Graduation Date

Fall 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Károly Mirnics

Second Advisor

Laurey Steinke

Third Advisor

William B. Rizzo

Fourth Advisor

Matthew Van Hook

Abstract

Cholesterol is essential for life. It is particularly important in the brain as it relies on de novo synthesis of cholesterol following the formation of the blood brain barrier (BBB). As such, disrupting sterol biosynthesis during neurodevelopment can have devastating outcomes. The most common post-lanosterol sterol biosynthesis disorder, Smith-Lemli-Opitz Syndrome, arises from a faulty DHCR7 enzyme. DHCR7 has also been shown to be inhibited by several psychotropic medications. Here we assess six beta-blockers and their effects on sterol biosynthesis in vitro. Two beta-blockers, metoprolol and nebivolol strongly inhibit DHCR7 in four separate in vitro models of both mouse and human origin. As metoprolol was the 5th most prescribed medication in the United States in 2019, we assessed its effects on sterol biosynthesis in adult mice. Finally, since metoprolol is prescribed during pregnancy, we used a time-pregnant maternal exposure model to examine the effects on the developing offspring. We show that metoprolol alters sterol biosynthesis in the brain as well as some peripheral organs in non-pregnant adult mice, at two different doses. Additionally, we show that metoprolol crosses the placenta and BBB of the offspring to disrupt sterol biosynthesis in the developing brain following maternal exposure. Our study provides evidence that metoprolol, and potentially other beta-blockers like nebivolol are capable of interfering with sterol biosynthesis in the developing brain when taken by pregnant individuals. Due to the potential for adverse outcomes arising from DHCR7 inhibition during critical developmental periods, extreme caution should be used when prescribing metoprolol during pregnancy.

Comments

2022 Copyright, the authors

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