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

作者全名："Liu, Fangfei; He, Junlin; Chen, Xuemei; Liu, Ronglu; Li, Fangfang; Geng, Yanqing; Dai, Yuhan; Zhang, Yan; Wang, Yingxiong; Mu, Xinyi"

作者地址："[Liu, Fangfei; Geng, Yanqing; Dai, Yuhan; Wang, Yingxiong; Mu, Xinyi] Chongqing Med Univ, Coll Basic Med, Dept Histol & Embryol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Liu, Fangfei; He, Junlin; Chen, Xuemei; Liu, Ronglu; Li, Fangfang; Geng, Yanqing; Dai, Yuhan; Zhang, Yan; Wang, Yingxiong; Mu, Xinyi] Chongqing Med Univ, Joint Int Res Lab Reprod & Dev, Chongqing, Peoples R China; [He, Junlin; Chen, Xuemei; Liu, Ronglu; Li, Fangfang; Zhang, Yan] Chongqing Med Univ, Sch Publ Hlth & Management, Lab Reprod Biol, Chongqing, Peoples R China"

通信作者："Mu, XY (通讯作者)，Chongqing Med Univ, Coll Basic Med, Dept Histol & Embryol, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：ANTIOXIDANTS & REDOX SIGNALING

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001162399500001

JCR分区：Q1

影响因子：6.6

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：APAP; meiotic prophase I; NAD(+); SIRT7

摘要："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 mu M) 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."

基金机构：National Natural Science Foundation [31601200]; Natural Science Foundation of Chongqing [cstc2020jcyj-msxmX0135]; Future Medical Youth Innovation Team Support Plan of Chongqing Medical University [W0041]

基金资助正文："This work was supported by grants from the National Natural Science Foundation (Grant No. 31601200), Natural Science Foundation of Chongqing (Grant No. cstc2020jcyj-msxmX0135), and Future Medical Youth Innovation Team Support Plan of Chongqing Medical University (W0041)."