Differential effects of chronic ethanol exposure on cytochrome P450 2E1 and the hypothalamic-pituitary-adrenal axis in the maternal-fetal unit of the guinea pig.
BACKGROUND
Ethanol neurobehavioural teratogenicity is a leading cause of developmental mental deficiency, in which the hippocampus is a target site of injury. The multi-faceted mechanism of ethanol teratogenicity is not completely understood. This study tested the hypothesis that chronic ethanol exposure (CEE), via chronic maternal ethanol administration, increases cytochrome P450 2E1 (CYP2E1) expression and alters hypothalamic-pituitary-adrenal (HPA) axis activity in the maternal-fetal unit during the third-trimester-equivalent of gestation.


METHODS
Pregnant Dunkin-Hartley-strain guinea pigs received daily oral administration of ethanol (4 g ethanol/kg maternal body weight) or isocaloric-sucrose/pair-feeding (control) throughout gestation (term, about gestational day (GD) 68). On GD 45, 55 and 65, pregnant animals were euthanized 2h after the last daily dose. Maternal and fetal body weights and fetal hippocampal brain weight were determined. Maternal and fetal samples were collected for the determination of liver CYP2E1 enzymatic activity and plasma free cortisol and ACTH concentrations.


RESULTS
CEE, with maternal blood ethanol concentration of 108-124 mg/dl at 2h after the last dose, decreased fetal hippocampal weight only at GD 65 and had no effect on fetal body weight compared with control. CYP2E1 activity increased with gestational age in the fetal liver microsomal and mitochondrial fractions. CEE increased CYP2E1 activity in the microsomal and mitochondrial fractions of maternal liver at the three gestational ages and in both hepatic subcellular fractions of the GD 65 fetus compared with control. There was a gestational-age-dependent increase in maternal and fetal plasma free cortisol concentrations, but no effect of CEE compared with control. Maternal and fetal plasma ACTH concentrations were unaffected by CEE compared with control, and were virtually unchanged during the third-trimester-equivalent that was studied.


CONCLUSIONS
These data demonstrate that, in the pregnant guinea pig, this CEE regimen increases liver CYP2E1 activity, without affecting HPA axis function, in the maternal-fetal unit during near-term gestation. The CEE-induced increase in liver CYP2E1 activity and potential oxidative stress in the maternal-fetal unit may play a role in the pathogenesis of ethanol teratogenicity.
Hewitt
Amy J
AJ
Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada.
Walker
Kevin R
KR
Kobus
Susan M
SM
Poklewska-Koziell
Margo
M
Reynolds
James N
JN
Brien
James F
JF
D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002675:Child, Preschool; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects* / Q000378:metabolism; D002658:Developmental Disabilities / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism* / Q000503:physiopathology; D006168:Guinea Pigs; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology
D019392:Cytochrome P-450 CYP2E1