Persistence in Alterations in the Ontogeny of Cerebral and Hepatic Cytochrome P450s following Prenatal Exposure to Low Doses of Lindane

Abstract

Oral administration of low doses (0.0625, 0.125, or 0.25 mg/kg body weight, po, corresponding to 1/1400th, 1/700th, or 1/350th of LD(50), respectively) of lindane, an organochlorine insecticide, to pregnant dams from gestation day 5-21 was found to produce dose-dependent alterations in the ontogenic profile of xenobiotic-metabolizing cytochrome P450s (CYPs) in the brain and liver of offspring. The increase in the cerebral and hepatic mRNA expression of CYP1A1, 1A2, 2B1, 2B2, and 2E1 was also found to be associated with an increase in the catalytic activity of these CYP isoenzymes in the brain and liver of the offspring at different stages during postnatal development. Interestingly, though the levels of CYPs were severalfold lower in brain when compared to the liver, almost equal magnitude of induction in these CYPs in brain have suggested that like in the liver, brain CYPs are responsive to the transplacental induction by environmental chemicals and that the increase is transcriptionally regulated. Moreover, due to its lipophilic nature, lindane may partition in mother's milk leading to further exposure of the offspring during the critical period of neurodevelopment which may explain the increase in CYP mRNA expression and associated catalytic activity especially during the early postnatal period. Interestingly, the increase in mRNA expression of these CYP isoforms was found to persist up to adulthood, suggesting that the low doses of lindane administered to the dams might program the brain and liver of the offspring to persistently express the xenobiotic-metabolizing CYP isoforms. As CYP-dependent metabolism of lindane is involved in its neurobehavioral toxicity, the potential of lindane to imprint the expression of cerebral and hepatic CYPs may help in identifying the role of these enzymes in the developmental neurotoxicity of the pesticide.