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
Abstract
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 here-in-after as AhRM) on mRNA expression of estrogen receptor (ERalpha), 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 ERalpha 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.
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Postnatal exposure (P1, 5, 10, 15, and 20) to a 1000× mixture of AHR agonists detected in human breast milk, including 3 DL PCBs (77, 126, and 169), reduced Dnmt1 mRNA abundance levels to 32% of controls in the hypothalamus of P21 female Sprague-Dawley rats.
“Similarly, postnatal exposure (P1, 5, 10, 15, and 20) to a 1000 × mixture of AHR agonists detected in human breast milk, including 3 DL PCBs (77, 126, and 169), reduced Dnmt1 mRNA abundance levels to 32% of controls in the hypothalamus of P21 female Sprague-Dawley rats [ 33 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [33]
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- Authors
- Desaulniers, D., Xiao, G.-H., Leingartner, K., Chu, I., Musicki, B., & Tsang, B. K.
- Affiliations
- Health Canada (CA)
- University of Ottawa (CA)
- Corresponding author
- Desaulniers, D.
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-04-27
- Volume
- 86
- Issue
- 1
- Pages
- 175-184
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2095806380
- Cited by
- 50
- References
- 81
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 3 · 2016: 6 · 2015: 4 · 2014: 2 · 2012: 3
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Thailand Science Research and Innovation
- Health Canada
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- aryl hydrocarbon receptor agonists, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, postnatal exposure, estrogen receptor alpha, catechol-O-methyltransferase, CYP1A1, CYP1B1, CYP2B1, DNMT1, estrogen metabolism, brain, liver, uterus, hypothalamus, prepubertal female rats, developmental neurotoxicity, endocrine disruptors, gene expression
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Animals, Base Sequence, Brain, Catechol O-Methyltransferase, Cytochrome P-450 Enzyme System, DNA (Cytosine-5-)-Methyltransferases, Female, Liver, RNA, Messenger, Uterus, Polymerase Chain Reaction, Rats, Sprague-Dawley, DNA Primers, Receptors, Aryl Hydrocarbon, Rats
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