In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes.
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.
Curran
Christine P
CP
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA.
Vorhees
Charles V
CV
Williams
Michael T
MT
Genter
Mary Beth
MB
Miller
Marian L
ML
Nebert
Daniel W
DW
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D045424:Complex Mixtures / Q000633:toxicity; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005838:Genotype; D005865:Gestational Age; D008098:Litter Size; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D013974:Thyroxine / Q000097:blood
D045424:Complex Mixtures; D004785:Environmental Pollutants; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; D019388:Cytochrome P-450 CYP1A2; D013974:Thyroxine