PPARalpha- and DEHP-Induced Cancers

Di(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer and a potentially nongenotoxic carcinogen. Its mechanism had been earlier proposed based on peroxisome proliferator-activated receptor alpha (PPARalpha) because metabolites of DEHP are agonists. However, recent evidence also suggests the involvement of non-PPARalpha multiple pathway in DEHP-induced carcinogenesis. Since there are differences in the function and constitutive expression of PPARalpha among rodents and humans, species differences are also thought to exist in the carcinogenesis. However, species differences were also seen in the lipase activity involved in the first step of the DEHP metabolism, which should be considered in DEHP-induced carcinogenesis. Taken together, it is very difficult to extrapolate the results from rodents to humans in the case of DEHP carcinogenicity. However, PPARalpha-null mice or mice with human PPARalpha gene have been developed, which may lend support to make such a difficult extrapolation. Overall, further mechanical study on DEHP-induced carcinogenicity is warranted using these mice.