Co-exposure to cannabinoids and nicotine increases senescence in prenatal human lung development

Tandem use of cigarettes and cannabis is increasing, particularly where recreational marijuana is legalized, posing a serious risk to fetal development. This study investigates the impact of cannabinoids (THC and CBD) and nicotine on fetal lung development using human lung explants from 10-16 weeks of gestation. Our results show that THC promotes epithelial cysting RESULTS: Our data revealed decreased proliferation (Ki-67) following treatment with CBD and CBD + THC+nicotine, whereas smooth muscle cell differentiation decreased across all conditions. Furthermore, the combination treatments induced a senescence-like phenotype as demonstrated by increased CDKN1A and CDKN2A expression and a strong reduction in LAMIN B1 staining. Additionally, DNA damage response markers ɣH2A.X and 53BP1 were significantly upregulated in the combination treatments. This was accompanied by an activation of the interferon pathway with increased expression of the downstream targets MX1 and IFI2. The addition of senolytics, Dasatinib and Quercetin (D + Q), reduced the senescence-associated secretory phenotype (SASP), such as IL-6, IL-8, M-CSF, MCP-3, MIP-1β, TNFα, MIP-3β, and TSLP, the senescence gene expressions, and reversed interferon pathway activation CONCLUSION: Our results demonstrate that co-exposure to nicotine and cannabis alters cellular proliferation and differentiation, induces a senescence-like phenotype and DNA damage response in human fetal lung cultures, which may be partially rescued using senolytics.

This study aims to assess the effect of cannabis and nicotine use during pregnancy on fetal human lung development. The combinatorial exposure to CBD, THC, and nicotine during pregnancy increases senescence-like phenotype, DNA damage response, and senescence-associated secretory phenotypes (SASP) secretion. The use of senolytics (D + Q) may prove to be a promising therapeutic option, alleviating several of the adverse effects induced by the different substances.