ToxSci Advance Access published online on April 27, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi178
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1 Health Canada, Healthy Environments and Consumer Safety Branch, Environmental & Occupational Toxicology Division, AL:0803D Tunney's Pasture, Ottawa, Ontario, Canada K1A 0L2
* To whom correspondence should be addressed. Non-ortho polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) are ubiquitous environmental contaminants, exerting toxicity mostly through activation of the aryl-hydrocarbon receptor (AhR), and are referred to as AhR agonists. The objective was to study, by real time RT-PCR, the effects of postnatal exposure to a reconstituted mixture of AhR agonists present in breast milk (3 non-ortho PCBs, 6 PCDDs, and 7 PCDFs, referred hereafter as AhRM) on mRNA expression of estrogen receptor (ERa), enzymes involved with the metabolism of estrogens [catechol-o-methyltransferase (Comt), cytochrome P450 (Cyp)1A1, 1B1 and 2B1], and DNA methyltransferase-1 (Dnmt1), in brain areas, liver and uterus of immature female rats. Neonates were exposed by gavage during postnatal day (PND) 1-20 with dosages equivalent to 1, 10, 100 and 1000 times the estimated average human exposure level, and were sacrificed at PND21. None of the endpoints were affected in uterine cross-sections, or samples of uterine tissue layers collected by laser capture microdissection. At 1000X, the AhRM reduced Dnmt1 mRNA abundance to 28% and 32% of control in the liver and hypothalamus, respectively. In the brain, Cyp1A1 was increased (409%) but ERa was reduced (66%). Similarly, mRNA abundance for Comt isoforms was reduced in the liver (45%), and brain areas (55-70%). AhRM at 100X, the lowest effective dose, exerted a 220% increase in brain cortex Comt [membrane bound (Mb)], 219% increase in hepatic Cyp1B1, and 63% decrease in hepatic Comt (soluble (S)+Mb). These results support that early exposure to environmental contaminants could lead to effects mediated by changes in DNA methylation and/or estrogen metabolism and signaling.
Received February 15, 2005
Accepted April 11, 2005
Reproductive and Developmental Toxicology
Comparisons of brain, uterus and liver mRNA expression for cytochrome P450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists
2 Reproductive Biology Unit and Division of Gynaecologic Oncology, Departments of Obstetrics & Gyneacology and Cellular & Molecular Medicine, University of Ottawa; Hormones, Growth and Development Program, Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9
D Desaulniers, E-mail: Daniel_Desaulniers{at}hc-sc.gc.ca
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