Global gene expression analysis in the livers of rat offspring perinatally exposed to low doses of 2,2',4,4'-tetrabromodiphenyl ether.
BACKGROUND
Polybrominated diphenyl ethers are a group of flame-retardant chemicals appearing increasingly in the environment. Their health effects and mechanisms of toxicity are poorly understood.


OBJECTIVE
We screened for the sensitive effects and mechanisms of toxicity of 2,2 ,4,4 -tetra-bromodiphenyl ether (BDE-47) by analyzing the gene expression profile in rats exposed to doses comparable to human exposure.


METHODS
Wistar dams were exposed to vehicle or BDE-47 (0.002 and 0.2 mg/kg body weight) every fifth day from gestation day 15 to postnatal day 20 by injections to caudal vein. Total RNA was extracted from the livers of pups and hybridized to the whole-genome RNA expression micro-arrays. The list of genes 2-fold differentially expressed was exported to PANTHER and Ingenuity Systems for analysis of enriched ontology groups and molecular pathways.


RESULTS
Oxidoreductase and transferase protein families were enriched in exposed rats as were these biological process categories: carbohydrate metabolism; electron transport; and lipid, fatty acid, and steroid metabolism. Four signaling pathways (cascades of activation of drug-metabolizing enzymes) and 10 metabolic pathways were significantly enriched. Drug-metabolizing enzymes appear to be regulated by BDE-47 through an aryl hydrocarbon receptor-independent mechanism. Direct interaction with retinoid X receptor or its upstream cascade may be involved. The main metabolic effects consisted of activation of metabolic pathways: alpha- and omega-oxidation of fatty acids, glycolysis, and starch hydrolysis.


CONCLUSIONS
Altered expression of genes involved in metabolic and signaling pathways and functions of the organism occurs after perinatal exposure of rat offspring to BDE-47 at doses relevant for the general population.
Suvorov
Alexander
A
Département Obstétrique Gynécologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Québec, Canada. Alexander.Suvorov@USherbrooke.ca
Takser
Larissa
L
D000818:Animals; D001483:Base Sequence; D003580:Cytochromes / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005411:Flame Retardants / Q000008:administration & dosage / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D055768:Halogenated Diphenyl Ethers; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D047488:Retinoid X Receptors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D003580:Cytochromes; D017931:DNA Primers; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D047488:Retinoid X Receptors; C511295:2,2',4,4'-tetrabromodiphenyl ether