The last step in the cholesterol biosynthesis pathway is conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, catalyzed by a single enzyme, 7-dehyrocholesterol reductase (DHCR7). To date, >150 DHCR7 loss-of-function mutations have been identified, with >1% heterozygous carriers in the human population. Heterozygous carriers have elevated 7-DHC levels. It has been well documented that 7-DHC is toxic, and its numerous spontaneous oxidative products (oxysterols) have disruptive effects on normal cell division and differentiation. 7-DHC levels can also markedly increase as a result of drug treatment. We recently performed a high throughput drug screening and found that aripiprazole (ARI- an atypical antipsychotic) and trazodone (TRZ - an antidepressant) both strongly increased 7-DHC levels. Further literature review revealed that ARI- and TRZ-treated patients have elevated 7-DHC levels, misclassifying some them as SLOS patients - even when they had two intact copies of the Dchr7 gene. In a follow-up experiments we observed that peripheral dermal fibroblasts from human DHCR7+/- mutation carriers also had elevated 7-DHC levels at baseline, which worsened as a result of ARI exposure. Our newest data indicate that ARI treatment of pregnant Dhcr7+/- mice have deleterious effects on the development of the offspring. Based on these data, we hypothesize that ARI/TRZ exposure and DHCR7+/- mutations potentiate each other, elevating 7-DHC levels into a pathological range. As a result, the spontaneous, toxic metabolites of 7-DHC will alter neural development and/or brain function, especially when DHCR7+/- mutation carrier mothers have DHCR7+/- offspring exposed to ARI or TRZ. We will test this central hypothesis in a patient-derived fibroblast model (Aim 1) and neurodevelopmental transgenic mouse models (Aims 2-3) at two different time points using a maternal genotype*offspring genotype*treatment paradigm. Aripiprazole, marketed under the name of Ablilify is the most prescribed drug in the US, and the possibility that heterocyclic cationic amphiphile exposure might be deleterious to >1% of the human DHCR7+/- mutation carriers warrants further investigation. Developing personalized medicine approaches requires understanding Gene*Treatment interactions, and knowing the interaction between maternal genotype*offspring genotype*treatment is necessary to precisely define the population that is potentially vulnerable to ARI/TRZ exposure.

Public Health Relevance

This project will test the vulnerability of the DHCR7+/- gene mutation carriers to aripiprazole (an atypical antipsychotic) and trazodone (an antidepressant) exposure. We will test biochemical, gene expression and behavioral consequences of the interaction between the DHCR7+/- gene mutation and treatment, assessing the long-lasting effects on the progeny.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH110636-01A1
Application #
9312958
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$497,513
Indirect Cost
$150,993
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198