Low-Level Exposure to Dinotefuran May Induce Damage to Ovarian and Female Germ Stem Cells of Adolescent Mice via ZBP1- and RIPK1-PANoptosome

Dinotefuran, the latest member of the neonicotinoid insecticides, is generally considered to have low mammalian toxicity. However, its effects on mammalian reproductive systems remain poorly understood. This study investigated ovarian damage in adolescent mice following oral administration of dinotefuran at 0.1, 0.2, and 0.4 mg/kg/day. It also examined damage to female germline stem cells (FGSCs) cultured in vitro and exposed to 170, 1000, and 6000 ng/L dinotefuran. In mice, dinotefuran reduced the number of follicles at all stages. Furthermore, it reduced serum E2 and ovarian anti-Müllerian hormone levels and the expression of estrogen receptors (GPER1 and ERβ). Doses ≥ 0.1 mg/kg/day induced dose-dependent oxidative stress and increased PANoptosis (apoptosis, pyroptosis, and necroptosis) in the ovaries. This was accompanied by significantly elevated gene and protein levels of ZBP1- and RIPK1-PANoptosome components. Moreover, FGSCs in the ovarian cortex were significantly damaged, with decreased expression of their marker genes and proteins. In vitro exposure to dinotefuran at concentrations of 170-6000 ng/L induced similar changes in FGSCs, and procyanidin inhibited dinotefuran-induced formation of both PANoptosomes in FGSCs. These findings suggest that low-level dinotefuran exposure, both in vivo and in vitro, induces ovarian and FGSC damage in adolescent mice through the ZBP1- and RIPK1-PANoptosome.