Isoprothiolane disrupts mitochondrial and endoplasmic reticulum homeostasis and impairs development of the embryonic nervous system in zebrafish.

Isoprothiolane (IPT) is a widely used fungicide in Asian rice cultivation, yet its toxicological profile remains incompletely characterized, particularly regarding dermal exposure relevant to occupational settings. This study evaluated the cytotoxic mechanisms and developmental consequences of IPT exposure using human keratinocytes (HaCaT), dermal fibroblasts (HDF), and zebrafish (Danio rerio) embryos. In human skin cells, IPT produced predominantly cytostatic effects associated with severe mitochondrial dysfunction, including membrane depolarization, impaired oxidative phosphorylation, and a near-complete loss of spare respiratory capacity. IPT also induced an ER stress-associated response, evidenced by increased BiP expression, eIF2α phosphorylation, and concentration-dependent induction of ATF4 and CHOP. In zebrafish embryos, IPT exposure resulted in concentration-dependent developmental toxicity characterized by pericardial edema, reduced heart rate, growth retardation, and defects in eye and brain development. Toxicological assessments demonstrated pronounced ROS accumulation and increased apoptosis signals in cranial and retinal regions, accompanied by disrupted angiogenesis and neural development. N-acetylcysteine (NAC) attenuated ROS accumulation and vascular and neural abnormalities, supporting a contributory role of oxidative stress in these developmental effects. Collectively, these findings reveal sublethal mitochondrial bioenergetic impairment and ER stress-associated responses in human skin-derived cells, together with oxidative stress-associated vascular and neural developmental abnormalities in zebrafish, providing a broader understanding of IPT toxicity.