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

Objectives: Administration of Δ-tetrahydrocannabinol (Δ-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced islet mass in female, but not male, offspring. The effects of Δ-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 Δ-THC may also affect alpha-cell function. The aim of the present study was to determine the effects of in-utero Δ-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 Δ-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 Δ-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 Δ-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, Δ-THC did not alter fasting blood glucose and serum insulin levels in either male or female adult offspring. However, female Δ-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.