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Preclinical Model of Prenatal Delta-9-Tetrahydrocannabinol Exposure to Assess Its Impact on Neurodevelopmental Outcomes
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Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction
Eric W Fish1, Laura B Murdaugh1, Chengjin Zhang2
1Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA.
Scientific Reports
|November 7, 2019
Summary
Cannabinoids (CBs) worsen alcohol-induced birth defects by disrupting Sonic Hedgehog (Shh) signaling. This study reveals CBs inhibit Shh, leading to developmental abnormalities, particularly in the eyes.
Area of Science:
- Developmental Biology
- Neuroscience
- Pharmacology
Background:
- Alcohol consumption during pregnancy is a known teratogen.
- Cannabinoids are increasingly used, raising concerns about co-exposure during development.
- Sonic Hedgehog (Shh) signaling is crucial for embryonic development.
Purpose of the Study:
- To investigate if cannabinoids potentiate alcohol-induced birth defects.
- To explore the mechanisms involving Sonic Hedgehog (Shh) signaling.
- To identify potential therapeutic targets for developmental abnormalities.
Main Methods:
- Utilized mouse and zebrafish models for teratogenicity testing.
- Assessed craniofacial and brain development following exposure.
- Investigated Shh signaling pathway activity, including Smoothened (Smo) inhibition.
- Employed proximity ligation assays to identify receptor interactions.
Main Results:
- Cannabinoids (Δ9-THC, CBD, HU-210, CP 55,940) induced alcohol-like developmental defects.
- Combined alcohol and cannabinoid exposure significantly increased birth defect incidence, especially ocular defects.
- Cannabinoids inhibited Shh signaling by targeting Smo.
- Shh mRNA or CB1 receptor antagonist administration attenuated cannabinoid-induced defects.
- Novel CB1-Smo heteromers were identified, suggesting allosteric interactions.
Conclusions:
- Cannabinoid and alcohol co-exposure poses significant risks to embryonic development.
- Cannabinoids disrupt embryonic development by inhibiting the Shh pathway via CB1-Smo interactions.
- Findings have implications for understanding developmental disorders, addiction, and cancer.
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