Maternal cariprazine exposure effects on lactating offspring sterol biosynthesis

Abstract

In the developing brain cholesterol is synthesized by both neurons and glia, and sterol biosynthesis peaks in early postnatal life. Genetic disruptions of sterol biosynthesis genes lead to complex intellectual and developmental disabilities. In addition, multiple commonly prescribed medications can impede sterol homeostasis. Of these, cariprazine (CAR) is one of the strongest prescription medications with sterol biosynthesis inhibiting side effects. CAR inhibits the final steps in cholesterol biosynthesis mediated by the enzyme dehydrocholesterol reductase 7 (DHCR7). This inhibition leads to accumulations of sterol precursors, including 7-dehydocholesterol (7-DHC). 7-DHC is the most oxidizable lipid known in mammals, and the 7-DHC derived oxysterols are toxic. There is limited information on CAR effects during lactation. We exposed lactating mice to daily CAR injections of 0.2 mg/kg CAR. At postnatal day 11 we found that CAR levels were similar in the brains of exposed pups and their lactating mothers. In addition, the exposed pup brains and livers had increased levels of 7-DHC and 8-DHC. This disruption of post-lanosterol sterol biosynthesis by CAR was not dependent on the sex of the pups or maternal genotype. However, CAR levels were genotype dependent, with Dhcr7+/- animals showing lower levels of CAR than their wild-type littermates. In summary, our current study fills a knowledge gap: CAR is excreted through milk, accumulates in the brain of the lactating pups, and disrupts sterol biosynthesis (and potentially many other physiological processes) in the developing postnatal brain.