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

Roxane Verdikt; Abigail A Armstrong; Jenny Cheng; Young Sun Hwang; Amander T Clark; Xia Yang; Patrick Allard

doi:10.1101/2023.03.13.531968

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

bioRxiv [Preprint]. 2023 Oct 2:2023.03.13.531968. doi: 10.1101/2023.03.13.531968.

Authors

Roxane Verdikt¹, Abigail A Armstrong², Jenny Cheng³, Young Sun Hwang⁴, Amander T Clark^{4

5

6}, Xia Yang^{7

8}, Patrick Allard^{1

9}

Affiliations

¹ Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Obstetrics/Gynecology and Reproductive Endocrinology and Infertility, University of California, Los Angeles, CA, USA.
³ Molecular, Cellular, and Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Center for Reproductive Science, Health and Education, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁷ Integrative Biology and Physiology Department, University of California, Los Angeles, CA, 90095, USA.
⁸ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Abstract

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 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 naïve 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.

Keywords: Metabolism; cannabis; embryonic stem cells; primordial germ cells; Δ9-THC.

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Preprint

Abstract

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