Bio: Prof. Wang Hua is Professor and doctoral supervisor of Anhui Medical University, recipient of national level talent awards, currently serving as the Dean of the School of Public Health. He is mainly engaged in research for environmental and reproductive toxicology. He has led four projects funded by the National Natural Science Foundation of China, two key sub-projects of National Key Research and Development Program of China, and has been awarded the Anhui Provincial Excellent Youth Science Foundation. Total 62 SCI papers have been published as corresponding or first author. He has received the first prize of Natural Science in Anhui Province, and two Chinese Medical Science and Technology Awards. He holds positions as a council member of the Asian Consortium for Arsenic and Health Research, executive committee member of the Epigenetic Toxicology Committee of the Chinese Society of Toxicology, and so on. He serves as an editorial board member for Food and Chemical Toxicology, and so on.

Abstract: The current study aimed to explore the effect of prenatal Cd exposure on fertility in multigenerational offspring and its underlying mechanism. The pregnant mice were exposed to Cd via drinking water. The multigenerational (F1–F3) offspring testes were collected, and the Leydig cells were then isolated. A novel murine multigenerational (F1–F3) male subfertility model through prenatal Cd exposure was developed. Testicular T synthesis repression and enhanced ubiquitination occurred across generations, resulting in multigenerational male subfertility. Enhanced ubiquitination in NR4A1, the upstream transcription factor of T synthetases, was confirmed to inhibit testicular T synthesis in multigenerational offspring via testicular injection of proteasome inhibitor MG132. Subsequently, RAPSN was identified as a novel ubiquitin E3 ligase, containing RING-H2_Rapsyn domain, to derive multigenerational testicular NR4A1 ubiquitination. Global transcriptome and m6A epi-transcriptome revealed that dysregulated m6A modification in Rapsn mRNA promoted testicular ubiquitination to derive multigenerational TD dependent male subfertility upon prenatal Cd exposure. Mechanically, the reduced m6A reader YTHDC2 was confirmed to increase the stability of m6A-methylated Rapsn mRNA in F1-F3 testes upon prenatal Cd exposure via prenatal YTHDC2 elevation and postnatal testicular AAV9-Ythdc2 injection. Overall, prenatal Cd exposure increases multigenerational susceptibility to male subfertility by increasing the stability of m6A-methylated Rapsn mRNA. These findings provide a new insight to study environmental toxicant-induced transgenerational toxicity.