The behavioral effects of gestational and lactational benzopyrene exposure vary by sex and genotype in mice with differences at the Ahr and Cyp1a2 loci

Honaker, A.; Kyntchev, A.; Foster, E.; Clough, K.; Asiedu, E.; Feltner, M.; Ferguson, V.; Forrest, P. T.; Sene, Y.; Mullaguru, J.; Niang, M. D.; Perry, C.; Curran, C. P.

doi:10.1101/2021.10.22.465510

bioRxiv · 10.1101/2021.10.22.465510

The behavioral effects of gestational and lactational benzopyrene exposure vary by sex and genotype in mice with differences at the Ahr and Cyp1a2 loci

Honaker, A.·Kyntchev, A.·Foster, E.·Clough, K.·Asiedu, E.·Feltner, M.·Ferguson, V.·Forrest, P. T.·Sene, Y.·Mullaguru, J.·Niang, M. D.·Perry, C.·Curran, C. P.

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Abstract

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) and known carcinogen in the Top 10 on the United States list of priority pollutants. Humans are exposed through a variety of sources including tobacco smoke, grilled foods and fossil fuel combustion. Recent studies of children exposed to higher levels of PAHs during pregnancy and early life have identified numerous adverse effects on the brain and behavior that persist into school age and adolescence. Our studies were designed to look for genotype and sex differences in susceptibility to gestational and lactational exposure to BaP using a mouse model with allelic differences in the aryl hydrocarbon receptor and the xenobiotic metabolizing enzyme CYP1A2. Pregnant dams were exposed to 10 mg/kg/day of BaP in corn oil-soaked cereal or the corn oil vehicle alone from gestational day 10 until weaning at postnatal day 25. Neurobehavioral testing began at P60 using one male and one female per litter. We found main effects of sex, genotype and treatment as well as significant gene x treatment and sex x treatment interactions. BaP-treated female mice had shorter latencies to fall in the Rotarod test. High-affinity AhrbCyp1a2(-/-) mice had greater impairments in Morris water maze. Interestingly, poor-affinity AhrdCyp1a2(-/-) mice also had deficits in spatial learning and memory regardless of treatment. We believe our findings provide future directions in identifying human populations at highest risk of early life BaP exposure, because our model mimics known human variation in our genes of interest. Our studies also highlight the value of testing both males and females in all neurobehavioral studies. HighlightsO_LIGestational and lactational benzo[a]pyrene (BaP) exposure has sex and genotype-specific neurobehavioral effects in mice. C_LIO_LIFemale mice were more susceptible to motor deficits following developmental BaP exposure. Males were more susceptible to deficits in reversal learning and memory. C_LIO_LIAhrbCyp1a2(-/-) knockout mice were more susceptible to spatial learning and memory deficits following developmental BaP exposure. C_LIO_LIPoor-affinity AhrdCyp1a2(-/-) mice had deficits in spatial learning and memory regardless of treatment. C_LI

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Honaker, A., Kyntchev, A., Foster, E., Clough, K., Asiedu, E., Feltner, M., Ferguson, V., Forrest, P. T., Sene, Y., Mullaguru, J., Niang, M. D., Perry, C., Curran, C. P.. 2021-10-24. The behavioral effects of gestational and lactational benzopyrene exposure vary by sex and genotype in mice with differences at the Ahr and Cyp1a2 loci. https://doi.org/10.1101/2021.10.22.465510

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