Epigenetic markers on DNA determine the pace and timing of protein production, and are thus one of the important influences on cell and tissue function. Cells adjust their epigenetic programs in response to the surrounding environment, but alterations can be lasting. It is thought that environmental influences on epigenetic programming of cellular behavior that occur in childhood set the stage for faster or slower onset of metabolic dysfunction in later life, once cell and tissue damage starts to accumulate. Researchers here provide a proof of principle of this process in rats.

Environmental exposures during early life exert a profound influence on developing organs, which can affect health across the life-course, and even transgenerationally. The adverse health impact of these exposures is thought to be mediated by reprogramming of normal physiologic responses, and forms the basis of the developmental origins of health and disease (DOHaD) paradigm. Fetal over- or under-nutrition has been linked to metabolic dysfunction in adulthood and increased risk for metabolic diseases including obesity, diabetes, and metabolic syndrome. Besides nutritional stressors, early-life exposures to environmental chemicals, including endocrine-disrupting chemicals (EDCs), can influence health and disease susceptibility across the life-course.

EDCs are defined as exogenous chemicals, or mixture of chemicals, that interfere with hormone action and many have been shown to impact metabolic function, and increase disease risk in metabolic organs such as the liver. Recently, the epigenetic machinery has emerged as a target for EDCs and other environmental exposures. When this machinery is perturbed early in life, the resulting epigenetic alterations can persist long after the initial environmental insult (often referred to as developmental reprogramming). Accordingly, research on the causes of the epidemic rise in metabolic diseases has expanded beyond genetics, over-nutrition, and energy expenditure to include the role of early-life EDC exposures. However, little is known about what determines vulnerability to early-life exposures, or specific targets and pathways linking developmental reprogramming by early-life exposures to later-life metabolic dysfunction.

Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid, and one-carbon metabolism.

Link: https://doi.org/10.1038/s41467-020-15847-z