ToxSci Advance Access originally published online on April 27, 2005
Toxicological Sciences 2005 86(1):175-184; doi:10.1093/toxsci/kfi178
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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
* Health Canada, Healthy Environments and Consumer Safety Branch, Environmental & Occupational Toxicology Division, Ottawa, Ontario, Canada K1A 0L2; 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, Ottawa, Ontario, Canada K1Y 4E9
Received February 15, 2005; accepted April 11, 2005
Non-ortho polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) are ubiquitous environmental contaminants that exert their 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 reverse-transcriptase–polymerase chain reaction (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 to hereinafter as AhRM) on mRNA expression of estrogen receptor (ER
), 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 PND 21. None of the end points were affected in uterine cross-sections, or in 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 ER 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)], a 219% increase in hepatic Cyp1B1, and a 63% decrease in hepatic Comt (soluble (S)+Mb). These results support the possibility that early exposure to environmental contaminants could lead to effects mediated by changes in DNA methylation and/or estrogen metabolism and signaling.
Key Words: polychlorinated dibenzodioxins; polychlorinated dibenzofurans; rat; uterus; DNA methyltransferase; catechol-o-methyltransferase.
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