Ahrd Cyp1a2(-/-) mice show increased susceptibility to PCB-induced developmental neurotoxicity
| Autor: | Amy Ashworth, Andrea Mynhier, Cellestine Kamau-Cheggeh, Emily Altenhofen, Ashton Samuels, Helen Frances Garber, Sarah Kraemer, Austin Brown, Anna Lang, Breann Hays, Amber Evans, Carly Strohmaier, Melinda Curran, Jocelyn Phillips Fowler, Christine Perdan Curran, Rikki Floyd |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Startle response Reflex Startle Time Factors Genotype Offspring Morris water navigation task Mice Transgenic Motor Activity Toxicology Open field Article Mice Cytochrome P-450 CYP1A2 Pregnancy Internal medicine medicine Basic Helix-Loop-Helix Transcription Factors Animals Maze Learning Mice Knockout biology medicine.diagnostic_test Behavior Animal General Neuroscience Neurotoxicity CYP1A2 food and beverages Recognition Psychology Aryl hydrocarbon receptor medicine.disease Polychlorinated Biphenyls Mice Inbred C57BL Endocrinology Phenotype Acoustic Stimulation Receptors Aryl Hydrocarbon Mice Inbred DBA Prenatal Exposure Delayed Effects biology.protein Environmental Pollutants Female Neurotoxicity Syndromes Corn oil |
| Zdroj: | Neurotoxicology. 33(6) |
| ISSN: | 1872-9711 |
| Popis: | 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 (P0.05). PCB-treated Ahr(d)Cyp1a2(-/-) mice had impairments in novel objective recognition (P0.05) and during all three hidden platform phases of Morris water maze (P0.01). 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. |
| Databáze: | OpenAIRE |
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