Lithium exposure causes ferroptosis to induce unexplained miscarriage through non-canonical MBOAT1 pathway.

Abstract

High incidence of unexplained miscarriage (UM) limits global human reproduction. Lithium (Li) batteries are widely used but rarely recycled, causing Li to spread into environments and enter human body. Notably, the healthy effects of Li exposure on UM are rarely explored. Herein, higher serum Li levels, villous tissue ferroptosis, and UM are associated. Exposure to high levels of Li causes placental ferroptosis to induce mouse miscarriage. Li exposure down-regulates ER levels to suppress ER-mediated METTL1 and MBOAT1 transcription, and also suppresses METTL1-mediated m7G modification on MBOAT1 mRNA to reduce MBOAT1 mRNA stability. Therefore, Li exposure causes ferroptosis in a GPX4-independent manner. Supplement with murine Mboat1 suppresses placental ferroptosis and relieves miscarriage in LiCl-exposed mouse model. This study discovers health risks and pathogenesis of Li exposure-induced UM, reveals potential biological targets, and also proposes an important Li exposure theme in energy-environment-health field, which deserves attention by global governments and enterprises.