Metabolic memory of Δ9-tetrahydrocannabinol exposure in pluripotent stem cells and primordial germ cells-like cells

Abstract

The high prevalence of cannabis use, the most consumed psychoactive drug in the world, is associated with increased usage by pregnant women, especially during the first trimester of pregnancy. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is severely lacking. Here, we leverage a stepwise in vitro differentiation system that captures the early embryonic developmental cascade bridging embryonic stem cells and primordial germ cells. We applied this model to investigate the impact of the most abundant phytocannabinoid, Δ9-THC, on these developmental stages. We demonstrate that Δ9-THC increases the proliferation of naive mouse embryonic stem cells but not of their primed counterpart. Surprisingly, this increased proliferation, dependent on the CB1 receptor binding, is only associated with moderate transcriptomic changes. Instead, Δ9-THC capitalizes on ESCs metabolic bivalence by primarily increasing their glycolytic rates and anabolic capabilities. A memory of this metabolic rewiring is retained throughout differentiation to Primordial Germ Cell-Like Cells in the absence of direct exposure and is associated with an alteration of their transcriptional profile. These results represent the first in-depth molecular characterization of the impact of Δ9-THC exposure on early developmental stages.