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Antenatal hypoxia and dexamethasone independently alter hepatic cytochrome P450 activity and glucocorticoid receptor
Millicent G A Bennett1, Ashley S Meakin1, Kimberley J Botting-Lawford2
1Early Origins of Adult Health Research Group, School of Pharmacy and Biomedical Science, College of Health, Robinson Research Institute, Adelaide University, Adelaide, Australia.
Insights
Hypoxic pregnancy and antenatal corticosteroids (ACS) alter fetal and adult liver enzyme activity. These changes in cytochrome P450 (CYP) activity may impact drug metabolism and health outcomes in offspring.
Area of Science:
- Reproductive biology
- Developmental programming
- Pharmacology
Background:
- Hypoxic pregnancy and antenatal corticosteroids (ACS) are associated with fetal growth restriction (FGR) and preterm birth.
- Offspring born FGR or preterm face increased risks for conditions requiring medications metabolized by hepatic cytochrome P450 (CYP) enzymes.
- Understanding how these conditions affect fetal and adult CYP activity is crucial for predicting long-term health risks.
Purpose of the Study:
- To investigate the impact of hypoxic pregnancy and ACS administration on fetal and adult offspring hepatic CYP activity.
- To determine how these interventions influence the expression of key regulatory proteins involved in glucocorticoid signaling and CYP regulation.
Main Methods:
- Ewes were exposed to normoxic or hypoxic conditions during pregnancy.
- Dexamethasone (Dex) or vehicle was administered to ewes.
- Hepatic CYP activity was measured using functional assays in fetal and 9-month-old offspring.
- Expression of glucocorticoid signaling and CYP-regulating proteins was analyzed via Western blot.
Main Results:
- Hypoxia increased fetal hepatic CYP2B6 and CYP2D6 activity and altered glucocorticoid receptor expression.
- Dexamethasone reduced fetal CYP3A metabolism and altered glucocorticoid receptor expression.
- In adult offspring, hypoxia reduced CYP2C19 activity, while dexamethasone decreased multiple CYP activities.
- Combined hypoxia and dexamethasone exposure altered glucocorticoid receptor expression in adult offspring.
Conclusions:
- Hypoxic pregnancy and antenatal corticosteroids differentially affect hepatic CYP activity in fetal and adult offspring.
- Observed changes in CYP activity suggest a potential loss of regulatory control, which may have implications for drug metabolism and health.
- Further research is needed to elucidate the long-term consequences of these altered metabolic pathways.
Abstract:
Hypoxic pregnancy promotes fetal growth restriction (FGR) and preterm birth, for which antenatal corticosteroids (ACS) are recommended to prevent respiratory distress. Adults born FGR or preterm are at greater risk of health conditions requiring medication(s), which are metabolised by hepatic cytochrome P450 (CYP) enzymes. We determined if ACS and/or hypoxic pregnancy alters fetal and adult offspring hepatic CYP activity. Ewes carrying singletons were randomly allocated to normoxic (Nx) or hypoxic (Hx; 11% O2) pregnancy from 105 to 138 dGA (term = 147 dGA). Dexamethasone (Dex, 12 mg IM) or vehicle (saline IV) was administered at 115 and 116 dGA. Ewes carrying male fetuses were humanely killed at 138 ± 2 dGA, while female fetuses lambed spontaneously and were humanely killed at 9 months (9 mo). Hepatic CYP activity was quantified using functional assays, and expression of glucocorticoid signalling and CYP regulating proteins was determined via Western blot. Hx increased fetal hepatic CYP2B6 and CYP2D6 activity, expression of 11β-HSD1&2 and reduced GRα-A nuclear expression, and cytosolic GRβ:α-A ratio. Dex reduced fetal CYP3A metabolism of testosterone to metabolites 6β-OHT and 2α-OHT, and GRα-A and GRβ cytosolic expression. Fetal CYP2B6 activity positively correlated with CAR in Nx, but not Hx. In 9 mo lambs, Hx reduced CYP2C19 activity and PPARα and GRβ cytosolic expression. Dex decreased CYP1A2, CYP2B6, CYP2E1 activity, and CYP3A testosterone metabolism to 6β-OHT. HxDex increased cytosolic and nuclear GRβ:α-A. Hx and Dex differentially effect hepatic CYP activity in offspring, and changes to CYP activity may be due to a loss of regulatory control.
