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Updated: Sep 30, 2025
Moderate Prenatal Alcohol Exposure and Quantification of Social Behavior in Adult Rats
Published on: December 14, 2014
Prenatal ethanol exposure induces dynamic changes of expression and activity of hepatic cytochrome P450 isoforms in
Xiaoxiang Sun1, Liang He1, Huichang Bi2
1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan 430071, Hubei Province, People's Republic of China.
Insights
Prenatal ethanol exposure (PEE) in rats programmed higher cytochrome P450 (CYP) gene expression but lower protein levels and activity in male offspring. These effects diminished with age, potentially impacting substance metabolism in early adulthood.
Area of Science:
- Pharmacology and Toxicology
- Developmental Biology
- Biochemistry
Background:
- Prenatal ethanol exposure (PEE) is a significant concern with potential long-term health consequences.
- Cytochrome P450 (CYP) isozymes are crucial for metabolizing endogenous and exogenous compounds.
- The impact of PEE on CYP expression and activity across different life stages remains incompletely understood.
Purpose of the Study:
- To determine the effect of prenatal ethanol exposure (PEE) on the expression and activity of cytochrome P450 (CYP) isozymes in male rat offspring.
- To investigate these effects at various developmental stages: late gestation, early postnatal, and adulthood.
- To explore the in vitro effects of ethanol and glucocorticoids on CYP expression.
Main Methods:
- Pregnant Wistar rats received ethanol (4 g/kg/d) during gestational days 9-20.
- CYP isozyme gene expression and activity were analyzed in male offspring on gestational day 20, postnatal day 84, and postnatal day 196.
- Enzyme kinetics of hepatic CYP2E1 were compared using aniline as a probe; in vitro studies used primary hepatocytes and human hepatic cell lines.
Main Results:
- PEE increased the gene expression of multiple CYP isozymes (Cyp1a2, 2b1, 2d1, 2e1, 3a1) in offspring on gestational day 20 and postnatal day 84, with Cyp2e1 showing an increasing trend even on postnatal day 196.
- PEE inhibited CYP2D1 and CYP2E1 activities in male offspring on postnatal day 84, although CYP activities normalized by postnatal day 196.
- PEE induced opposing changes in hepatic CYP2E1 gene and protein levels pre- and postnatally, correlating with weaker aniline metabolism in PEE liver microsomes due to lower protein levels.
Conclusions:
- PEE programs altered CYP profiles in male offspring, characterized by increased gene expression but decreased protein levels and enzyme activity, particularly in early adulthood.
- These age-dependent changes in CYP expression and activity suggest a potential impairment in the metabolism of endogenous and exogenous substances.
- In vitro experiments demonstrated that ethanol and/or glucocorticoid treatment increased CYP expression, highlighting complex regulatory interactions.
Abstract:
This study aimed at determining the effect of prenatal ethanol exposure (PEE) on the expression and activity of cytochrome P450 (CYP) isozymes at different life stages of male rat offspring. Pregnant Wistar rats were administered with ethanol (4 g/kg/d) intragastrically from gestational day (GD) 9-20. Male offspring's gene and activity of CYP isozymes were analyzed on GD 20 (only expression), postnatal day (PD) 84 and 196. Using aniline as probe, we compared the enzyme kinetics of hepatic CYP2E1 between two groups. Expression of CYP isozymes was examined in rat primary hepatocytes and human hepatic cell lines treated with ethanol or/and glucocorticoid. Gene level of Cyp1a2, 2b1, 2d1, 2e1, 3a1 and aryl hydrocarbon receptor were increased in PEE group on GD 20 and PD 84 and Cyp2e1 still exhibited an increasing trend on PD 196 compared with the control. PEE inhibited CYP2D1 and 2E1 activities in male offspring on PD 84. CYP activities in two groups became the same level on PD 196. PEE induced an opposite change in gene and protein level of hepatic CYP2E1 before and after birth. In consistent with lower protein level, aniline metabolism in PEE was weaker in liver microsome. Both single and combined use of ethanol or/and glucocorticoid increased CYPs expression in vitro. In conclusion, PEE programmed a higher gene and lower protein level of CYPs in male offspring, which dwindled with age. Impairment of protein levels and enzyme activities of CYPs may affect individual metabolism of endogenous and exogenous substances in early adulthood.
