Reproductive toxicology最新文献

{"title":"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","authors":"Lin Tao ,&nbsp;Jing Yang ,&nbsp;Zhongmei Hu ,&nbsp;Dengqing Liao ,&nbsp;Shimin Xiong ,&nbsp;LuLu Dai ,&nbsp;Yuan-zhong Zhou ,&nbsp;Xubo Shen","doi":"10.1016/j.reprotox.2025.109081","DOIUrl":"10.1016/j.reprotox.2025.109081","url":null,"abstract":"<div><div>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 (<em>F</em>=2.8, <em>P</em> = 0.019), a non-linear negative association between MIBP and estradiol (<em>F</em>=3.3, <em>P</em> = 0.002), and an inverted U-shaped relationship between MEOHP and estradiol (<em>F</em>=4.4, <em>P</em> = 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.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109081"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking T-type calcium channels disrupts spermatogenesis in vivo and adversely affects spermatocytes in vitro by impairing mitochondrial function and autophagic flux","authors":"Xiuling Zhao ,&nbsp;Lei Wang ,&nbsp;Shiqin Huang ,&nbsp;Lin Liu ,&nbsp;Xiaorong Wang ,&nbsp;Liping Pu ,&nbsp;Hao Chen ,&nbsp;Junyu Nie","doi":"10.1016/j.reprotox.2025.109048","DOIUrl":"10.1016/j.reprotox.2025.109048","url":null,"abstract":"<div><div>T-type calcium channels are pivotal in spermatogenesis. To evaluate the molecular mechanisms by which T-type calcium channels regulate spermatogenesis, we constructed animal and cellular models using T-type calcium channel inhibitor flunarizine (FNZ). Intraperitoneal administration of FNZ (30 mg/kg) significantly impaired sperm motility, inhibited testicular germ cell proliferation, and disrupted sperm mitochondrial function in male mice. FNZ, at concentrations of 7.5 μM, 15 μM, and 30 μM, significantly inhibited mouse spermatocyte (GC-2) cells proliferation. The detrimental effects of FNZ were mediated through the disruption of calcium homeostasis, mitochondrial dysfunction, and the induction of apoptosis. Moreover, FNZ exposure resulted in the accumulation of autophagosomes and an upregulation of P62 protein, which is implicated in autophagic degradation. Notably, the autophagy activator Rapamycin (Rapa) was found to mitigate FNZ-induced cellular damage in GC-2 cells by enhancing autophagy process. Conversely, chloroquine (CQ), an autophagy inhibitor that disrupts lysosomal degradation, corroborated the role of FNZ in autophagy modulation. Our results indicate that FNZ induces mitochondrial damage, impairs sperm motility and spermatocyte proliferation, and is accompanied by obstacles to autophagic flux.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109048"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational exposure to poly/perfluoroalkyl substances and risk of congenital structural malformations: A nested case-control study","authors":"Yanhong Wu ,&nbsp;Yilin Lv ,&nbsp;Shuang Ran ,&nbsp;Wanqin Xie ,&nbsp;Haiyan Zhou ,&nbsp;Ziwei Zhang ,&nbsp;Huamin Yuan ,&nbsp;Xingli Li","doi":"10.1016/j.reprotox.2025.109074","DOIUrl":"10.1016/j.reprotox.2025.109074","url":null,"abstract":"<div><div>Congenital structural malformations (CSM) have become a significant public health and social issue, affecting the health status of children and the level of population quality. Emerging research increasingly suggests that environmental pollutants may contribute to the development of CSM. However, current epidemiologic evidence on the effects of per- and polyfluoroalkyl substances (PFAS) on CSM is limited and restrictive. A nested case-control study examined how maternal exposure to PFAS during pregnancy affects the risk of CSM. Logistic regression and Bayesian kernel machine regression (BKMR) were used to assess the effects of single PFAS and PFAS mixture exposure on CSM. Perfluorodecanoic acid (PDA) showed a strong positive association with CSM in the logistic regression model (Adjusted OR: 4.79, 95 % CI: 1.55 ∼ 18.52). The BKMR analysis indicated an increased risk of CSM as PFAS mixture levels rose above the 55th percentile. Individual PFAS were ranked by posterior inclusion probabilities (PIPs), with PDA (PIP = 1.00), perfluorooctanoic acid (PFOA) (PIP = 1.00), potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (9Cl_PF3ONS) (PIP = 0.88), and perfluorononanoic acid (PFNA) (PIP = 0.82) contributing most to the mixture’s effect on CSM. No significant interactions were observed between PFAS mixtures when other exposures were held constant at the 50th percentile. In conclusion, we found that prenatal exposure to PDA and PFAS mixtures was significantly linked to a heightened risk of CSM, with PDA, PFOA, 9Cl_PF3ONS, and PFNA being significant contributors to the mixture effect. In addition, our study did not identify any previous interactions of PFAS.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109074"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulatory role of epigallocatechin-3-gallate (EGCG) on male and female reproductive disorders","authors":"Nayanika Roy ,&nbsp;Sarika Borle ,&nbsp;Dipty Singh","doi":"10.1016/j.reprotox.2025.109049","DOIUrl":"10.1016/j.reprotox.2025.109049","url":null,"abstract":"<div><div>Epigallocatechin-3-gallate (EGCG), a key bioactive compound in green tea, has gained prominence in recent years due to its numerous health-promoting benefits. Owing to its potent antioxidant, anti-inflammatory, and hormone-modulating properties, EGCG represents a promising therapeutic candidate for the management of andrological, gynecological, and pregnancy-associated disorders. In males, oxidative stress is a major factor in sperm dysfunction, leading to poor motility, abnormal morphology, and DNA fragmentation. EGCG enhances sperm quality by reducing oxidative damage, improving testosterone levels, mitigating testicular inflammation and protecting against environmental toxins that contribute to male infertility. In females, EGCG supports ovarian function, improves oocyte quality, and helps regulate hormonal imbalances by modulating estrogen synthesis, reducing inflammatory markers, and preventing abnormal cell proliferation in various gynaecological disorders. Additionally, its anti-cancer properties suggest a protective effect against prostate, ovarian, cervical, and endometrial cancers. During pregnancy, oxidative stress and inflammation can contribute to complications such as preeclampsia, gestational diabetes, and fetal alcohol syndrome. EGCG’s ability to enhance vascular health, improve placental function, and regulate immune responses suggests its potential in promoting a healthy pregnancy and fetal development. Though evidences support the merits of EGCG in reproductive health scenario, further research is needed to establish optimal dosages and long-term safety. This narrative review examines the therapeutic potential of EGCG in male and female reproductive disorders, as well as pregnancy, highlighting its antioxidant, anti-inflammatory, anti-cancer, anti-apoptosis and hormone-regulating properties. Additionally, it incorporates recent findings demonstrating the integration of EGCG into reproductive healthcare offering a promising natural therapeutic approach to improve fertility and pregnancy outcomes.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109049"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In utero exposure to acetaminophen and childhood attention deficit hyperactivity disorder: An ongoing controversy","authors":"Per Damkier,&nbsp;Erika B. Gram","doi":"10.1016/j.reprotox.2025.109076","DOIUrl":"10.1016/j.reprotox.2025.109076","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109076"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relevance of Aryl hydrocarbon receptor signalling in the inhibitory effect of environmental pollutant TCDD on promoter-specific aromatase (CYP19A1) expression in granulosa cells","authors":"Deeksha Sharma ,&nbsp;Payal Rani ,&nbsp;Suneel Kumar Onteru ,&nbsp;Dheer Singh","doi":"10.1016/j.reprotox.2025.109085","DOIUrl":"10.1016/j.reprotox.2025.109085","url":null,"abstract":"<div><div>Estrogens are major female reproductive hormones, synthesized in granulosa cells by aromatase (<em>CYP19A1</em>). <em>Aromatase</em> expression is controlled via tissue-specific promoters and dysregulated by endocrine disruptors like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD, a well-known reproductive toxicant, acts through the aryl hydrocarbon receptor (AhR), yet its promoter-specific regulation in buffalo, a key livestock species of major agricultural value, has not been addressed.The effect of TCDD was examined on promoter-specific expression of <em>CYP19A1</em> and estrogen production in cultured buffalo granulosa cells. Granulosa cells were exposed to TCDD at concentrations of 5, 10, and 15 pg/mL for 6, 12, and 24 h. In parallel, cells were treated with AhR inhibitor CH-223191 alone and in combination. Gene expression analysis showed that TCDD significantly (<em>P &lt; 0.05)</em> decreased <em>CYP19A1</em> expression at all tested concentrations and time points. Promoter-specific transcript analysis demonstrated that suppression was mediated via downregulation of proximal promoter PII. Chromatin immunoprecipitation followed by qPCR analysis confirmed TCDD downregulated <em>CYP19A1</em> expression driven by PII. Consistently, estradiol production was significantly reduced in TCDD treated cells as measured by ELISA. TCDD increased the expression of AhR downstream genes, <em>ARNT</em> and <em>CYP1A2.</em> AhR inhibitor treatment alone decreased expression of AhR marker gene (<em>CYP1A1</em>) without affecting <em>CYP19A1.</em> Overall, TCDD disrupts estrogen biosynthesis in buffalo granulosa cells by selectively downregulating proximal promoter-specific (PII)-<em>CYP19A1</em> expression and estrogen production via AhR signaling. Importantly, these effects were reversed by pharmacological inhibition of AhR, highlighting a mechanistic basis for dioxin-induced toxicity and potential of buffalo granulosa cells as a model for comparative reproductive toxicology.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109085"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irreversible male infertility from sleep restriction: A dual hit on testicular steroidogenesis and Keap1-Nrf2-mediated antioxidant defense","authors":"Keke Chen ,&nbsp;Fengyou Luo ,&nbsp;Xiling Huang ,&nbsp;Kaixing Huang ,&nbsp;Xiaoyu Liu ,&nbsp;Qiping Hu ,&nbsp;Changlong Xu","doi":"10.1016/j.reprotox.2025.109083","DOIUrl":"10.1016/j.reprotox.2025.109083","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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&amp;E), apoptosis (TUNEL), serum hormones (ELISA), and the expression of key molecules in testosterone synthesis and Keap1-Nrf2 pathways (qPCR, Western Blot, IF, IHC).</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109083"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From exposure to outcomes: How air pollutants impact maternal and foetal health","authors":"Garvita Parikh,&nbsp;Bhoomika Patel","doi":"10.1016/j.reprotox.2025.109080","DOIUrl":"10.1016/j.reprotox.2025.109080","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109080"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of bisphenol A exposure with in vitro fertilization outcomes: A meta-analysis and systematic review","authors":"Mengke Yuan ,&nbsp;Jie Chai ,&nbsp;Jingyan Song ,&nbsp;Xinyan Wang ,&nbsp;Zhengao Sun ,&nbsp;Xianling Cao","doi":"10.1016/j.reprotox.2025.109071","DOIUrl":"10.1016/j.reprotox.2025.109071","url":null,"abstract":"<div><h3>Background</h3><div>The impact of bisphenol A (BPA) on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcomes remains unclear.</div></div><div><h3>Methods</h3><div>This systematic review and meta-analysis evaluated studies from Pubmed, Web of Science, EMBASE, and Cochrane Library (up to April 19, 2024), analyzing data using regression coefficient (β) and their 95 % confidence intervals (CIs).</div></div><div><h3>Results</h3><div>A total of 478 references were identified and 14 studies with different IVF/ICSI outcomes were included in the final meta-analysis. The included studies reported that the median or geometric mean (GM) of specific gravity (SG) or creatinine (Cr)-adjusted maternal urinary BPA ranged from 0.063 to 2.61 ng/ml. The meta-analysis results indicated a significant negative correlation between urinary, serum, follicular fluid (FF), and semen BPA exposure and several key IVF/ICSI outcomes, particularly in terms of normal fertilization rates (β: −0.05; 95 % CI: −0.07, −0.03) and the number of high-quality embryos (β: −0.05; 95 % CI: −0.09, −0.01). In the subgroup analysis based on BPA exposure level, higher BPA exposure was significantly associated with decreased normal fertilization rate in IVF/ICSI, particularly in populations with BPA median or GM concentrations above 1.55 ng/ml (β: −0.19; 95 % CI: −0.27, −0.11). However, no significant association was observed between BPA exposure and clinical pregnancy rates, blastocyst formation, or implantation success rates, which may be attributed to the limited number of studies and variability in study design and populations.</div></div><div><h3>Conclusion</h3><div>This meta-analysis suggests that BPA, a common environmental pollutant, may reduce reproductive success during IVF/ICSI by disrupting endocrine function and compromising gamete quality and early embryo development. However, due to study limitations, further research is needed to confirm our findings and explore the mechanisms underlying reproductive toxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109071"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions","authors":"Nazli Pinar Arslan ,&nbsp;Zuleyha Akpinar ,&nbsp;Havva Aybek ,&nbsp;Meryem Doymus ,&nbsp;Gulsum Asilkan-Kaldik ,&nbsp;Nevzat Esim ,&nbsp;Mesut Taskin","doi":"10.1016/j.reprotox.2025.109067","DOIUrl":"10.1016/j.reprotox.2025.109067","url":null,"abstract":"<div><div>In mammalian cells, nicotinamide adenine dinucleotide (NAD⁺) participates in the regulation of diverse cellular processes such as ATP production, oxidative stress resistance, DNA repair, metabolic homeostasis, and inflammation. Due to these properties, exogenously applied NAD⁺ precursors (nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide) can protect organs and cells of mammalian against detrimental effects of various stress factors and diseases. For instance, NAD⁺ and its precursors have critical importance for the <em>in vivo</em> and <em>in vitro</em> fertilization success of mammals. This review summarizes that the natural aging process, diseases, and toxic compounds cause the detrimental effects in the reproductive parameters of the <em>in vivo</em> models, such as the meiotic defects and the reductions in cellular NAD⁺ level, mitochondrial functions, sperm and oocyte quality, blastocyst and embryo formation rate, implantation success, whereas the intragastric, intraperitoneal or oral administration of NAD⁺ precursors prevents or attenuates these detrimental effects. Similarly, the supplementation of NAD⁺ precursors can protect the oocytes and sperms against the cryopreservation process, aging and toxic compounds in the <em>in vitro</em> and also enhances blastocyst and embryo formation <em>in vitro</em>. This review study also revealed that the ability of NAD⁺ precursors-loaded drug delivery systems to prevent reproductive defects has not yet been investigated in literature. Therefore, we recommend the development of NAD⁺ precursor-loaded drug delivery systems targeting reproductive system organs and/or cell organelles (mitochondria, endoplasmic reticulum and nucleus). To achieve this, hormone receptors in testicular and ovarian cells can be targeted. Similarly, triphenylphosphonium (TPP⁺) can be used to specifically target mitochondria.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109067"},"PeriodicalIF":2.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145107891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}