Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review

Abstract

Mendelian diseases contain important biological information regarding developmental effects of gene mutations that can guide drug discovery and toxicity efforts. In this review, we focus on Smith–Lemli–Opitz syndrome (SLOS), a rare Mendelian disease characterized by compound heterozygous mutations in 7-dehydrocholesterol reductase (DHCR7) resulting in severe fetal deformities. We present a compilation of SLOS-inducing DHCR7 mutations and the geographic distribution of those mutations in healthy and diseased populations. We observed that several mutations thought to be disease causing occur in healthy populations, indicating an incomplete understanding of the condition and highlighting new research opportunities. We describe the functional environment around DHCR7, including pharmacological DHCR7 inhibitors and cholesterol and vitamin D synthesis. Using PubMed, we investigated the fetal outcomes following prenatal exposure to DHCR7 modulators. First-trimester exposure to DHCR7 inhibitors resulted in outcomes similar to those of known teratogens (50 vs 48% born-healthy). DHCR7 activity should be considered during drug development and prenatal toxicity assessment.

Development of A Machine Learning Algorithm to Classify Drugs Of Unknown Fetal Effect

“…Nine pregnancies were exposed in the 3–6 month pre-conception period while 28 pregnancies were exposed during the first trimester – 22 resulted in fetal loss. Haloperidol increases the expression of 7-dehydrocholesterol reductase (DHCR7) - an enzyme important in the conversion of 7-dehydrocholesterol to cholesterol 34 . While exposure to pharmacological DHCR7 inhibitors increases the risk of fetal anomalies, the effects of drugs that merely increase the gene’s expression are less-well known 34 .…”

“…Haloperidol increases the expression of 7-dehydrocholesterol reductase (DHCR7) - an enzyme important in the conversion of 7-dehydrocholesterol to cholesterol 34 . While exposure to pharmacological DHCR7 inhibitors increases the risk of fetal anomalies, the effects of drugs that merely increase the gene’s expression are less-well known 34 . Drugs increasing DHCR7 expression are not known to increase fetal loss; however increasing DHCR7 volume would lower the amount of available 7-dehydrocholesterol used to produce vitamin D 34 .…”

“…While exposure to pharmacological DHCR7 inhibitors increases the risk of fetal anomalies, the effects of drugs that merely increase the gene’s expression are less-well known 34 . Drugs increasing DHCR7 expression are not known to increase fetal loss; however increasing DHCR7 volume would lower the amount of available 7-dehydrocholesterol used to produce vitamin D 34 . Therefore, drugs increasing DHCR7 expression could inadvertently lower maternal vitamin D levels.…”

“…This is important because it shows that a drug’s mechanism of action and how it interfaces with vitamin-related mechanisms is extremely important in determining fetal outcome. This was known for specific drugs 34 , but not across a larger cohort of fetal drug exposures. This knowledge can inform future fetal toxicity studies.…”

Enabling pregnant women and their physicians to make informed medication decisions using artificial intelligence

“…Boland et al's method also used chemical information on the drugs and whether or not the drug was known to target a vitamin gene or a known Mendelian disease gene to improve the performance of the method [79]. The importance of understanding Mendelian disease genes and pharmacologics that target them (even as unintended targets or 'off-targets') in fetal outcomes was established via an extensive manual review process [80] that helped to inform the design of our later machine learning approach [79].…”