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.

Fig. 1.

Relative mRNA expression of cytochrome P450. Mean relative mRNA ± S.E. (n = 3 or 4) at different time points during gestation (GD; gray bars) and postpartum periods (PD; black bars). mRNA data were normalized to GAPDH and compared with virgin mice by paired t tests. *Statistically significant (P < 0.05) difference between the pregnant or postpartum mice group and the corresponding age-matched control virgin mice. The lines at 1.0 represent the normalized virgin data.

Fig. 2.

Relative mRNA expression of carboxylesterases and paraoxonase 1. Mean relative mRNA ± S.E. (n = 3 or 4) at different time points during gestation (GD; gray bars) and postpartum periods (PD; black bars). mRNA data normalized to GAPDH and serum Pon1 activities as percent of virgin activities were compared with virgin mice by paired t tests. *Statistically significant (P < 0.05) difference between the pregnant or postpartum mice group and the corresponding age-matched control virgin mice. The lines at 1.0 represent the normalized virgin data.