Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, United States
Abigail A Armstrong
Department of Obstetrics/Gynecology and Reproductive Endocrinology and Infertility, University of California, Los Angeles, Los Angeles, United States
Jenny Cheng
Molecular, Cellular, and Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, United States
Young Sun Hwang
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
Amander T Clark
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States; Center for Reproductive Science, Health and Education, University of California, Los Angeles, Los Angeles, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
Integrative Biology and Physiology Department, University of California, Los Angeles, Los Angeles, United States; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States
Cannabis, the most consumed illicit psychoactive drug in the world, is increasingly used by pregnant women. However, while cannabinoid receptors are expressed in the early embryo, the impact of phytocannabinoids exposure on early embryonic processes is lacking. Here, we leverage a stepwise in vitro differentiation system that captures the early embryonic developmental cascade to investigate the impact of exposure to the most abundant phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC). We demonstrate that Δ9-THC increases the proliferation of naive mouse embryonic stem cells (ESCs) 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 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 stages of germline development.
