SAT-201 Diet-Induced Obesity and Prenatal Androgen Exposure Increase Transgenerational Susceptibility to Metabolic Dysfunction in Male Adult Offspring

Abstract

It is suggested that intrauterine environment play a role in the development of PCOS, and that first generation (F1) male offspring of the prenatal androgenized (PNA)-mice model exhibit metabolic dysfunction such as increased body weight and insulin resistance. Whether prenatal androgenisation, with or without diet-induced obesity, cause transgenerational effects on the male offspring through the paternal lineage have not previously been investigated. Therefore, we investigated how maternal high-fat high sucrose (HFHS) diet-induced obesity and in utero exposure to dihydrotestosterone (DHT) during embryonic day (E) 16.5-E18.5 (to create a PNA model) affect the metabolic phenotype of first, second and third (F1 to F3) generation male offspring. F1 and F2 male offspring were mated with females fed control diet (CD) to follow the paternal lineage. We found that F1 males born from mothers exposed to DHT and fed CD have longer anogenital distance (AGD), demonstrating androgen exposure in utero with no effect on F2 and F3 male offspring. F1 males from DHT exposed mothers with diet-induced obesity weigh more compared to F1 males from lean or obese mothers, with no differences in F2 and F3 male offspring. However, the F3 males from DHT exposed great-grand-mothers with diet-induced obesity have higher fat mass compared to other groups indicating a transgenerational effect. Moreover, F1 males from mothers with diet-induced obesity were insulin resistant with increased HOMA-IR and F3 male offspring from the same group exhibited impaired glucose tolerance as measured with oral glucose tolerance test. At night, when mice are more active, had F1 males from DHT exposed mothers fed CD or diet-induced obesity, and from vehicle treated mothers with diet-induced obesity, lower energy expenditure (EE) and respiratory exchange ratio (RER) measurement. Of note, the metabolic phenotype was exaggerated in F3 male offspring, with significantly lower EE, RER and total activity both during day and night time. These results likely reflect the higher body weight and increased fat mass in F1 and F3 male offspring. Taken together, these results demonstrate that diet-induced obesity before and during pregnancy together with androgen exposure cause a transgenerational effect on metabolic features in male offspring following the male germline.