Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Hardy, Daniel B.

Affiliation

Lawson Health Research Institute

Abstract

Fetal growth restriction (FGR) is associated with dysregulated placental gene expression tied to an increased risk of schizophrenia (SCZ). In rat offspring, it has been demonstrated that prenatal THC exposure results in FGR and SCZ-like phenotypes. However, it is unknown whether THC can induce placental gene expression associated with SCZ. It was hypothesized that established predictive markers of SCZ would be altered in preclinical models of gestational THC exposure. Offspring exposed to prenatal THC were found to have reduced birth weight and altered expression of SCZ-associated genes in the placenta and the adult brain. A subset of the genes altered in the rodent placenta were found to be changed in BeWo cells and cerebral organoids after THC exposure. Collectively, these findings demonstrate that prenatal THC exposure can alter gene expression in established placental markers of SCZ in animal and human models, suggesting a connection between early THC exposure and SCZ.

Summary for Lay Audience

In the last 10 years, cannabis use has substantially increased among the pregnant population, with approximately 5% of pregnant women reporting use of cannabis daily. Despite this increase in use, the effects of cannabis in pregnancy are still being explored. ∆9-Tetrahydrocannabinol (THC), the component in cannabis that elicits the “high” feeling, negatively affects the fetal organ, the placenta, which transfers nutrients to the fetus. Dysfunctional placentae are linked to decreased birth weight, which is observed in babies exposed to cannabis in the womb. Low birth weight is associated with multiple long-term negative health effects, such as increased risk of neuropsychiatric disorders like schizophrenia (SCZ). SCZ is a serious psychological disorder that affects one’s ability to distinguish reality. Recent studies have found that those with low birth weight expressed genes associated with SCZ in their placenta differently than those from normal pregnancies. However, it is unknown if THC can induce this differential gene expression. To determine if THC can change placental gene expression, pregnant rats were exposed to edible THC. It was found that rats exposed to THC before birth demonstrated changes in gene expression associated with SCZ in their placenta. Similar expression changes were found in the brains of adult rats that were exposed to THC in the womb. These gene changes were then investigated in human cell models. Placental cells treated with THC for 24 hours demonstrated gene expression changes similar to what was observed in the rat placenta. To model the human brain, small clusters of brain cells derived from patient stem cells, called organoids, were used. Organoids were derived from SCZ and control patients and treated with THC. SCZ and control cells reacted differently to THC and had different expression patterns of genes associated with SCZ. This work demonstrated that THC in rat pregnancy can alter offspring gene expression associated with SCZ in the placenta and adult brain. Additionally, some similar changes were observed in human cell models. These findings suggest that exposure to cannabis may increase the risk of SCZ in offspring, and this increased risk can potentially be assessed early through placental gene expression analysis.

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