Comment Submissions - Developmental and Reproductive Toxicant Identification Committee Meeting Scheduled for December 11, 2019, Notice of Availability of Hazard Identification Materials for Cannabis (Marijuana) Smoke and Δ-9-Tetrahydrocannabinol (THC)

Dear OEHHA This important study to your discussion is at the link: https://www.nature.com/articles/s41598-019-52336-w Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction Eric W. Fish, Laura B. Murdaugh, Chengjin Zhang, Karen E. Boschen, Oswald Boa-Amponsem, Haley N. Mendoza-Romero, Michael Tarpley, Lhoucine Chdid, Somnath Mukhopadhyay, Gregory J. Cole, Kevin P. Williams & Scott E. Parnell Scientific Reports volume 9, Article number: 16057 (2019) Cite this article Article metrics 1314 Accesses 162 Altmetric Metricsdetails Abstract We tested whether cannabinoids (CBs) potentiate alcohol-induced birth defects in mice and zebrafish, and explored the underlying pathogenic mechanisms on Sonic Hedgehog (Shh) signaling. The CBs, Δ9-THC, cannabidiol, HU-210, and CP 55,940 caused alcohol-like effects on craniofacial and brain development, phenocopying Shh mutations. Combined exposure to even low doses of alcohol with THC, HU-210, or CP 55,940 caused a greater incidence of birth defects, particularly of the eyes, than did either treatment alone. Consistent with the hypothesis that these defects are caused by deficient Shh, we found that CBs reduced Shh signaling by inhibiting Smoothened (Smo), while Shh mRNA or a CB1 receptor antagonist attenuated CB-induced birth defects. Proximity ligation experiments identified novel CB1-Smo heteromers, suggesting allosteric CB1-Smo interactions. In addition to raising concerns about the safety of cannabinoid and alcohol exposure during early embryonic development, this study establishes a novel link between two distinct signaling pathways and has widespread implications for development, as well as diseases such as addiction and cancer. We demonstrate that exposure to phyto- and synthetic CBs during the neurulation stage of embryonic development can cause birth defects like those of prenatal alcohol exposure in mouse and zebrafish models. The exposure periods are the equivalent to the third and fourth weeks of human pregnancy, before most pregnancies are recognized. The similarity between CB-exposed and alcohol-exposed fetuses suggests that some potential CB-induced birth defects may be misidentified as caused by fetal alcohol exposure alone. Our finding that simultaneous exposure to CBs and alcohol induces the highest rate of defects, and that even low doses of alcohol and CBs can potentiate each other’s effects, emphasizes the need for clinical studies to examine fetal outcomes when alcohol and CB exposure occurs at the same time. Fish, E.W., Murdaugh, L.B., Zhang, C. et al. Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction. Sci Rep 9, 16057 (2019) doi:10.1038/s41598-019-52336-w Download citation Received 01 February 2019 Accepted 16 October 2019 Published 05 November 2019 DOI https://doi.org/10.1038/s41598-019-52336-w