Maternal Administration of Acetaminophen Affects Meiosis Through its Metabolite NAPQI Targeting SIRT7 in Fetal Oocytes.

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.

Maternal exposure to cetylpyridinium chloride impairs oogenesis by causing mitochondria disorder in neonates.

Cetylpyridinium Chloride (CPC) is a common disinfectant with potential mitochondrial toxicity. However, the effects of CPC on female reproduction remains unclear. In the present study, pregnant mice were exposed to environmentally relevant doses of CPC for 3 days, the effects were evaluated in the female offspring. Maternal exposure to CPC caused loss of oocytes in neonatal ovaries. TEM analysis of neonatal ovaries showed CPC caused aberrant mitochondrial morphology including vacuolated and disorganized structure, reduced functional cristae. In addition, CPC decreased mitochondrial membrane potential in neonatal oocytes. Seahorse analysis showed that CPC hampered mitochondrial reserve, manifested as reduced spare respiratory capacity. Furthermore, CPC damaged mitochondrial function and impaired developmental competence of MII oocytes, suggesting a persisting impact into adulthood. In summary, this is the first known demonstration that maternal exposure to CPC caused mitochondrial disorders in neonatal ovaries and had long-term effects on fertility of the female offspring.