Placental RTN3L‐dependent ER‐Phagy Contributes to Fetal Testicular Dysplasia Upon Environmental Stress

Abstract Prenatal environmental stress damages fetal testicular development, leading to male infertility. However, the precise mechanisms underlying the impact of gestational environmental stress on fetal testicular development require further investigation. This study demonstrates that gestational environmental stressor cadmium exposure caused placental estradiol synthesis inhibition and fetal testicular dysplasia. Gestational estradiol supplementation restores fetal testicular dysplasia caused by environmental stress‐induced placental estradiol synthesis inhibition. Analysis of human placentae and cadmium‐stimulated human primary placental trophoblasts confirmed that ER‐phagy is associated with the inhibition of estradiol synthesis in placentae. Subsequently, the data reveals that environmental stress significantly activates RTN3L‐mediated ER‐phagy. RTN3L ‐deficient cells and placental Rtn3l ‐specific knockout mice confirm that environmental stress‐activated RTN3L‐mediated ER‐phagy inhibited placental estradiol synthesis. Total N6‐methyladenosine level increasing in gestational environmental stress‐exposed placentae. METTL3‐mediated N6‐methyladenosine modification suppression obviously restrains environmental stress‐activated RTN3L‐dependent ER‐phagy. In conclusion, gestational environmental stress activates ER‐phagy by increasing placental Rtn3l mRNA N6‐methyladenosine modification, inhibiting placental estradiol synthesis, and contributing to fetal testicular dysplasia. The study demonstrates the early prevention and treatment of adult male infertility from the perspective of fetal‐derived diseases.