SO₂ derivatives impair ovarian function by inhibiting Serpine1/NF-κB pathway-mediated ovarian granulosa cell survival

Sulfur dioxide (SO₂) is a contributor to air pollution. Human evidence has demonstrated an association between SO₂ exposure and diminished ovarian reserve. The toxicity of SO₂ is mainly attributed to its derivatives, bisulfite and sulfite, which have a variety of adverse effects on both human health and the environment, yet have been widely used as additives in food processing and transportation. However, the reproductive toxicity of SO₂ derivatives remained elusive. In this study, we explored the impact of SO₂ derivatives (bisulfite and sulfite) on ovarian function and further investigated the underlying mechanism. Exposure to SO₂ derivatives in vivo could significantly reduce the ovarian reserve, the number and the quality of oocytes retrieved, induce ovarian granulosa cell apoptosis, and lead to an increased number of atretic follicles, thus affecting the ovarian function of mice. In addition, we isolated and cultured the primary mouse ovarian granulosa cells (mGCs) to explore the impact of SO₂ derivatives on the biological functions of mGCs and investigate the mechanism by which SO₂ derivatives induced apoptosis of mGCs. We detected that SO₂ derivatives could induce cell cycle arrest, apoptosis, a decrease of mitochondrial membrane potential, increased abnormal mitochondria, and impaired function of sex hormone synthesis and secretion. Further, we found that SO₂ derivatives could significantly downregulate the Serpine1 gene expression, inhibiting the NF-κB signaling pathway and thereby inducing the apoptosis of mGCs.