Sex-dependent Effect of In-utero Exposure to Δ9-Tetrahydrocannabinol on Glucagon and Stathmin-2 in Adult Rat Offspring

Farzad Asadi; Juan Andres Fernandez Andrade; Ryan Gillies; Kendrick Lee; Savita Dhanvantari; Daniel Barry Hardy; Edith Juliana Arany

doi:10.1016/j.jcjd.2022.06.009

Sex-dependent Effect of In-utero Exposure to Δ^9-Tetrahydrocannabinol on Glucagon and Stathmin-2 in Adult Rat Offspring

Can J Diabetes. 2022 Dec;46(8):851-862. doi: 10.1016/j.jcjd.2022.06.009. Epub 2022 Jul 5.

Authors

Farzad Asadi¹, Juan Andres Fernandez Andrade², Ryan Gillies¹, Kendrick Lee³, Savita Dhanvantari⁴, Daniel Barry Hardy⁵, Edith Juliana Arany⁶

Affiliations

¹ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
² Lawson Health Research Institute, London, Ontario, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
³ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Obstetrics and Gynecology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁵ Lawson Health Research Institute, London, Ontario, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Obstetrics and Gynecology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁶ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: earany@uwo.ca.

PMID: 35985923
DOI: 10.1016/j.jcjd.2022.06.009

Abstract

Objectives: Administration of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced islet mass in female, but not male, offspring. The effects of Δ⁹-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 Δ⁹-THC may also affect alpha-cell function. The aim of the present study was to determine the effects of in-utero Δ⁹-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 Δ⁹-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 Δ⁹-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 Δ⁹-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, Δ⁹-THC did not alter fasting blood glucose and serum insulin levels in either male or female adult offspring. However, female Δ⁹-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.

Keywords: glucagon; insulin resistance; islet; résistance à l’insuline; stathmin-2; stathmine-2; îlots; Δ(9)-THC.

MeSH terms

Animals
Dronabinol / adverse effects
Female
Glucagon
Glucose Intolerance*
Insulin
Insulin Resistance*
Male
Pregnancy
Prenatal Exposure Delayed Effects* / chemically induced
Rats
Rats, Wistar
Stathmin

Substances

Dronabinol
Glucagon
Insulin
Stathmin