Developmental Origin of Health and Disease (DOHaD) and the circadian clock: epigenetics pre- and early postnatal circadian rhythm disturbance in mice

摘要

Background: The mammalian circadian clock imposes near 24-hour (circa-dies) rhythmicity on physiology, metabolism and behavior, and allows organisms to anticipate daily recurring environmental changes (i.e. light-dark cycle). To keep pace with the day-night cycle, the clock is daily synchronized by light. Epidemiological and animal studies have associated chronic circadian rhythm disturbance (CRD) in adults (as encountered during shift work and jet lag) with a variety of diseases, including cancer, metabolic syndrome and cardiovascular disease. According to the Developmental Origins of Health and Disease (DOHaD) theory, fetal programming permanently shapes the body's structure, function, and metabolism. In this scenario gestational environmental factors (e.g. nutritional insults), interacting with the genes, contribute to later life disease. Using an animal experimental approach, we have investigated whether gestational CRD leaves epigenetic marks on the fetal genome that remain present throughout life and that touch upon circadian performance, physiology and metabolism, and as a direct consequence, affect the vulnerability to later-life disease. Methods: Pregnant C57BL6 mice were subjected to either a constant 12hr light: 12-hr dark (LD 12:12) cycle (control) or to repeated (i.e. once every 3 days) 8-hr phase advanced (east-bound jet lag, EJL) or delayed (westbound jet lag, WJL) LD 12:12 cycles. At the day of delivery, dams and their offspring were kept again under a constant light-dark cycle. Offspring was followed in time for the occurrence of health effects. Results: In the first weeks after birth, both EJL and WJL offspring showed a reduced weight gain, resulting in a life-long reduction in body weight. At the age of 3 months, circadian performance was assessed in male offspring. EJL offspring displayed an faster circadian clock. Furthermore, EJL offspring adjusted more rapidly to an 8 hr phase advance, while, oppositely, WJL offspring took less time to overcome an 8 hr phase delay. Strikingly, analysis of the bones (i.e. femur) of 6-month-old male offspring by microcomputed tomography revealed reduced tra-becular and cortical bone mass in EJL offspring. Especially in the diaphysis, endocortical volume, perimeter and moment of inertia (a proxy for bone strength), were significantly reduced, whereas cortical thickness was elevated. Analysis of the cardiovascular system of 9-month-old female offspring revealed left ventricle hypertrophy in the EJL offspring. Epigenetic analysis of the livers of control, EJL and WJL offspring revealed markedly differentially DNA methylation patterns in the livers of EJL and WBL offspring, as compared to control offspring. Conclusions: We have shown that circadian rhythm disturbance in pregnant female mice by a chronic jet lag affects the development of the circadian system and predisposes to health effects in adult life.