Specific Hepatorenal Toxicity and Cross-Species Susceptibility of Eight Representative Pesticides

Chronic exposure to pesticides poses significant hepatorenal toxicity risks, yet a systematic comparison of their effects across species and tissues is lacking. In this study, we systematically evaluated the cytotoxicity of eight pesticides using human (CCC-HEL-1 hepatocytes; 293T renal cells) and rodent (IAR hepatocytes; NRK renal cells) cellular models. Our results showed substantial variations in potency, with chlorothalonil exhibiting the highest toxicity (IC50 = 32.55 mg/L in 293T cells) and chlorpyrifos the lowest (IC50 = 444.5 mg/L in 293T cells). Principal component analysis revealed distinct species- and tissue-specific response patterns, highlighting the unique resistance of NRK cells. Mechanistic investigations demonstrated organ-specific biomarker alterations, such as elevated hepatic ALP and suppressed renal KIM-1. Remarkably, the MRP2 transporter exhibited tissue-specific divergence, being significantly downregulated in renal cells (all 8 pesticides, <i>p</i> < 0.005) and most hepatic cells (7/8 pesticides, <i>p</i> < 0.05), while propiconazole uniquely upregulated it in hepatocytes (1.5-fold, <i>p</i> < 0.05). Collectively, these findings offer critical mechanistic insights into pesticide-specific toxicity and cross-species susceptibility, providing valuable data to improve human health risk assessment in food safety and toxicology.