Lead exposure acts as a risk factor of PCOS development via SOD2-mediated mtDNA leakage.

Lead (Pb), a ubiquitous environmental pollutant, contributes to the development of various diseases. But little information is available regarding its effect on polycystic ovary syndrome (PCOS) that is the main cause of female infertility. Here, we discovered that Pb exposure replicated the PCOS-like phenotypes in mice via the advancement of ovarian inflammatory response. After transferring to the mitochondria, Pb disrupted the interaction of Mn2+ and SOD2, and then decreased the enzymatic activity of SOD2, resulting in the mitochondrial superoxide anion accumulation and oxidized potential. Enhancement of SOD2 alleviated the PCOS-like phenotype induced by Pb and counteracted the induction of Pb on ovarian inflammatory response. Due to the attenuation of SOD2 function, Pb exposure induced the mitochondrial dysfunction along with the insufficiency of mitophagy and lysosomal acidification. This brought about the leakage of mtDNA into the cytosol through opening the mitochondrial permeability transition pore and subsequently triggered the cGAS-STING-TBK1 pathway. Further analysis evidenced that Pb exposure activated the NF-κB signaling whose inhibition mitigated the inflammatory response by Pb, whereas inhibition of TBK1 prevented the activation of Pb on NF-κB. Collectively, Pb exposure contributed to PCOS development via mtDNA-mediated cGAS-STING-TBK1-NF-κB pathway after disrupting the SOD2 function.