Effects of developmental exposure to mixtures of environmental contaminants on the hepatic metabolism of estradiol-17β in immature female Sprague Dawley rats.
Exposure to environmental contaminants induces the activation of cytochrome P450s (CYP) which lead to the hydroxylation of contaminants and endogenous hormones such as estrogens. The hydroxylation of estrogens forms catecholestrogens (CEs), one of them being the mutagenic 4-hydroxyestradiol-17β (4-OH-E2). Catecholestrogens are transformed by catechol-o-methyltransferases (COMTs) into nonreactive methoxyestrogens. To investigate the hepatic metabolism of estradiol-17β in female offspring at postnatal day (PND) 21, pregnant rats were dosed daily from gestation day 1 until PND 21 with 2 dose levels of organochlorine pesticides (OCPs; 0.019 or 1.9 mg/kg per d), methylmercury (MeHg; 0.02 or 2 mg/kg per d), polychlorinated biphenyls (PCBs; 0.011 or 1.1 mg/kg per d), or a mixture (M; 0.05 or 5 mg/kg per d) including all 3 groups of chemicals. Concentrations of organochlorines in the mixture M were based on their proportions in serum of the Canadian Arctic population. The messenger RNA (mRNA) expressions of CYP and COMT were analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). High-performance thin layer chromatography and phosphor imaging were used to measure the transformation of (14)C substrates into estrogen metabolites. The low-dose treatments or the MeHg groups had no effect. The high-dose OCP, PCB, and M group increased the production of 2-OH-E2 and 6α-OH-E2, while only the PCB and M groups increased the 2-OH-CE/methoxyestrogen ratio. In all groups, the cytosolic COMT activity exceeded the microsomal production rate of 4-OH-E2. Although the M treatment included the PCB and OCP mixtures, it did not modify the estrogen metabolism more than did the PCB mixture alone. This endocrine disruption information contributes to our understanding of chemical interactions in the toxicology of chemical mixtures.
Health Canada, Healthy Environments and Consumer Safety Branch, Hazard Identification Division, AL:0803D Tunney's Pasture, Ottawa, ON, K1A 0K9, Canada. daniel.desaulniers@hc-sc.gc.ca
Daniel
D
Desaulniers
K
K
Leingartner
G
G
Pelletier
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GH
Xiao
W J
WJ
Bowers
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D008767:Methylmercury Compounds / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D006843:Hydrocarbons, Chlorinated; D008767:Methylmercury Compounds; D010575:Pesticides; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D002394:Catechol O-Methyltransferase