Glucocorticoids, Stress and Delta-9 Tetrahydrocannabinol (THC) during Early Embryonic Development

Abstract

Elevated molecular stress in women is known to have negative impacts on the reproductive development of oocytes and the embryos prior to implantation. In recent years, the prevalence of cannabis use among women of reproductive age has risen due to its ability to relieve psychological stress and nausea, which are mediated by its psychoactive component, ∆-9-tetrahydrocannabinol (THC). Although cannabis is the most popular recreational drug of the 21st century, much is unknown about its influence on molecular stress in reproductive tissues. The current literature has demonstrated that THC causes dose- and time-dependent alterations in glucocorticoid signaling, which have the potential to compromise morphology, development, and quality of oocytes and embryos. However, there are inconsistencies across studies regarding the mechanisms for THC-dependent changes in stress hormones and how either compounds may drive or arrest development. Factors such as variability between animal models, physiologically relevant doses, and undiscovered downstream gene targets of both glucocorticoids and THC could account for such inconsistencies. This review evaluates the results of studies which have investigated the effects of glucocorticoids on reproductive development and how THC may alter stress signaling in relevant tissues.

Keywords: THC; embryos; glucocorticoids; molecular stress; oocytes; pre-implantation development.

Figure 1

Intracellular regulatory mechanisms stimulated by endocannabinoid and glucocorticoid receptors. Activation of transmembrane cannabinoid receptors CB1 and CB2 stimulates intracellular production of ceramides and inhibition of adenylyl cyclase and p21ras. Activation of membrane bound or cytoplasmic GR results in the cleavage of the peptide into a transcription factor. The two systems converge on transcriptional regulation and modulation of MAPK signaling pathways. Modified from Misner, 2020 [55].

Figure 2

Cannabinoid receptors in the basolateral amygdala (BLA) modulate physiological stress response from the HPA by acting as a brake on glutamate release. Under basal conditions in BLA neurons, inhibitory cannabinoid receptors are activated by high levels of synaptic endocannabinoids, causing inhibition of glutamate release to neurons in the paraventricular nucleus of the hypothalamus. Stress conditions cause the hydrolysis of endocannabinoids (via FAAH), which decreases the activation of cannabinoid receptors and relieves inhibition of glutamate release to the hypothalamus.

Figure 3

Localization of the endocannabinoid system within ovarian follicles of several mammalian species. CB1 and CB2 are detected in human, bovine, and murine follicles throughout development. Detection of CB1 receptors in rodent specimens have been limited to the granulosa cells of Graafian follicles. CB1 receptors have been detected in the granulosa cells of Graafian follicles in mice. AEA levels in human follicles increase throughout folliculogenesis, peaking in Graafian follicles. Both AEA and 2-AG have been detected in granulosa cells of all follicles. MAGL and FAAH are detected in granulosa cells throughout folliculogenesis in humans.

Figure 4

Localization of stress signaling components within ovarian follicles of several mammalian species. Nuclear glucocorticoid receptor NR3C1 has been detected throughout folliculogenesis in human, primate, and ovine models. GRs are also present throughout folliculogenesis in bovine and murine models, though only reported in oocytes in the latter. Enzymes HSD11B1 and HSD11B2 have been detected in human granulosa cells and bovine follicles throughout folliculogenesis.

Figure 5

Outcomes of in vivo and in vitro glucocorticoid exposure in oocytes and embryos from mice, lamb, goat, and cow models. Glucocorticoid inhibition of oocyte maturation in vitro is observed in all animal models. Glucocorticoid exposure in mouse embryos inhibited development, while maternal exposure to glucocorticoids caused increased apoptosis in granulosa cells of subsequent embryos. In goats and cows, maternal glucocorticoid exposure increased fertilization success in goats and blastocyst rate in cows, though da Silva et al. (2018) also report a decrease in cleavage rate in cow embryos [12].

Figure 6

Systemic, cellular, and molecular changes to glucocorticoid and glucocorticoid receptors following THC exposure in humans and mice. Chronic cannabis usage in humans increases baseline cortisol levels and decreases reactivity to stress. Both humans and mice experience an increase in glucocorticoid levels following THC exposure. Decreased expression of GLUT1 and GRs have been observed in both species in response to THC.