Title: Genetic differences in lethality of newborn mice treated in utero with coplanar versus non-coplanar hexabromobiphenyl.

Authors: Curran, Christine P; Miller, Kevin A; Dalton, Timothy P; Vorhees, Charles V; Miller, Marian L; Shertzer, Howard G; Nebert, Daniel W

Published In Toxicol Sci, (2006 Feb)

Abstract: 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.

PubMed ID: 16291824

MeSH Terms: Animals; Animals, Newborn; Brain/drug effects; Brain/ultrastructure; Cytochrome P-450 CYP1A1/biosynthesis; Environmental Pollutants/pharmacokinetics; Environmental Pollutants/toxicity*; Enzyme Induction; Female; Gestational Age; Injections, Intraperitoneal; Liver/drug effects; Liver/enzymology; Liver/ultrastructure; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Polybrominated Biphenyls/pharmacokinetics; Polybrominated Biphenyls/toxicity*; Pregnancy; Prenatal Exposure Delayed Effects/chemically induced; Prenatal Exposure Delayed Effects/genetics*; Receptors, Aryl Hydrocarbon/genetics*; Stereoisomerism; Structure-Activity Relationship