Non-heritable risk factors for autism spectrum disorder (ASD) and developmental delay (DD) include maternal conditions associated with metabolic dysregulation, most notably pre-pregnancy obesity, excessive gestational weight gain, and complications associated with poor metabolic health, including chronic and gestational forms of hypertension, diabetes and dyslipidemia. Obesity has reached epidemic proportions in the U.S., with more than half of pregnant women overweight or obese. Racial and socioeconomic disparities are profound. The proposed research plan will explore physiological characteristics of maternal obesity that may be involved in neurodevelopmental compromise in a non-human primate model. We will compare inflammatory and metabolic changes to the gestational milieu in obese and normal-weighted mothers, as well as histologic and epigenetic modifications to the placenta and infant brain. Additionally, we will evaluate the effectiveness of two maternal intervention strategies, gestational weight maintenance and daily administration of the pharmacologic agent pravastatin through pregnancy, in reversing the effects of maternal obesity on the maternal and placental environments. Weight management has been recommended by both the Institute of Medicine and the American Congress of Obstetricians and Gynecologists for management of obesity in pregnancy, and the pharmacological properties of pravastatin provide biological plausibility for its use in preventing the systemic, placental and fetal consequences of maternal obesity. This proposal strives to utilize fully the unique resources inherent in the third trimester rhesus monkey model to address this serious clinical problem with substantial public health impact. Our interdisciplinary team weaves the expertise of investigators with extensive collaborative experience in maternal health and fetal development, reproductive physiology, nutrition, immunology, epigenetics, metabolomics, lipomics, biostatistics and neurodevelopment in both humans and non-human primates.
The specific aims of the project will: 1) explore the physiologic effects of maternal obesity that underlie neurodevelopmental impairment and 2) determine whether two interventional strategies will prevent the effects of maternal obesity. The outcome of these studies will have direct translational value by informing women and their health providers of the risks of maternal obesity to the developing brain and will provide information on preventive options to help obese women and their health care providers lessen risk for their babies.
The proposed research plan will explore physiological characteristics of maternal obesity that may be involved in neurodevelopmental compromise in a non-human primate model. We will compare metabolic and inflammatory changes in the fetal environment as well as modifications to the placenta and brain in offspring born to obese and healthy-weighted mothers. Additionally, we will evaluate the effectiveness of two maternal intervention strategies.
| Walker, Cheryl K; VandeVoort, Catherine A; Li, Chin-Shang et al. (2018) Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta). Dev Psychobiol 60:629-638 |
