Impact of Maternal Intake of Artificial Sweetener, Acesulfame-K, on Metabolic and Reproductive Health Outcomes in Male and Female Mouse Offspring

Abstract

Guidelines advising pregnant women to avoid food and beverages with high fat and sugar have led to an increase in the consumption of “diet” options sweetened by artificial sweeteners (AS). Yet, there is limited information regarding the impact of AS intake during pregnancy on the long-term risk of cardiometabolic and reproductive complications in adult offspring. This study examined the influence of maternal acesulfame-K (Ace-K) and fructose consumption on metabolic and reproductive outcomes in offspring. Pregnant C57BL/6 mice received standard chow ad-libitum with either water (CD), fructose (Fr; 20% kcal intake), or AS (AS; 12.5 mM Ace-K) throughout pregnancy and lactation (n = 8/group). Postweaning offspring were maintained on a CD diet for the remainder of the experiment. Body weight, food intake, and water intake were measured weekly. Oral glucose tolerance tests (OGTT) were undertaken at 12 weeks, and the offspring were culled at week 14. Female, but not male, AS groups exhibited decreased glucose tolerance compared to Fr. There was an increase in gonadal fat adipocyte size in male offspring from AS and Fr groups compared to CD groups. In female offspring, adipocyte size was increased in the Fr group compared to the CD group. In female, but not male offspring, there was a trend toward increase in Fasn gene expression in AS group compared to the CD group. Maternal AS and Fr also negatively impacted upon female offspring estrus cycles and induced alterations to markers associated with ovulation. In summary, exposure to Ace-k via the maternal diet leads to impaired glucose tolerance and impacts adipocyte size in a sex-specific manner as well as significantly affecting estrus cycles and related gene markers in female offspring. This has implications in terms of providing tailored dietary advice for pregnant women and highlights the potential negative influence of artificial sweetener intake in the context of intergenerational impacts.

Maternal Intake of Either Fructose or the Artificial Sweetener Acesulfame-K Results in Differential and Sex-Specific Alterations in Markers of Skin Inflammation and Wound Healing Responsiveness in Mouse Offspring: A Pilot Study

“…Table A2. Birth, weaning, and cull weight, and glucose/HOMA-IR measures in female and male offspring as previously reported in [14].…”

“…Dermal adipocytes, located within the hypodermis, play several roles in wound repair, including communication with fibroblasts and the inducement of inflammation through recruitment of inflammatory factors and key immune cells such as macrophages [30]. In a previous study by our group using this model, maternal Ace-K and FR-intake increased adipocyte hypertrophy in gonadal adipose tissue, while subcutaneous adipose tissue was found to be hypertrophic in the female offspring of Ace-K-fed mothers [14]. Adipocyte hypertrophy is a common predictor of adipose metabolic disease and is associated with the increased recruitment of pro-inflammatory adipokines [31].…”

“…A recent systematic review demonstrated that maternal exposure to AS during pregnancy is associated with an increased risk of preterm birth and increased birth weight [13]. Previous work by our group has demonstrated that exposure to Ace-K and FR results in maternal glucose intolerance and reduced pregnancy duration, as well as glucose intolerance and adipocyte hypertrophy in female but not male offspring [14][15][16].…”

“…All of the offspring were fed the standard control diet and water ad libitum from weaning until the end of the experiment (11 weeks). The primary outcomes for this cohort related to adipose tissue dysfunction, glucose tolerance and reproductive function have been published previously [14][15][16] and serve to validate the model used. For this pilot study, a sub-cohort of animals was used (n = 6 per sex per dietary group).…”

“…Weights at birth, weaning, and cull, and plasma glucose at cull, and HOMA were recorded and reported in a previous study by our group (Appendix A Table A2) [14].…”