The clinical use of doxorubicin (DOX) is limited by toxicity in rapidly dividing tissues, notably the testes. This study evaluated allicin as a protective agent against DOX‑induced reproductive toxicity in male rats. Thirty-six male Sprague Dawley rats were randomly divided into six groups (n = 6): Group 1 received saline; Group 2 received DOX (a cumulative dose of 7.5 mg/kg, i.p. on days 8, 11, and 14); Group 3 received allicin alone (dissolved in corn oil, 20 mg/kg/day, orally for 14 days); Group 4 received DOX + allicin (10 mg/kg/day); Group 5 received DOX + allicin (20 mg/kg/day); and Group 6 received corn oil as the vehicle control. DOX treatment induced severe oxidative stress (OS), as evidenced by a 6.5-fold increase in malondialdehyde (MDA) and an 83 % decrease in superoxide dismutase (SOD) activity, indicating lipid peroxidation and impaired antioxidant defence. Allicin coadministration reduced MDA by 47 % and recovered SOD activity to 73 % of the control level. Furthermore, the TUNEL assay revealed a 4.6-fold increase in apoptotic index in DOX-treated rats, which allicin significantly attenuated dose-dependently. DOX upregulated MMP-9 (3.1-fold) and downregulated Cx43 and mTOR to 15 % and 18 % of the control levels, respectively, while allicin normalized these levels. Reproductive outcomes were compromised by DOX, with a 38 % decline in sperm count, a 65 % reduction in viability, a 93 % drop in testosterone, and a 51 % increase in morphological abnormalities; allicin improved these metrics by up to 60 %. Hematologically, DOX induced pancytopenia, which was partially reversed by allicin, resulting in an increase in leukocytes, erythrocytes, and platelets. In summary, allicin ameliorated DOX‑induced testicular and systemic toxicity through antioxidant, anti‑apoptotic, and gene‑regulatory mechanisms.

多柔比星（DOX）的临床使用受到快速分裂组织（特别是睾丸）毒性的限制。本研究评估了大蒜素作为雄性大鼠抗DOX诱导生殖毒性的保护剂。36只雄性Sprague Dawley大鼠随机分为6组（n = 6）： 1组给予生理盐水；2组接受DOX治疗（累积剂量7.5mg/kg，第8、11、14天一次）；3组单独给予大蒜素（溶于玉米油中，20mg/kg/d，口服，连用14 d）；4组给予DOX +大蒜素（10mg/kg/d）；5组给予DOX +大蒜素（20mg/kg/d）；第6组以玉米油为对照。DOX处理诱导了严重的氧化应激（OS），丙二醛（MDA）增加6.5倍，超氧化物歧化酶（SOD）活性降低83%，表明脂质过氧化和抗氧化防御受损。大蒜素共给药使MDA降低47%，使SOD活性恢复到对照水平的73%。此外，TUNEL实验显示，dox处理大鼠的凋亡指数增加4.6倍，大蒜素显著降低剂量依赖性。DOX上调MMP-9（3.1倍），下调Cx43和mTOR至对照水平的15%和18%，而大蒜素使这些水平正常化。DOX影响生殖结果，精子数量下降38%，生存能力下降65%，睾丸激素下降93%，形态异常增加51%；大蒜素将这些指标提高了60%。血液学上，DOX诱导全血细胞减少，大蒜素部分逆转，导致白细胞、红细胞和血小板增加。总之，大蒜素通过抗氧化、抗凋亡和基因调控机制改善DOX诱导的睾丸和全身毒性。

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引用次数: 0

Effects of exposure to 17 endocrine disrupting chemicals on sex steroid hormone levels in 12- to 19-year-old males in the United States 接触17种内分泌干扰化学物质对美国12- 19岁男性性类固醇激素水平的影响。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-14 DOI: 10.1016/j.reprotox.2025.109078

Adila Adili, Haoran Liu, Hui Tian, Yuanyuan Ji, Xiaofang Han

Endocrine disrupting chemicals are widespread in the environment and can interfere with reproductive hormone regulation, but their effects during adolescence are not yet clear. This study investigated the associations between exposure to multiple endocrine disrupting chemicals and sex steroid hormone levels in adolescent males. Data were obtained from the National Health and Nutrition Examination Survey 2013–2016, including males aged 12–19 years. Urinary concentrations of 17 endocrine disrupting chemicals, including phthalates, phenols, and parabens, were analyzed in relation to serum sex hormones. Associations were examined using linear regression, quantile g-computation, and Bayesian kernel machine regression to capture both single and mixture exposures. Linear regression identified inverse associations of mono-(3-carboxypropyl) phthalate with total testosterone, estradiol, free androgen index, free testosterone, and bioavailable testosterone. Mono-(2-ethyl-5-hydroxyhexyl) phthalate was inversely associated with estradiol, free androgen index, free testosterone, and bioavailable testosterone, but positively associated with sex hormone-binding globulin. Quantile g-computation confirmed these relationships, while Bayesian kernel machine regression demonstrated that combined exposure to 17 endocrine disrupting chemicals collectively reduced total testosterone, estradiol, free androgen index, free testosterone, and bioavailable testosterone, while increasing sex hormone-binding globulin. These findings reveal a consistent pattern of elevated binding globulin levels accompanied by decreased bioactive sex hormones. In conclusion, exposure to endocrine disrupting chemicals, both individually and as mixtures, is associated with altered sex steroid hormone levels in adolescent males. These results underscore the importance of environmental regulation to limit exposure during this critical developmental stage and highlight the potential role of chemical mixtures in adolescent reproductive health.

干扰内分泌的化学物质在环境中广泛存在，可以干扰生殖激素的调节，但它们对青春期的影响尚不清楚。本研究调查了青春期男性接触多种内分泌干扰物质与性类固醇激素水平之间的关系。数据来自2013-2016年全国健康与营养检查调查，包括12-19岁的男性。分析了17种内分泌干扰化学物质（包括邻苯二甲酸酯、酚类和对羟基苯甲酸酯）的尿浓度与血清性激素的关系。使用线性回归、分位数g计算和贝叶斯核机回归来检测关联，以捕获单一和混合暴露。线性回归发现邻苯二甲酸单-（3-羧基丙基）酯与总睾酮、雌二醇、游离雄激素指数、游离睾酮和生物可利用睾酮呈负相关。邻苯二甲酸单-（2-乙基-5-羟基己基）与雌二醇、游离雄激素指数、游离睾酮和生物可利用睾酮呈负相关，但与性激素结合球蛋白呈正相关。分位数g计算证实了这些关系，而贝叶斯核机回归表明，17种内分泌干扰化学物质的联合暴露共同降低了总睾酮、雌二醇、游离雄激素指数、游离睾酮和生物可利用睾酮，同时增加了性激素结合球蛋白。这些发现揭示了结合球蛋白水平升高伴随生物活性性激素下降的一致模式。总之，暴露于干扰内分泌的化学物质，无论是单独的还是混合的，都与青春期男性的性类固醇激素水平改变有关。这些结果强调了在这一关键发育阶段进行环境管制以限制接触的重要性，并强调了化学混合物在青少年生殖健康中的潜在作用。

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引用次数: 0

Association of individual and combined exposure to polycyclic aromatic hydrocarbon (PAH) and phthalate (PAE) metabolites with maternal estradiol levels in early pregnancy: A cross-sectional study 个体和联合暴露于多环芳烃（PAH）和邻苯二甲酸酯（PAE）代谢物与妊娠早期母体雌二醇水平的关系：一项横断面研究

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-11 DOI: 10.1016/j.reprotox.2025.109081

Lin Tao , Jing Yang , Zhongmei Hu , Dengqing Liao , Shimin Xiong , LuLu Dai , Yuan-zhong Zhou , Xubo Shen

Polycyclic aromatic hydrocarbons (PAHs) and phthalates (PAEs) exert endocrine-disrupting effects; however, research investigating the relationship between co-exposure to these two classes of pollutants and sex hormone levels in pregnant women remains limited. To address this gap, we enrolled 454 women in early pregnancy from the Zunyi Birth Cohort (ZBC) and used linear mixed-effects models (LMM), Bayesian kernel machine regression (BKMR), and restricted cubic spline (RCS) models to examine associations between early-pregnancy both individual and combined exposur to PAHs and PAEs and maternal estradiol levels. LMM results revealed no significant associations between PAH metabolites and estradiol, but significant associations between PAE metabolites and estradiol—primarily driven by monoisobutyl phthalate (MIBP) and monobutyl phthalate (MBP), with corresponding β values (95 % confidence intervals [CIs]) of −534.77 (-761.17, −308.37) and 473.19 (233.80, 712.58), respectively. BKMR analyses showed that exposure to PAH metabolites alone was negatively associated with estradiol, primarily involving 4-hydroxyphenanthrene (4-OHPH) and 1-hydroxypyrene (1-OHPYR). Exposure to PAE metabolites alone was also negatively associated with estradiol, driven mainly by monoethyl phthalate (MEP), MIBP, and MBP. Concurrent exposure to PAE and PAH metabolites was negatively associated with estradiol, with key contributors including 2-hydroxyfluorene (2-OHFLU), MiBP, MBP, mono(2-ethylhexyl) phthalate (MEHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). RCS results demonstrated an inverted U-shaped relationship between 2-OHFLU and estradiol (F=2.8, P = 0.019), a non-linear negative association between MIBP and estradiol (F=3.3, P = 0.002), and an inverted U-shaped relationship between MEOHP and estradiol (F=4.4, P = 0.005). Collectively, these findings indicate that both individual and combined exposure to PAHs and PAEs in early pregnancy is associated with estradiol levels in pregnant women, with evidence of exposure-response relationships. Reducing exposure to PAH and PAE metabolites in early pregnancy is recommended to further safeguard maternal and fetal health.

多环芳烃（PAHs）和邻苯二甲酸酯（PAEs）具有内分泌干扰作用；然而，关于孕妇同时接触这两类污染物与性激素水平之间关系的研究仍然有限。为了解决这一差距，我们从遵义出生队列（ZBC）中纳入了454名早孕妇女，并使用线性混合效应模型（LMM）、贝叶斯核机回归（BKMR）和限制性三次样条（RCS）模型来研究早孕个体和联合暴露于多环芳烃和PAEs与母体雌二醇水平之间的关系。LMM结果显示，PAH代谢物与雌二醇之间没有显著相关性，但PAE代谢物与雌二醇之间存在显著相关性——主要由邻苯二甲酸单异丁酯（MIBP）和邻苯二甲酸单丁酯（MBP）推动，相应的β值（95%置信区间[ci]）分别为-534.77（-761.17,-308.37）和473.19（233.80,712.58）。BKMR分析显示，单独暴露于多环芳烃代谢物与雌二醇呈负相关，主要涉及4-羟基菲（4-OHPH）和1-羟基芘（1-OHPYR）。单独暴露于PAE代谢物也与雌二醇呈负相关，主要由邻苯二甲酸一乙酯（MEP）、MIBP和MBP驱动。同时暴露于PAE和PAH代谢物与雌二醇呈负相关，主要影响因素包括2-羟基芴（2-OHFLU）、MiBP、MBP、邻苯二甲酸单（2-乙基己基）酯（MEHP）和邻苯二甲酸单（2-乙基-5-氧己基）酯（MEOHP）。RCS结果显示，2-OHFLU与雌二醇呈倒u型关系（F=2.8， P=0.019）， MIBP与雌二醇呈非线性负相关（F=3.3， P=0.002）， MEOHP与雌二醇呈倒u型关系（F=4.4， P=0.005）。总的来说，这些发现表明，怀孕早期单独或联合暴露于多环芳烃和多环芳烃与孕妇的雌二醇水平有关，并有证据表明暴露-反应关系。建议在妊娠早期减少接触多环芳烃和多环芳烃代谢物，以进一步保障母婴健康。

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引用次数: 0

From exposure to outcomes: How air pollutants impact maternal and foetal health 从接触到结果：空气污染物如何影响孕产妇和胎儿健康。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-11 DOI: 10.1016/j.reprotox.2025.109080

Garvita Parikh, Bhoomika Patel

Air pollution is a leading environmental risk factor, contributing significantly to respiratory illnesses, cardiovascular diseases, and other chronic conditions; ultimately increasing the global burden of ailments. While the harmful effects of air pollutants on the respiratory and cardiovascular systems are well-known, concerns over their impact on pregnancy outcomes are rising. Pregnant women and their developing fetuses are particularly more susceptible to the harmful effects of air pollutants, which can penetrate the placental barrier and lead to a wide range of negative consequences, such as preeclampsia, premature rupture of membranes, gestational diabetes, and placenta previa. These consequences concurrently lead to adversarial birth outcomes like congenital abnormalities, developmental delays, preterm birth, etc. This review elucidates the link between maternal exposure to air pollutants and the subsequent occurrence of adverse pregnancy and birth outcomes. It also explores the utility of various biomarkers, including inflammatory markers, oxidative stress markers, and molecular markers, used to assess the presence of air pollutants and their impact on pregnancy and birth outcomes. Furthermore, through assimilating these insights, this review emphasizes the crucial need for targeted interventions and policies to mitigate the air pollutants deadly effect on sensitive and vulnerable groups.

空气污染是一个主要的环境风险因素，严重导致呼吸系统疾病、心血管疾病和其他慢性疾病；最终增加全球疾病负担。虽然空气污染物对呼吸系统和心血管系统的有害影响是众所周知的，但对其对妊娠结局的影响的担忧正在增加。孕妇及其发育中的胎儿特别容易受到空气污染物的有害影响，空气污染物可以穿透胎盘屏障，导致一系列负面后果，如先兆子痫、胎膜早破、妊娠糖尿病和前置胎盘。这些后果同时导致不利的出生结果，如先天性异常、发育迟缓、早产等。这篇综述阐明了母亲暴露于空气污染物和随后发生的不良妊娠和分娩结局之间的联系。它还探讨了各种生物标志物的用途，包括炎症标志物、氧化应激标志物和分子标志物，用于评估空气污染物的存在及其对妊娠和分娩结果的影响。此外，通过吸收这些见解，本综述强调了有针对性的干预措施和政策的迫切需要，以减轻空气污染物对敏感和弱势群体的致命影响。

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引用次数: 0

In utero exposure to acetaminophen and childhood attention deficit hyperactivity disorder: An ongoing controversy 子宫内暴露于对乙酰氨基酚和儿童注意缺陷多动障碍：一个持续的争议

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-08 DOI: 10.1016/j.reprotox.2025.109076

Per Damkier, Erika B. Gram

Attention Deficit Hyperactivity Disorder (ADHD) in children as related to maternal use of acetaminophen (paracetamol, APAP) remains an ongoing controversy. In a recent paper in Nature Mental Health, Baker et al. reports on ADHD in children as related to maternal use of acetaminophen APAP in pregnancy. We discuss the methodological strengths and limitations and the extent to which this paper informs clinical practice.

儿童注意缺陷多动障碍（ADHD）与母亲使用对乙酰氨基酚（paracetamol， APAP）的关系仍然是一个持续的争议。在《自然心理健康》杂志最近的一篇论文中，Baker等人报道了儿童多动症与母亲在怀孕期间使用对乙酰氨基酚APAP有关。我们讨论了方法学的优势和局限性，以及本文对临床实践的影响程度。

引用次数: 0

Multidimensional mechanistic analysis elucidates spermatogenesis disruption induced by bisphenol S 双酚S诱导精子发生破坏的多维机制分析

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-08 DOI: 10.1016/j.reprotox.2025.109079

Lei Xu , Bin Huang , Shengliang Gu , Yitao Xing , Fugang Zhang , Wei Fu , Ting Chen , Zhuojun Yuan , Guozheng Qin

Bisphenol S (BPS), a primary substitute for bisphenol A, has led to widespread environmental exposure globally. However, the effects of BPS on spermatogenesis disruption (SD) remain contentious, and the underlying mechanisms responsible for SD induced by BPS are not fully understood. In this study, we employed a multidimensional computational strategy, integrating network toxicology, bioinformatics, systematic machine learning, single-cell analysis, and biomolecular modeling, to comprehensively elucidate the molecular mechanisms by which BPS induces SD. Our findings suggest that BPS may disrupt spermatogenesis by interfering with multiple signaling pathways, including the cAMP signaling pathway, MAPK pathway, VEGF pathway, and PI3K-Akt pathway, thereby forming a synergistic toxic network. Through systematic screening utilizing 113 combinations of machine learning algorithms, we identified CTSK, GSTZ1, and PDE4D as core diagnostic biomarkers for SD, positing that these genes may serve as potential hub targets through which BPS disrupts spermatogenesis. Moreover, our analysis of testicular tissue-specific co-expression networks and single-cell data revealed that these hub genes are specifically expressed in testicular tissue, predominantly enriched in reproductive cell types such as Sertoli cells, peritubular myoid cells, spermatogonia, and spermatocytes. Biomolecular modeling further indicated a strong binding affinity between BPS and these hub proteins. This research not only provides critical insights into the reproductive toxicity risk assessment of BPS by elucidating its impact on spermatogenesis but also reveals novel biomarkers and potential intervention targets based on a multidimensional mechanistic analysis, thereby advancing the field of BPS reproductive toxicology.

双酚S （BPS）是双酚a的主要替代品，在全球范围内引起了广泛的环境暴露。然而，BPS对精子发生中断（SD）的影响仍然存在争议，并且BPS诱导SD的潜在机制尚未完全了解。本研究采用多维计算策略，结合网络毒理学、生物信息学、系统机器学习、单细胞分析和生物分子模型，全面阐明BPS诱导SD的分子机制。我们的研究结果表明，BPS可能通过干扰多种信号通路，包括cAMP信号通路、MAPK信号通路、VEGF信号通路和PI3K-Akt信号通路，从而形成一个协同毒性网络，从而破坏精子发生。通过使用113种机器学习算法组合的系统筛选，我们确定了CTSK， GSTZ1和PDE4D作为SD的核心诊断生物标志物，假设这些基因可能是BPS破坏精子发生的潜在枢纽靶点。此外，我们对睾丸组织特异性共表达网络和单细胞数据的分析显示，这些中心基因在睾丸组织中特异性表达，主要富集于生殖细胞类型，如支持细胞、小管周围肌样细胞、精原细胞和精母细胞。生物分子模型进一步表明BPS与这些枢纽蛋白之间具有很强的结合亲和力。本研究不仅通过阐明其对精子发生的影响，为BPS生殖毒性风险评估提供了重要见解，而且基于多维机制分析揭示了新的生物标志物和潜在的干预靶点，从而推动了BPS生殖毒理学领域的发展。

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引用次数: 0

Vitamin D supplementation stimulates germ cell proliferation in a restraint-stressed mouse 维生素D补充刺激生殖细胞增殖抑制应激小鼠。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-08 DOI: 10.1016/j.reprotox.2025.109077

Rahul Kumar , Lalrawngbawli Annie , Guruswami Gurusubramanian , Ajit Singh , Vikas Kumar Roy

Restraint stress in the rodent model has been used for anxiety, depression, alongside testicular dysfunction. Vitamin D regulates testicular function, but its effect on restraint stress-related testicular impairment has not been investigated yet. Therefore, the present study has investigated the effects of vitamin D on the testicular function in restraint-stressed mice. The results showed that vitamin D has improved the sperm parameters and testicular architecture. Moreover, testicular architecture showed better protection in the lower dose, along with decreased oxidative stress. Elevated apoptosis in the lower dose of vitamin D-treated mice could be a disposal mechanism for damaged germ cells. The markers of proliferation (GCNA) were elevated in both doses of vitamin D-treated groups, which showed that vitamin D stimulates germ cell proliferation, thereby improving the testicular architecture. However, PCNA expression did not change, and this could be involved in the DNA repair mechanism. The expression of NF-κB was elevated in all the stressed groups, irrespective of vitamin D treatment. Since NF-κB has pro- and anti-apoptotic effects in the testis, thus, its exact role with respect to apoptosis is not known in the present study. We examined the levels of the Vitamin D Receptor (VDR) in the testis. Our findings indicated that VDR expression was reduced in the restraint-stressed group. In conclusion, vitamin D could improve testicular function in the stressed condition by stimulating germ cell proliferation and due to proliferation, the apoptosis could have also been modulated.

克制应激在啮齿动物模型中已被用于焦虑、抑郁和睾丸功能障碍。维生素D可调节睾丸功能，但其对约束应激相关性睾丸损伤的影响尚未研究。因此，本研究探讨了维生素D对抑制应激小鼠睾丸功能的影响。结果表明，维生素D改善了精子参数和睾丸结构。此外，睾丸结构在低剂量下表现出更好的保护作用，同时氧化应激降低。低剂量维生素d处理小鼠中细胞凋亡的升高可能是对受损生殖细胞的一种处理机制。两剂量维生素D处理组的增殖标志物（GCNA）均升高，表明维生素D刺激生殖细胞增殖，从而改善睾丸结构。然而，PCNA的表达并没有改变，这可能与DNA修复机制有关。与维生素D治疗无关，所有应激组的NF-κB表达均升高。由于NF-κ b在睾丸中具有促凋亡和抗凋亡的作用，因此，其在细胞凋亡中的确切作用在本研究中尚不清楚。我们检查了睾丸中维生素D受体（VDR）的水平。我们的研究结果表明，抑制应激组的VDR表达降低。综上所述，维生素D可能通过刺激生殖细胞增殖来改善应激条件下睾丸功能，并通过增殖调节生殖细胞凋亡。

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引用次数: 0

Direct and intergenerational effects in reproductive parameters of adult male Wistar rats and their offspring after subchronic exposure to polystyrene nanoplastics 亚慢性聚苯乙烯纳米塑料暴露对成年雄性Wistar大鼠及其后代生殖参数的直接和代际影响。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-01 DOI: 10.1016/j.reprotox.2025.109075

Lethícia Valencise , Ana Flávia Quiarato Lozano , Jorge Willian Franco de Barros , Carina Funck Godoy , Cibele dos Santos Borges , Daniel G. Cyr , Wilma De Grava Kempinas

Polystyrene is among the most prevalent types of plastic debris. Polystyrene nanoplastics (PS-NP) cause several alterations in young rodent reproductive tissue and fertility. Here, we investigated if the exposure to PS-NP (500 nm) in adult (90 days-old) male Wistar rats affects reproductive parameters and causes intergenerational effects on the offspring. Study 1: animals (n = 10/group) were exposed by gavage to either distilled water (vehicle; Control group), 0.15 mg/d of PS-NP (Low Dose) or 1.50 mg/d of PS-NP (High Dose) for 60 days. Sperm quality and testosterone serum levels were measured. Study 2: the exposure protocol was repeated using only Control (n = 10) and High Dose (n = 9) groups, then blood leukocytes, histopathology of the testis and the epididymis, and fertility parameters were evaluated. At the end of treatment males (F0) were mated with untreated females (70 – 90 days-old) to produce the first generation (F1) evaluated on Study 3 (Control: n = 7; High Dose: n = 8). Study 3: intergenerational damage was assessed in the male and female offspring (F1). The presence of sperm cytoplasmic droplets and the relative number of sperm in the cauda epididymis increased in the High Dose group (Study 1), as well as the relative number of monocytes in the blood stream (Study 2). Intergenerational effects were observed such as the dysregulation of the estrous cycle of F1-females (Study 3). Given that rats exhibit significantly higher fertility rates than humans, these results could imply that long-term environmental exposure to different types of plastics might have potential consequences for human reproductive health.

聚苯乙烯是最常见的塑料碎片之一。聚苯乙烯纳米塑料（PS-NP）引起幼鼠生殖组织和生育能力的一些改变。在这里，我们研究了成年（90日龄）雄性Wistar大鼠暴露于PS-NP （500nm）是否会影响生殖参数，并对后代产生代际影响。研究1：动物（n = 10/组）分别灌胃蒸馏水（对照组）、0.15mg/d的PS-NP（低剂量）或1.50mg/d的PS-NP（高剂量），持续60天。测量精子质量和血清睾酮水平。研究2：仅对照组（n = 10）和高剂量组（n = 9）重复暴露方案，然后评估血液白细胞，睾丸和附睾的组织病理学和生育参数。在治疗结束时，雄性（F0）与未治疗的雌性（70 - 90日龄）交配，产生研究3中评估的第一代（F1）（对照组：n = 7；高剂量：n = 8）。研究3：评估了雄性和雌性后代的代际损害（F1）。高剂量组精子细胞质液滴的存在和附睾尾精子的相对数量增加（研究1），血流中单核细胞的相对数量也增加（研究2）。代间效应被观察到，例如f1雌性的发情周期失调（研究3）。鉴于大鼠的生育率明显高于人类，这些结果可能意味着，长期接触不同类型的塑料可能对人类生殖健康产生潜在影响。

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