3,3',4,4'-tetrachloroazobenzene (
TCAB) is a contaminant formed during manufacture of various
herbicide compounds. A recent National Toxicology Program study showed B6C3F1 mice exposed to
TCAB developed a treatment-related increase in lung
carcinomas in the high-dose group, and urethral
carcinomas, an extremely rare lesion in rodents, in all dose groups. As the potential for environmental exposure to
TCAB is widespread, and the mechanisms of urethral
carcinogenesis are unknown,
TCAB-induced urethral and pulmonary
tumors were evaluated for alterations in critical human cancer genes, Kras and Tp53.
Uroplakin III, CK20, and CK7 immunohistochemistry was performed to confirm the urothelial origin of urethral
tumors.
TCAB-induced urethral
carcinomas harbored transforming point mutations in K-ras (38%) and Tp53 (63%), and 71% displayed nuclear TP53 expression, consistent with formation of
mutant protein. Transition mutations accounted for 88% of Tp53 mutations in urethral
carcinomas, suggesting that
TCAB or its metabolites target
guanine or
cytosine bases and that these mutations are involved in urethral
carcinogenesis. Pulmonary
carcinomas in
TCAB-exposed animals harbored similar rates of Tp53 (55%) and Kras (36%) mutations as urethral
carcinomas, suggesting that
TCAB may induce mutations at multiple sites by a common mechanism. In conclusion,
TCAB is carcinogenic at multiple sites in male and female B6C3F1 mice through mechanisms involving Tp53 and Kras mutation.