Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City & Aquaculture Engineering Technology Research Center, College of Fisheries, Southwest University, Chongqing 400715, China.
Key Laboratory of Freshwater Fish Reproduction and Development (Ministry of Education), Key Laboratory of Aquatic Science of Chongqing, Southwest University, Chongqing 400715, China.
Toxicol Sci. 2024 Sep 1;201(1):118-128. doi: 10.1093/toxsci/kfae071.
High-dose perfluorooctanoic acid (PFOA) impairs oocyte maturation and offspring quality. However, the physiological concentrations of PFOA in follicular fluids of patients with premature ovarian insufficiency (POI) were detected at lower levels, thus the relationship between physiological PFOA and reproductive disorders remains elusive. Here, we investigated whether physiological PFOA exposure affects gonad function in adult zebrafish. Physiological PFOA exposure resulted in POI-like phenotypes in adult females, which exhibited decreased spawning frequency, reduced number of ovulated eggs, abnormal gonadal index, and aberrant embryonic mortality. Meanwhile, oocytes from PFOA-exposed zebrafish showed mitochondrial disintegration and diminished mitochondrial membrane potential. Unlike the high-dose treated oocytes exhibiting high reactive oxygen species (ROS) levels and excessive apoptosis, physiological PFOA reduced the ROS levels and did not trigger apoptosis. Interestingly, physiological PFOA exposure would not affect testis function, indicating specific toxicity in females. Mechanistically, PFOA suppressed the NAD+ biosynthesis and impaired mitochondrial function in oocytes, thus disrupting oocyte maturation and ovarian fertility. Nicotinamide mononucleotide (NMN), a precursor for NAD+ biosynthesis, alleviated the PFOA-induced toxic effects in oocytes and improved the oocyte maturation and fertility upon PFOA exposure. Our findings discover new insights into PFOA-induced reproductive toxicity and provide NMN as a potential drug for POI therapy.
高剂量全氟辛酸（PFOA）会损害卵母细胞成熟和后代质量。然而，在卵巢早衰（POI）患者的卵泡液中检测到的生理浓度的 PFOA 水平较低，因此生理 PFOA 与生殖障碍之间的关系仍不清楚。在这里，我们研究了生理 PFOA 暴露是否会影响成年斑马鱼的性腺功能。生理 PFOA 暴露会导致成年雌性出现类似 POI 的表型，表现为产卵频率降低、排卵卵子数量减少、性腺指数异常和胚胎死亡率异常。同时，来自 PFOA 暴露的斑马鱼的卵母细胞显示出线粒体解体和线粒体膜电位降低。与高剂量处理的卵母细胞表现出高活性氧（ROS）水平和过度凋亡不同，生理 PFOA 降低了 ROS 水平，并未引发凋亡。有趣的是，生理 PFOA 暴露不会影响睾丸功能，表明其对雌性具有特异性毒性。在机制上，PFOA 抑制了卵母细胞中的 NAD+ 生物合成和线粒体功能，从而破坏了卵母细胞的成熟和卵巢的生育能力。烟酰胺单核苷酸（NMN）是 NAD+ 生物合成的前体，可缓解 PFOA 对卵母细胞的毒性作用，并在 PFOA 暴露时改善卵母细胞成熟和生育能力。我们的研究结果为 PFOA 诱导的生殖毒性提供了新的见解，并为 POI 治疗提供了 NMN 作为潜在药物的可能性。
