Antenatal hypoxia and dexamethasone independently alter hepatic cytochrome P450 activity and glucocorticoid receptor isoform cellular localisation in ovine offspring

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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% O 2 ) pregnancy from 105-138 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.

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