Exposure to environmentally relevant concentrations of zearalenone disrupts blood-testis barrier via inositol-requiring enzyme 1α-dependent GA binding protein transcription factor α mRNA decay.

Male infertility is a growing global health issue, with declining sperm quality being a major contributing factor. Zearalenone (ZEA), a widespread mycotoxin, is frequently detected in human populations through contaminated food and water. Here, we investigated the mechanism by which environmentally relevant concentrations of ZEA disrupt the blood-testis barrier (BTB) and impair sperm quality. We found that exposure to ZEA disrupted BTB integrity and reduced sperm quality in mice. Mechanistically, ZEA activated the inositol-requiring enzyme 1α (IRE1α), leading to regulated IRE1α-dependent decay (RIDD) of GA binding protein transcription factor α (Gabpa) mRNA. GABPA binds directly to and transcriptionally activates the promoters of genes encoding the tight junction proteins ZO1 and Occludin. This binding was attenuated by ZEA treatment. GABPA overexpression rescued the ZEA-induced downregulation of ZO1 and Occludin and restored barrier function, whereas GABPA knockdown exacerbated these defects. Both Ern1 (encoding IRE1α) knockdown and pharmacological inhibition of IRE1α RNase activity with 4μ8C rescued GABPA expression, restored BTB function, and ameliorated ZEA-induced sperm defects. Our findings unveil a novel IRE1α-GABPA signaling axis as a central mechanism in ZEA-mediated male reproductive toxicity, highlighting IRE1α and GABPA as potential therapeutic targets for intervention against environmental pollutant-induced infertility.