Document Detail

Genetic differences in lethality of newborn mice treated in utero with coplanar versus non-coplanar hexabromobiphenyl.
MedLine Citation:
PMID:  16291824     Owner:  NLM     Status:  MEDLINE    
Polybrominated biphenyl (PBB) exposure in humans is known to cause immunotoxicity and disorders related to the central nervous system. Coplanar PBBs bind to the aryl hydrocarbon receptor (AHR) in vertebrates. We compared the coplanar PBB, 3,3',4,4',5,5'-hexabromobiphenyl (cHBB), with its stereoisomer, the non-coplanar PBB, 2,2',4,4'6,6'-hexabromobiphenyl (ncHBB), using C57BL/6J (B6) inbred mice (having the high-affinity AHR) and congenic B6.D2-Ahr d mice (having the low-affinity AHR in a >99.8% C57BL/6J genetic background). Pregnant dams were treated i.p. with vehicle alone, cHBB, or ncHBB on gestational day 5 (GD 5). Unexpectedly, neonatal lethality within the first 72 h postpartum was significant in cHBB-treated B6 mice at doses as low as 2.5 mg/kg, whereas no deaths were seen in B6 pups whose mother had received ncHBB 100 mg/kg or in either B6.D2-Ahr d or Ahr(-/-) knockout mice whose mother had received cHBB 100 mg/kg. Histological and gross anatomical analyses of a battery of tissues in the mother or fetus at GD 18, as well as 24 h postpartum, revealed no significant differences, except for decreased thymus and spleen weights in cHBB-treated B6 GD 18 fetuses. Cross-fostering and genetics experiments confirmed the association of neonatal deaths principally with in utero (rather than lactational) exposure to cHBB, and also no paternal effect. For the end points of mouse neonatal lethality and immunotoxicity, cHBB appears to act through the high-affinity AHR receptor. Although dioxin in utero is well known to cause AHR-dependent cleft palate and hydronephrosis, cHBB did not; thus, chronic activation of the AHR appears to be necessary but not sufficient for AHR-mediated teratogenicity.
Christine P Curran; Kevin A Miller; Timothy P Dalton; Charles V Vorhees; Marian L Miller; Howard G Shertzer; Daniel W Nebert
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-11-16
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  89     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-01-12     Completed Date:  2006-03-10     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  454-64     Citation Subset:  IM    
Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056, USA.
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MeSH Terms
Animals, Newborn
Brain / drug effects,  ultrastructure
Cytochrome P-450 CYP1A1 / biosynthesis
Environmental Pollutants / pharmacokinetics,  toxicity*
Enzyme Induction
Gestational Age
Injections, Intraperitoneal
Liver / drug effects,  enzymology,  ultrastructure
Mice, Inbred C57BL
Mice, Knockout
Polybrominated Biphenyls / pharmacokinetics,  toxicity*
Prenatal Exposure Delayed Effects / chemically induced,  genetics*
Receptors, Aryl Hydrocarbon / genetics*
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/2,2',4,4',6,6'-hexabromobiphenyl; 0/Environmental Pollutants; 0/Polybrominated Biphenyls; 0/Receptors, Aryl Hydrocarbon; 60044-26-0/3,3',4,4',5,5'-hexabromobiphenyl; EC P-450 CYP1A1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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