title: Ahrd Cyp1a2(-/-) mice show increased susceptibility to PCB-induced developmental neurotoxicity.
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 Ahr(b)Cyp1a2(-/-) mice with the high-affinity Ahr(b) allele and lacking CYP1A2 were most susceptible while Ahr(b)Cyp1a2(+/+) and poor-affinity Ahr(d)Cyp1a2(+/+) mice were resistant. To follow up, a fourth line of mice was generated with the Ahr(d)Cyp1a2(-/-) genotype and compared with the background strain Ahr(b)Cyp1a2(+/+). 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 Ahr(b)Cyp1a2(+/+) mice, but no differences were seen in control vs. PCB-treated Ahr(d)Cyp1a2(-/-) mice. PCB-treated Ahr(d)Cyp1a2(-/-) 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 Ahr(d)Cyp1a2(-/-) 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.
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA. Electronic address: curranc1@nku.edu.
authors.forename: Christine Perdan
authors.initials: CP
authors.lastname: Curran
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Altenhofen
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Cellestine
authors.initials: C
authors.lastname: Kamau-Cheggeh
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Curran
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Evans
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Rikki
authors.initials: R
authors.lastname: Floyd
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Fowler
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Garber
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Breann
authors.initials: B
authors.lastname: Hays
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kraemer
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lang
authors.affiliation: Eastern Kentucky University, Richmond, KY, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mynhier
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Ashton
authors.initials: A
authors.lastname: Samuels
authors.affiliation: Department of Biological Sciences, Northern Kentucky University, Highland Heights, KY, USA.
authors.forename: Carly
authors.initials: C
authors.lastname: Strohmaier
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D019388:Cytochrome P-450 CYP1A2 / Q000172:deficiency* / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005838:Genotype; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D010641:Phenotype; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D013997:Time Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019388:Cytochrome P-450 CYP1A2; D004785:Environmental Pollutants; D011078:Polychlorinated Biphenyls; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse