Goyak KO, Sarang SS, Franzen A, Borghoff SJ, Ryman-Rasmussen JP. 2022. Adverse outcome pathway (AOP): α2u-globulin nephropathy and kidney tumors in male rats. Crit Rev Toxicol, open access.
The purpose of this assessment was to elucidate and assess the confidence in an AOP for male-rat-specific kidney toxicity of α2u-N induced kidney tumors through the evaluation of primary literature, reviews, and regulatory guidance.
This assessment developed a high confidence AOP for kidney tumors in male rats based on an MIE of reversible binding of chemical stressors to the α2u-globulin protein. This chemical binding leads to a reduction in the catabolism rate of α2u (KE1); resulting in the accumulation of the α2u in the form of protein droplets in the lysosomes of RPT cells (KE2). Exacerbation of α2u accumulation in the RPT cells results in cytotoxicity and compensatory cell proliferation (KE3). Chronic cytotoxicity and regenerative cell proliferation leads to atypical hyperplasia (KE4) that is indicated by mineralization of the RPTs (AE) leading to, with continued chronic exposure, the formation of kidney adenomas and carcinomas in male rats (AO).
This work established a high-confidence AOP for male rat kidney tumors through the accumulation of the male rat-specific protein α2u. This AOP will be useful both for chemical screening using NAMs developed for measuring the MIE with critical KEs (e.g. decreased α2u catabolism) for use in either prioritization of chemical testing or hazard characterization in regulatory settings.