PROJECT SUMMARY/ABSTRACT The broad, long-term goal of this novel training and research program is to identify whether in utero circadian- related exposures, such as circadian disruption from night shift work, is associated with epigenetic alterations to imprinted genes and increased susceptibility to developing diabetes later in life. Type 2 diabetes (T2D) is a metabolic condition that affects more than 9% of the U.S. population, with more than 100 million Americans with diabetes or prediabetes, characterized by elevated blood sugar; one of the serious complications of T2D is vision loss and blindness due to diabetic retinopathy. While large epidemiological studies have found that shift work, an occupational form of circadian disruption, increases the risk of developing T2D, the influence of in utero circadian disruption on diabetes susceptibility has yet to be studied. Circadian misalignment or shift work, a proxy for light exposure out of sync with the internal timekeeping system, can cause altered hormonal signaling, dyslipidemia, and metabolic disorders. This poses a substantial risk to public health, given that more than 15% of the U.S. work force works outside of the traditional hours of 6AM-6PM, with more than 9% of working women employed in an evening or night shift position. The placenta, as master regulator of development, mediates the maternal and fetal environments to direct fetal growth. Within the placenta, imprinted genes are nutrient sensors that are extremely sensitive to environmental exposures, promoting or inhibiting fetal growth and exerting long-lasting effects on metabolic health. Pregnancy is a metabolically challenging state, and because circadian disruption alters metabolism and nutrient handling, circadian disruption may affect imprinted genes. Early-life exposures that influence developmental imprinting and metabolic trajectories can later contribute to chronic disease, such as diabetes. Therefore, we hypothesize that in utero circadian disruption increases susceptibility to diabetes and diabetic retinopathy by epigenetically altering imprinted genes. To examine this hypothesis, we propose two independent but highly complementary aims: (1) in a human birth cohort, we will investigate associations between circadian-related exposures and placental imprinted gene methylation and expression and if these altered molecular features are associated with newborn birth weight and (2) test whether in utero circadian disruption affects diabetes susceptibility and metabolism, epigenetic patterning, and visual outcomes in mice. The impact of this research is in identifying epigenetic and metabolic mechanisms underlying health effects of circadian disruption, which can be used to inform targeted prevention or treatment efforts.

PROJECT NARRATIVE Type 2 diabetes (T2D) is a metabolic condition that affects more than 9% of the U.S. population, more than 15% of the U.S. work force works outside of the traditional hours of 6AM-6PM, and circadian misalignment or shift work can contribute to metabolic disorders. The purpose of this study is to investigate whether in utero circadian-related exposures are associated with epigenetic changes genes critical in development and with increased susceptibility to diabetes and diabetic retinopathy later in life. This research will provide novel insight into the mechanistic influences of circadian rhythms on human health and development.