Document Detail

In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes.
MedLine Citation:
PMID:  20961953     Owner:  NLM     Status:  MEDLINE    
Polychlorinated biphenyls (PCBs) are persistent toxic pollutants occurring as complex mixtures in the environment. Humans are known genetically to have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2) levels and > 12-fold differences in aryl hydrocarbon receptor (AHR) affinity, both of which could affect PCB pharmacokinetics. Thus, we compared Ahr(b1)_Cyp1a2(+/+) high-affinity AHR wild-type, Ahr(d)_Cyp1a2(+/+) poor affinity AHR wild-type, Ahr(b1)_Cyp1a2(-/-) knockout, and Ahr(d)_Cyp1a2(-/-) knockout mouse lines. We chose a mixture of three coplanar and five noncoplanar PCBs to reproduce that seen in human tissues, breast milk, and the food supply. The mixture was given by gavage to the mother on gestational day 10.5 (GD10.5) and postnatal day 5 (PND5); tissues were collected from pups and mothers at GD11.5, GD18.5, PND6, PND13, and PND28. Ahr(b1)_Cyp1a2(-/-) pups showed lower weight at birth and slower rate of growth postnatally. Absence of CYP1A2 resulted in significant splenic atrophy at PND13 and PND28. Presence of high-affinity AHR enhanced thymic atrophy and liver hypertrophy in the pups. Concentrations of each congener were analyzed at all time points: maximal noncoplanar congener levels in maternal tissues were observed from GD18 until PND6, whereas the highest levels in pups were found between PND6 and PND28. Coplanar PCB concentrations were generally higher in Ahr(d)-containing pup tissues; these findings are consistent with earlier studies demonstrating the crucial importance of AHR-mediated inducible CYP1 in the gastrointestinal tract as a means of detoxication of oral planar polycyclic aromatic hydrocarbons.
Christine P Curran; Charles V Vorhees; Michael T Williams; Mary Beth Genter; Marian L Miller; Daniel W Nebert
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-10-20
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  119     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-20     Completed Date:  2011-03-25     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  189-208     Citation Subset:  IM    
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA.
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MeSH Terms
Animals, Newborn
Body Weight / drug effects
Complex Mixtures / toxicity
Cytochrome P-450 CYP1A2 / genetics*
Environmental Pollutants / toxicity*
Gestational Age
Litter Size
Maternal Exposure / adverse effects*
Mice, Knockout
Milk / chemistry
Polychlorinated Biphenyls / toxicity*
Prenatal Exposure Delayed Effects / blood,  chemically induced*,  genetics,  pathology
Receptors, Aryl Hydrocarbon / genetics*
Thyroxine / blood
Grant Support
Reg. No./Substance:
0/Complex Mixtures; 0/Environmental Pollutants; 0/Polychlorinated Biphenyls; 0/Receptors, Aryl Hydrocarbon; 7488-70-2/Thyroxine; EC P-450 CYP1A2

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