Abstract
Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith–Lemli–Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-copy Dhcr7+/− mutation and maternal ARI exposure on the developing offspring brain. We generated a time-pregnant mouse model where WT and Dhcr7+/− embryos were maternally exposed to ARI or vehicle (VEH) from E12 to E19 (5 mg/kg). Levels of cholesterol, its precursors, ARI and its metabolites were measured at P0. We found that ARI and its metabolites were transported across the placenta and reached the brain of offspring. Maternal ARI exposure led to decreased viability of embryos and increased 7-DHC levels, regardless of maternal or offspring Dhcr7 genotype. In addition, Dhcr7+/− pups were more vulnerable to maternal ARI exposure than their WT littermates, and maternal Dhcr7+/− genotype also exacerbated offspring response to ARI treatment. Finally, both 7-DHC levels and 7-DHC/cholesterol ratio is the highest in Dhcr7+/− pups from Dhcr7+/− mothers exposed to ARI, underscoring a potentially dangerous interaction between maternal genotype×embryonic genotype×treatment. Our findings have important clinical implications. SLOS patients should avoid drugs that increase 7-DHC levels such as ARI, trazodone and haloperidol. In addition, treatment with 7-DHC elevating substances might be potentially unsafe for the 1–1.5% of population with single-allele disruptions of the DHCR7 gene. Finally, prenatal and parental genetic testing for DHCR7 should be considered before prescribing sterol-interfering medications during pregnancy.
Highlights
Proper cholesterol metabolism is essential for normal brain function
Smith–Lemli–Opitz Syndrome (SLOS) is caused by mutations in both copies in the gene encoding the last enzyme in the cholesterol biosynthesis pathway—7-dehydrocholesterol reductase (DHCR7) (Scheme 1, supplemental material) [7, 10,11,12]
The vulnerability of individuals with a DHCR7+/− genotype to side effects of ARI has potential clinical implications, as (1) cholesterol has to be synthesized de novo during embryonic development [2, 4]; (2) ARI is often prescribed to pregnant women [30,31,32,33,34,35]; 3) ARI is transported across the placenta and crosses the blood–brain barrier [36, 37]; (4) ARI disrupts the cholesterol biosynthesis and elevates 7DHC levels in the toxic range [22,23,24, 28]; (5) 1–1.5% of the population carries a DHCR7+/− mutation and might be more vulnerable to this medication
Summary
The vulnerability of individuals with a DHCR7+/− genotype to side effects of ARI has potential clinical implications, as (1) cholesterol has to be synthesized de novo during embryonic development [2, 4]; (2) ARI is often prescribed to pregnant women [30,31,32,33,34,35]; 3) ARI is transported across the placenta and crosses the blood–brain barrier [36, 37]; (4) ARI disrupts the cholesterol biosynthesis and elevates 7DHC levels in the toxic range [22,23,24, 28]; (5) 1–1.5% of the population carries a DHCR7+/− mutation and might be more vulnerable to this medication Based on these facts, we hypothesized that maternal ARI exposure will inhibit DHCR7 and increase 7-DHC in the developing brain of offspring, posing a serious risk to embryonic development. The levels of cholesterol, its precursors, ARI, and its metabolites were measured at P0
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