AhrdCyp1a2(-/-) mice show increased susceptibility to PCB-induced developmental neurotoxicity

Christine Perdan Curran, Emily Altenhofen, Amy Ashworth, Austin Brown, Cellestine Kamau-Cheggeh, Melinda Curran, Amber Evans, Rikki Floyd, Jocelyn Fowler, Helen Garber, Breann Hays, Sarah Kraemer, Anna Lang, Andrea Mynhier, Ashton Samuels, Carly Strohmaier

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Polychlorinated biphenyls (PCBs) are developmental neurotoxicants that produce cognitive and behavioral changes in children exposed during gestation and lactation. Coplanar PCBs bind the aryl hydrocarbon receptor (AHR) and can be sequestered in liver by cytochrome P450 1A2 (CYP1A2). The AHR is a ligand-activated transcription factor which increases expression of the CYP1 family, including CYP1A2. Our previous work examining genetic susceptibility to developmental PCB neurotoxicity showed that AhrbCyp1a2(-/-) mice with the high-affinity Ahrb allele and lacking CYP1A2 were most susceptible while AhrbCyp1a2(+/+) and poor-affinity AhrdCyp1a2(+/+) mice were resistant. To follow up, a fourth line of mice was generated with the AhrdCyp1a2(-/-) genotype and compared with the background strain AhrbCyp1a2(+/+). Dams received a PCB mixture or the corn oil vehicle at gestational Day 10 (GD10) and postnatal Day 5 (PND5). Offspring were tested at PND60 in open field locomotor, acoustic startle with pre-pulse inhibition (PPI), novel object recognition and Morris water maze. Locomotor activity was increased in PCB-treated AhrbCyp1a2(+/+) mice, but no differences were seen in control vs. PCB-treated AhrdCyp1a2(-/-) mice. PCB-treated AhrdCyp1a2(-/-) mice had a higher baseline startle response and significantly reduced pre-pulse inhibition at the 74dB level compared with corn oil-treated controls (P<0.05). PCB-treated AhrdCyp1a2(-/-) mice had impairments in novel objective recognition (P<0.05) and during all three hidden platform phases of Morris water maze (P<0.01). Combined with our previous findings, these results indicate Cyp1a2 genotype is more important in susceptibility to PCB-induced deficits in learning and memory, but Ahr genotype appears more important when assessing acoustic startle-PPI and locomotor activity.

Original languageEnglish (US)
Pages (from-to)1436-1442
Number of pages7
JournalNeurotoxicology
Volume33
Issue number6
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Aryl hydrocarbon receptor
  • CYP1A2
  • Developmental neurotoxicity
  • PCBs
  • Polychlorinated biphenyls

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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