Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development.

Area of Science:

• Developmental Biology
• Teratology
• Molecular Pharmacology

Background:

• Developmental disorders often result from gene-environment interactions.
• Hedgehog (HH) signaling is crucial for development; its inhibition causes birth defects like holoprosencephaly (HPE).
• Cannabinoids, including THC, are known HH pathway inhibitors, but their embryonic effects and mechanisms are poorly understood.

Purpose of the Study:

• To investigate the effects of the cannabinoid THC on HH-dependent developmental processes in mammalian embryos.
• To elucidate the mechanism by which THC inhibits the HH signaling pathway.
• To assess the public health implications of cannabis use during pregnancy concerning developmental risks.

Main Methods:

• Utilized Cdon mutant mice exhibiting a subthreshold HH signaling deficit.
• Administered Δ9-tetrahydrocannabinol (THC) to assess teratogenic effects and HH pathway disruption.
• Performed in vitro experiments to identify the direct molecular target of THC's HH inhibitory action.

Main Results:

• THC induced hallmark HH loss-of-function phenotypes, including HPE and ventral neural tube defects, in Cdon mutant mice.
• THC functions as a conditional teratogen, exacerbating pre-existing, subthreshold HH pathway deficits.
• In vitro studies revealed THC directly inhibits smoothened (SMO), a key HH signal transducer, independent of the cannabinoid receptor type 1 (CB1).

Conclusions:

• THC can act as a conditional teratogen, posing developmental risks when combined with genetic predispositions.
• The mechanism of HH inhibition by THC involves direct SMO inhibition, not mediated by CB1.
• Findings highlight significant public health concerns regarding prenatal cannabis exposure and potential contributions to developmental disorders.