Glycation-Driven Mitochondrial and ER Stress Underlies Iodoacetic Acid-Induced Apoptosis in Porcine Uterus and Oviduct Epithelial Cells

Iodoacetic acid (IAA), a highly cytotoxic disinfection byproduct commonly detected in drinking water, poses a potential risk to female reproductive health. The direct molecular mechanisms underlying its effects on the reproductive system epithelium remain unclear. This study demonstrates that IAA induces glycational stress in primary porcine uterine (UECs) and oviduct epithelial cells (OECs), representing an early event contributing to extensive cellular toxicity. IAA exposure inhibited Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) enzymatic activity and promoted the accumulation of advanced glycation end products (AGEs) Nε-(carboxymethyl)lysine (CML), triggering mitochondrial dysfunction, redox imbalance, calcium dyshomeostasis, and endoplasmic reticulum stress. These disturbances activated a dysregulated signaling network involving the p38 MAPK, AKT, and NF-κB pathways, ultimately causing G1/S cell cycle arrest and apoptosis. Notably, pretreatment with the AGE inhibitor pyridoxamine reduced CML accumulation, restored mitochondrial function, and alleviated apoptotic cell death. These findings identify glycational stress as a key initiating mechanism for IAA-induced reproductive epithelial toxicity, providing mechanistic insight into the potential health risks of environmental disinfection byproducts.