CYP3A triggers BDE47-induced ferritinophagy and ferroptosis in spermatogenic cells through ROS-mediated m6A regulation of ATG12OA
Cytochrome P450 CYP3A(CYP3A)is among the most abundant hepatic cytochrome P450 subfamilies and also mediates the metabolism and toxicity of xenobiotics.Previous studies have reported that CYP3A is also expressed in the testis;however,its role and molecular mechanism in mediating male reproductive damage remain unclear.In this study,through in vitro and in vivo experiments,we demonstrated the role of CYP3A in 2,2'',4,4''-tetrabromodiphenyl ether(BDE47)-induced reproductive toxicity.The results showed that BDE47 induced CYP3A expression in mouse testes,leading to oxidative stress and ferroptosis through excessive reactive oxygen species(ROS)and ferrous iron(Fe^(2+))overload,which was demonstrated by CYP3A overexpression or knockdown experiments in GC-2 cells.Mechanistically,in addition to direct ROS generation during metabolic processing,ferritinophagy contributed to intracellular Fe^(2+)accumulation.Specifically,BDE47-induced ROS was associated with reduced N6-methyladenosine(m6A)modification of Atg12 mRNA and increased autophagyrelated(ATG12)expression,thereby promoting ferritin heavy chain 1(FTH1)degradation and subsequent Fe^(2+)overload.These results were further validated by experiments using hydrogen peroxide or antioxidants in GC-2cells,as well as by Atg12 haploinsufficiency in mice.Our findings demonstrate that CYP3A plays a critical role in male reproductive toxicity induced by BDE47.
Shuyu Xu;Wenxia Fan;Jiangxue Qian;Yuewen He;Chunjin Li;Chao Chen;Li Wang;Yongquan Yu;Chao Wang;Shoulin Wang
State Key Lab of Reproductive Medicine and Offspring Health,Institute of Toxicology,Nanjing Medical University,Nanjing,Jiangsu 211116,China Key Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaState Key Lab of Reproductive Medicine and Offspring Health,Institute of Toxicology,Nanjing Medical University,Nanjing,Jiangsu 211116,China Key Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaState Key Lab of Reproductive Medicine and Offspring Health,Institute of Toxicology,Nanjing Medical University,Nanjing,Jiangsu 211116,China Key Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaKey Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,ChinaState Key Lab of Reproductive Medicine and Offspring Health,Institute of Toxicology,Nanjing Medical University,Nanjing,Jiangsu 211116,China Key Lab of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211116,China
医药卫生
cytochrome P4503A22''44''-tetrabromodiphenyl etherreactive oxygen speciesferritinophagyN6-methyladenosinemale reproductive damage
《The Journal of Biomedical Research》 2026 (4)
P.364-382,I0001-I0003,22
supported by the National Natural Science Foundation of China(Grant Nos.82173562and 91743205 to S.W.,82273584 and 81903353 to C.W.)the key projects of Changzhou Medical Center of Nanjing Medical University(Grant No.CMCM202315 to S.W.)the Basic Research Program of Jiangsu Province(Grant No.BK20251854to C.W.)。
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