Effect of subacute and prenatal DINCH plasticizer exposure on rat dams and male offspring hepatic function: The role of PPAR-α

Plasticizers are compounds added to plastics to modify their physical proprieties. The most well-known class of plasticizers, the phthalates, has been shown to possess antiandrogenic and tumor promoting activities. 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH) was approved for use in food contact containers in 2006 and has been used as a replacement for phthalates in toys and children products. However, we reported previously that the DINCH metabolite MINCH acts on primary rat adipocytes through the peroxisome proliferator activated receptor (PPAR)-alpha pathway in a manner similar to phthalates. Evidence from our studies, as well as from the current bibliography on DINCH, suggests that the liver might be one of its target organs. In the present study, we collected tissues from dams exposed subacutely and progeny at postnatal day (PND) 3 and 60 exposed in utero to DINCH (1, 10 and 100 mg/kg bw/day). Exposure to DINCH drastically affected liver gene expression in all 3 age groups tested and in particular at the dose of 1 mg/kg bw/day. The PPAR-a pathway along with other metabolic and DNA replication pathways were affected by DINCH. Modifications in PPAR-a and superoxide dismutase (SOD)-1 protein levels were observed in dams at PND21, as well as male progeny at PND3 and 60. No sign of fibrosis or direct liver toxicity was observed after 8 days of stimulus with low doses of DINCH. This study provides evidence that DINCH is not a biologically inert molecule in the rat, and in the liver its actions are mediated, at least in part, by PPAR-alpha.