Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA.
Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
Sci Rep. 2019 Nov 5;9(1):16057. doi: 10.1038/s41598-019-52336-w.
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, Δ-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.
我们测试了大麻素（CBs）是否会增强小鼠和斑马鱼的酒精诱导的出生缺陷，并探讨了其对 Sonic Hedgehog（Shh）信号的潜在致病机制。大麻素 Δ-THC、大麻二酚、HU-210 和 CP 55,940 对颅面和大脑发育产生了类似酒精的影响，模拟了 Shh 突变。即使联合暴露于低剂量的酒精与 THC、HU-210 或 CP 55,940 也会比单独治疗引起更高的出生缺陷发生率，特别是眼睛缺陷。与这些缺陷是由 Shh 信号不足引起的假设一致，我们发现大麻素通过抑制 Smoothened（Smo）来减少 Shh 信号，而 Shh mRNA 或 CB1 受体拮抗剂则减弱了 CB 诱导的出生缺陷。邻近连接实验鉴定了新型 CB1-Smo 异源二聚体，表明存在别构的 CB1-Smo 相互作用。除了对大麻素和酒精暴露在胚胎早期发育期间的安全性提出担忧外，这项研究还在两个不同信号通路之间建立了新的联系，对发育以及成瘾和癌症等疾病具有广泛的意义。
