Sex-dependent Effect of In-utero Exposure to A9-Tetrahydrocannabinol on Glucagon and Stathmin-2 in Adult Rat Offspring

Objectives: Administration of A9-tetrahydrocannabinol (A9-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced islet mass in female, but not male, offspring. The effects of A9- THC on other islet hormones is not known. One downstream target of the cannabinoid receptor, stathmin-2 (Stmn2), has recently been shown to suppress glucagon secretion, thereby suggesting A9-THC may also affect alpha-cell function. The aim of the present study was to determine the effects of in-utero A9-THC exposure on the profile of glucagon, insulin and Stmn2 in the rat offspring islet and serum.Methods: Pregnant Wistar rat dams were injected with A9-THC (3 mg/kg per day, intraperitoneally) or vehicle from gestational day 6 to birth. Offspring were euthanized at postnatal day 21 (PND21) or at 5 months (adult) to collect blood and pancreata.Results: At PND21, control and A9-THC-exposed offspring showed that Stmn2 had a strong colocalization with glucagon (Pearson's correlation coefficient >0.6), and a weak colocalization with insulin (Pearson's correlation coefficient <0.4) in both males and females, with no changes by either treatment or sex. In adult female offspring in the A9-THC group, intensity analysis indicated an increased insulin-to-glucagon (I/G; p<0.05) ratio and a decreased glucagon-to-Stmn2 (G/S; p<0.01) ratio, and no changes in these ratios in adult males. Furthermore, A9-THC did not alter fasting blood glucose and serum insulin levels in either male or female adult offspring. However, female A9-THC-exposed offspring exhibited an increased I/G ratio (p<0.05) and decreased G/S ratio in serum by adulthood (p<0.05).Conclusion: Collectively, the reduced G/S ratio in both islet and serum in association with an increased serum I/G ratio has direct correlations with early glucose intolerance and insulin resistance observed exclusively in females' offspring in this prenatal cannabinoid model.Crown Copyright (c) 2022. Published on behalf of the Canadian Diabetes Association.

Automated summary

Administration of A9-tetrahydrocannabinol to pregnant rats resulted in glucose intolerance, insulin resistance, and reduced islet mass in female offspring, with no significant effects observed in male offspring. The study also showed that A9-THC may affect alpha-cell function through its impact on Stmn2 levels.