Aristolochic acid-induced genotoxicity and toxicogenomic changes in rodents

Li, Xi-Lin; Guo, Xiao-Qing; Wang, Hai-Rong; Chen, Tao; Mei, Nan

doi:10.4103/wjtcm.wjtcm_33_19

Title: Aristolochic acid-induced genotoxicity and toxicogenomic changes in rodents

Journal Article · Fri Mar 13 00:00:00 UTC 2020 · World Journal of Traditional Chinese Medicine

DOI: https://doi.org/10.4103/wjtcm.wjtcm_33_19 · OSTI ID:1629867

Li, Xi-Lin ^[1]; Guo, Xiao-Qing ^[2]; Wang, Hai-Rong ^[3]; Chen, Tao ^[2]; Mei, Nan ^[2]

U.S. Food and Drug Administration (FDA), Jefferson, AR (United States); DOE/OSTI
U.S. Food and Drug Administration (FDA), Jefferson, AR (United States)
Tianjin Center for New Drug Safety Assessment and Research (China)

Aristolochic acid (AA) is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines. AA is a causative agent for Chinese herbs nephropathy, a term replaced later by AA nephropathy. Evidence indicates that AA is nephrotoxic, genotoxic, and carcinogenic in humans; and it also induces tumors in the forestomach, kidney, renal pelvis, urinary bladder, and lung of rats and mice. Therefore, plants containing AA have been classified as carcinogenic to humans (Group 1) by the International Agency for Research on Cancer. In our laboratories, we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks. Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney, liver, and spleen of rats, as well as significant alteration of gene expression in both its target and nontarget tissues. AA treatments altered mutagenesis- or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling. We also applied benchmark dose (BMD) modeling to the 3-month AA-induced genotoxicity data. The obtained BMDL10 (the lower 95% confidence interval of the BMD₁₀ that is a 10% increase over the background level) for AA-induced mutations in the kidney of rats was about 7 μg/kg body weight per day. This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression, microRNA expression, and proteomics; and presents updated information focused on AA-induced genotoxicity in rodents.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: National Center for Toxicological Research (NCTR); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: SC0014664

OSTI ID:: 1629867

Journal Information:: World Journal of Traditional Chinese Medicine, Journal Name: World Journal of Traditional Chinese Medicine Journal Issue: 1 Vol. 6; ISSN 2311-8571

Publisher:: Wolters KluwerCopyright Statement

Country of Publication:: United States

Language:: English

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