Additive effects of arsenic and aristolochic acid in chemical carcinogenesis of upper urinary tract urothelium.

Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic towards the risk of developing upper tract urothelial carcinoma (UTUC).

Hospital-based (n=89) and population-based (2,921 cases, 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0-3 based on concentrations in well water and the presence of arseniasis-related diseases.

In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44% and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and non-endemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC.

Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan.

This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020 Dec 04 [Epub ahead of print]

Chung-Hsin Chen, Arthur P Grollman, Chao-Yuan Huang, Chia-Tung Shun, Viktoriya S Sidorenko, Keiji Hashimoto, Masaaki Moriya, Robert J Turesky, Byeong Hwa Yun, Karen Tsai, Stephanie Wu, Po-Ya Chuang, Chao-Hsiun Tang, Wen-Horng Yang, Tzong-Shin Tsai, Yuh-Shyan Tsai, Kathleen G Dickman, Yeong-Shiau Pu

Department of Urology, National Taiwan University Hospital., Department of Pharmacological Sciences, Stony Brook University., Department of Forensic Medicine and Pathology, National Taiwan University Hospital., Departments of Pharmacological Sciences, Stony Brook University., Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota., School of Medicine, Stony Brook University., School of Health Care Administration, Taipei Medical University., Department of Urology, National Cheng Kung University., Departments of Pharmacological Sciences and Medicine/Nephrology, Stony Brook University., Department of Urology, National Taiwan University Hospital .

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