Chronic hypoxia or MitoQ treatment in pregnancy independently alter hepatic cytochrome P450 activity in fetal sheep and 9-month-old lambs

Fetal hypoxaemia promotes oxidative stress and increases risk of chronic diseases in later life. The medications for managing chronic diseases are often metabolised by hepatic cytochrome P450 (CYP) enzymes; however, it is unknown if oxidative stress in utero programs altered CYP activity. Maternal treatment with the antioxidant MitoQ protects against hypertension in adult offspring, programmed by fetal hypoxaemia. We hypothesised that fetal hypoxaemia alters offspring CYP activity and MitoQ would rescue this. From 105-138 days gestational age (dGA), ewes carrying singletons were randomly allocated to normoxic (n = 34, 21 % O₂) or hypoxic (n = 36, 11 % O₂) pregnancy with maternal vehicle (n = 34) or MitoQ (n = 36, 6 mg kg^-1 MS010 IV) daily bolus. Male fetuses were humanely killed at 137 ± 2 dGA while female fetuses lambed spontaneously and were humanely killed at 9 months of age (9mo). Hepatic CYP activity and protein abundance were quantified using functional assays and Western blot. Hypoxic pregnancy increased fetal ATF-6 expression, decreased 9mo CYP2B6 and CYP2E1 activity, and decreased mitochondrial abundance at 9mo. MitoQ decreased fetal CYP3A activity, while at 9mo CYP3A activity increased and CYP1A2 activity decreased. MitoQ decreased fetal mitochondrial abundance and expression of mitochondrial complexes I and IV, but at 9mo complex II and IV expression increased. MitoQ also increased fetal and 9mo ATF-6 expression and 9mo HNF-4ɑ and PPARɑ expression. Fetal hypoxaemia and maternal MitoQ treatment independently programmed hepatic CYP activity in fetal sheep and 9mo lambs. These effects may impact therapeutic efficacy and safety for treatment of chronic diseases in offspring from complicated pregnancies.