title: In utero and lactational exposure to PCBs in mice: adult offspring show altered learning and memory depending on Cyp1a2 and Ahr genotypes.
abstract: BACKGROUND
  Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response.
  
  
  OBJECTIVE
  We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs.
  
  
  METHODS
  We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity-AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity-AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity-AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(-/-)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189-208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors.
  
  
  RESULTS
  We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(-/-) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on at least one measure of learning or behavior.
  
  
  CONCLUSIONS
  High levels of maternal hepatic CYP1A2 offer the most important protection against deficits in learning and memory in offspring exposed to a mixture of coplanar and noncoplanar PCBs. High-affinity AHR is the next most important factor in protection of offspring.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Curran
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Patel
authors.forename: Tori L
authors.initials: TL
authors.lastname: Schaefer
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Skelton
authors.forename: Michael T
authors.initials: MT
authors.lastname: Williams
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D045424:Complex Mixtures / Q000633:toxicity; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D017774:Long-Term Potentiation; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry; D009043:Motor Activity; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D013216:Reflex, Startle
chemical_list: D015306:Biogenic Monoamines; D045424:Complex Mixtures; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; D019388:Cytochrome P-450 CYP1A2