PERINATAL EXPOSURE TO HIGH DIETARY AGES DELAYS PUBERTY ONSET AND DISRUPTS FOLLICULOGENESIS IN FEMALE OFFSPRING

Nutrition is an important source of exogenous advanced glycation end-products (AGEs) where thermally processed foods present in western-style diets contain large amounts of these pro-inflammatory molecules. Maternal nutrition and the intrauterine environment are important in determining susceptibility to reproductive and metabolic disturbances. The objective of this study was to determine whether perinatal exposure to high amounts of dietary AGEs affect metabolic and the reproductive parameters in female mice offspring. Animal experiments in a university setting. 7 week old female CD1 mice were placed on either a diet low (L-AGE) or high (H-AGE) in AGEs for 2 weeks before mating and then for additional 6 weeks throughout pregnancy and lactation. Offspring from L-AGE dams (n=10) and H-AGE dams (n=13) were all weaned onto the L-AGE diet and studied through 16 weeks of age. Offspring were counted and weighed at birth then weekly. Body weight, growth curve, pubertal onset (age at vaginal opening), estrus cyclicity (vaginal smear), serum levels of anti-Mullerian hormone (AMH), leptin and adiponectin as well as insulin tolerance test (ITT) and glucose tolerance test (GTT) were performed. Ovaries were harvested for follicular count and gene expression by RT-PCR. Data were reported as mean ± SEM. For GTT and ITT, the total area under the curve (AUC) for 120 minutes for glucose concentrations in mg/dL was calculated. Mann-Whitney U test and repeated measures ANOVA were performed as appropriate. Pups exposed to perinatal H-AGE diet had significantly lower body weight at birth compared to pups exposed to perinatal L-AGE diet (1.38 ± 0.1 vs. 1.58 ± 0.16 grams, p<0.05; respectively). Adult offspring exposed to perinatal H-AGE diet exhibited delayed growth and lower serum levels of leptin and AMH (p<0.05 for all). There was no significant difference in AUC for GTT (p=0.7) or ITT (p=0.2) between both groups. Perinatal exposure to H-AGE diet affected the reproductive potential in the adult female offspring by exhibiting delayed vaginal opening and irregular estrus cycles by spending less time in the proestrus phase and more time in the metestrus phase (p=0.04). Adult offspring exposed to perinatal H-AGE diet had significantly fewer corpora lutea (CL) in their ovarian sections, exhibited arrested folliculogenesis with most follicles in the secondary follicle stage, and had significantly lower ovarian mRNA expression levels of Amh (p=0.005), Amhr2 (p=0.02), and Cyp19a1 (p=0.03) compared to adult offspring exposed to perinatal L-AGE diet. These results indicate that perinatal exposure to a diet elevated in AGEs causes deficits in perinatal growth, pubertal onset, and reproductive organ development in female mice. Whether these findings translate to humans remains to be determined in future studies.