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.
Highlights
Fetal Alcohol Spectrum Disorder (FASD) is common; recent conservative prevalence rates range from 1–5%1
The teratology studies demonstrate that eyes are sensitive to prenatal CB exposures, but because at gestational day (GD) 8 the eyes develop from the same neuroepithelium as the brain, we observed numerous severe brain dysmorphologies, ranging from exencephaly to holoprosencephaly
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
Summary
Fetal Alcohol Spectrum Disorder (FASD) is common; recent conservative prevalence rates range from 1–5%1. Binge alcohol drinking (i.e. more than 4 or 5 drinks in two hours for women and men, respectively) is increasingly popular among young people, and is especially damaging to the embryo during the third to fourth weeks of pregnancy, when most pregnancies are unrecognized[2,3] Alcohol exposure during this period causes characteristic craniofacial malformations of Fetal Alcohol Syndrome (FAS) including small palpebral fissures (micropthalmia), a smooth philtrum, and brain malformations in the holoprosencephaly spectrum[3]. During neurulation (gestational day [GD] 8–10 in the mouse, equivalent to the late third and early fourth weeks of human gestation), the neural tube closes, and the eyes and brain form out of the neuroepithelium As predicted by these developmental events, CP 55,940 caused significant brain and eye defects, ranging from mild microphthalmia to severe anophthalmia, which are common in FASD25. We report that in the embryo, Smo and CB1 form heteromers that are likely targets of the teratogenic effects of simultaneous alcohol and CB exposure
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