Developmental benzopyrene exposure alters stress hormones, neurotransmitters and behavioral responses of mice dependent on Cyp1 genotype

Abstract

Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) produced during combustion processes and when grilling foods. Epidemiological studies indicate exposure to PAHs during pregnancy lead to learning and memory deficits as well as behavioral problems that persist into adolescence. Studies in rodents and zebrafish have frequently reported anxiolytic effects of BaP exposure in adult animals and in developmental studies. We conducted sequential experiments of Cyp1a1(-/-) and Cyp1b1(-/-) knockout mice compared with wild type C57BL/6J mice to determine if genotype changes the response to developmental BaP exposure. We treated pregnant dams from gestational day 10 to postnatal day 25 (P25) with BaP in corn oil-soaked cereal or the corn oil vehicle and tested one male and one female offspring beginning at P60. We found increased exploratory behavior in the elevated zero maze for Cyp1a1(-/-) knockout mice, but no significant differences in Cyp1b1(-/-) knockouts. In contrast, Cyp1b1(-/-) knockout mice buried fewer marbles in a second test of anxiety-like behavior. There were no significant differences when Cyp1a1(-/-) knockout mice were tested. BaP decreased immobility time in Cyp1a1(-/-) knockouts in the forced swim test, but increased immobility time in wild type and Cyp1b1(-/-) knockout mice. We measured plasma corticosterone levels at baseline and following the forced swim test and monoamine neurotransmitters at the end of behavioral testing. BaP treatment increased corticosterone in wild type mice, but decreased it in Cyp1a1(-/-) knockout mice. Both BaP-exposed and corn oil control Cyp1b1(-/-) knockout mice had higher corticosterone levels compared with wild type mice. Dopamine and serotonin signaling were altered in the hypothalamus dependent on genotype, treatment and sex. Together, these data suggest that both CYP1A1 and CYP1B1 have a normal role in brain functioning or development, and that CYP1 genotype alters the response to developmental BaP exposure in behavioral and biochemical tests related to stress, anxiety and depression. HighlightsO_LIBaP-exposed Cyp1a1(-/-) mice had lower corticosterone and decreased immobility in the forced swim test C_LIO_LIBaP exposure increased FST immobility in wild type and Cyp1b1(-/-) mice C_LIO_LICyp1a1(-/-) and Cyp1b1(-/-) knockout mice showed less anxiety-like behavior C_LIO_LIDevelopmental BaP exposure altered corticosterone levels dependent on Cyp1 genotype C_LIO_LIGenotype, treatment and sex all impacted neurotransmitter levels in the hypothalamus C_LIO_LIGenetic differences in CYP enzymes altered susceptibility to developmental BaP exposure C_LI