title: Alteration of the expression of pesticide-metabolizing enzymes in pregnant mice: potential role in the increased vulnerability of the developing brain.
abstract: Studies on therapeutic drug disposition in humans have shown significant alterations as the result of pregnancy. However, it is not known whether pesticide metabolic capacity changes throughout pregnancy, which could affect exposure of the developing brain. We sought to determine the effect of pregnancy on the expression of hepatic enzymes involved in the metabolism of pesticides. Livers were collected from virgin and pregnant C57BL/6 mice at gestational days (GD)7, GD11, GD14, GD17, and postpartum days (PD)1, PD15, and PD30. Relative mRNA expression of several enzymes involved in the metabolism of pesticides, including hepatic cytochromes (Cyp) P450s, carboxylesterases (Ces), and paraoxonase 1 (Pon1), were assessed in mice during gestation and the postpartum period. Compared with virgin mice, alterations in the expression occurred at multiple time points, with the largest changes observed on GD14. At this time point, the expression of most of the Cyps involved in pesticide metabolism in the liver (Cyp1a2, Cyp2d22, Cyp2c37, Cyp2c50, Cyp2c54, and Cyp3a11) were downregulated by 30% or more. Expression of various Ces isoforms and Pon1 were also decreased along with Pon1 activity. These data demonstrate significant alterations in the expression of key enzymes that detoxify pesticides during pregnancy, which could alter exposure of developing animals to these chemicals.
authors.affiliation: Environmental and Occupational Health Sciences Institute, Piscataway, NJ 08854, USA.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Fortin
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000196:embryology; D043182:Carboxylesterase / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000196:embryology / Q000209:etiology; D010575:Pesticides / Q000378:metabolism* / Q000633:toxicity; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D010575:Pesticides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D043182:Carboxylesterase; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse