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Aim: Acetaminophen (APAP) is clinically recommended as analgesic and antipyretic among pregnant women. However, accumulating laboratory evidence shows that the use of APAP during pregnancy may alter fetal development. Since fetal stage is a susceptible window for early oogenesis, we aim to assess the potential effects of maternal administration of APAP on fetal oocytes. Results: Pregnant mice at 14.5 dpc (days post-coitus) were orally administered with APAP (50 and 150mg/kg.bw/day) for 3 days; meanwhile, 14.5 dpc ovaries were collected and cultured with APAP or its metabolite N-acetyl-p-benzoquinone imine (NAPQI; 5 and 15 μM) for 3 days. It showed that APAP caused meiotic aberrations in fetal oocytes through its metabolite NAPQI, including meiotic prophase I (MPI) progression delay and homologous recombination defects. Co-treatment with nicotinamide (NAM) or nicotinamide riboside chloride (NRC), nicotinamide adenine dinucleotide (NAD+) supplements, efficiently restored the MPI arrest, whereas the addition of the inhibitor of sirtuin 7 (SIRT7) invalidated the effect of the NAD+ supplement. In addition, RNA sequencing revealed distorted transcriptomes of fetal ovaries treated with NAPQI. Furthermore, the fecundity of female offspring was affected, exhibiting delayed primordial folliculogenesis and puberty onset, reduced levels of ovarian hormones, and impaired developmental competence of MII oocytes. Innovation: These findings provide the first known demonstration that NAPQI, converted from maternal administration of APAP, disturbs meiotic process of fetal oocytes and further impairs female fecundity in adulthood. The concomitant oral dosing with NAM further supports the benefits of NAD+ supplements on oogenesis. Conclusion: Short-term administration of APAP to pregnant mouse caused meiotic aberrations in fetal oocytes by its metabolite NAPQI, whereas co-treatment with NAD+ supplement efficiently relieves the adverse effects by interacting with SIRT7. [ABSTRACT FROM AUTHOR]

The primordial follicle pool established in early life determines the ovarian reserve in the female reproductive lifespan. Premature exhaustion of primordial follicles contributes to primary ovarian insufficiency (POI), that is dependent by the initial size of the primordial follicle pool and by the rate of its activation and depletion. AAI, a powerful nephrotoxin with carcinogenic potential, is present in the Aristolochiaceae species, which can release AAI into soil as a persistent pollutant. In order to assess the potential risk of Aristolochic Acid I (AAI) exposure on mammalian oogenesis, we uncovered its adverse effect on primordial folliculogenesis in the neonatal mouse ovary and its effect on female fertility in adulthood. Pregnant mice were orally administrated with doses of AAI without hepatic or renal toxicity during late-gestation. Ovaries from offspring of administered female displayed gross aberrations during primordial folliculogenesis. Also, unenclosed oocytes in germ-cell cysts showed increased DNA damage. Furthermore, several key factors, including NANOS3, SOX9, KLF4, that govern early gonad’s differentiation were abnormally expressed in the exposed ovary, while the follicle formation was partially restored by knockdown of Nanos3 or sox9. In adulthood, these aberrations evolved into a significant reduction in offspring number and impaired ovarian reserve. Together, our results show that AAI influences primordial folliculogenesis and, importantly, affected female fertility. This study shows that administration of drugs herbs or consumption of vegetables that contain AAs during pregnancy may adversely influence the fertility of offspring.