Early-life BPS exposure induces reproductive toxicity in offspring mice via ferroptosis.

Bisphenol S (BPS), a widely utilized environmental endocrine disruptor, poses significant risks to environmental pollution and human health. While the reproductive toxicity of BPS is recognized, its transgenerational consequences, particularly from early-life exposure, remain poorly defined. In this study, we established a mouse model of early-life BPS exposure to assess its effects on male reproductive development in offspring. Our findings demonstrate that early-life BPS (0.2, 2, 20 mg/L) exposure impairs testicular architecture, diminishes sperm quantity, elevates sperm morphological abnormalities, and dysregulates the expression of CYP11A1, CYP17A1, STAR, and HSD17B3. These changes collectively result in suppressed testosterone production and disrupted spermatogenesis in offspring mice. Additionally, early-life BPS exposure triggered oxidative stress, elevating malondialdehyde levels while reducing superoxide dismutase and glutathione. In offspring mice, BPS induced testicular iron accumulation and mitochondrial damage. This was accompanied by elevated expression of ACSL4 and TFR1, alongside reduced levels of GPX4 and SLC7A11. In TM3 Leydig cells, Fer-1 (1 µM) effectively restored BPS (80 µM)-induced testosterone deficiency and normalized the expression of key ferroptosis-related proteins. Collectively, this study establishes ferroptosis as a critical mechanism in the transgenerational male reproductive damage induced by BPS, thereby providing novel insights into the toxicological effects of environmental endocrine disruptors.