- Treviño, Lindsey S;
- Dong, Jianrong;
- Kaushal, Ahkilesh;
- Katz, Tiffany A;
- Jangid, Rahul Kumar;
- Robertson, Matthew J;
- Grimm, Sandra L;
- Ambati, Chandra Shekar R;
- Putluri, Vasanta;
- Cox, Aaron R;
- Kim, Kang Ho;
- May, Thaddeus D;
- Gallo, Morgan R;
- Moore, David D;
- Hartig, Sean M;
- Foulds, Charles E;
- Putluri, Nagireddy;
- Coarfa, Cristian;
- Walker, Cheryl Lyn
Our early-life environment has a profound influence on developing organs that impacts metabolic function and determines disease susceptibility across the life-course. 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. These findings demonstrate the importance of epigenome:environment interactions, which early in life accelerate epigenomic aging, and later in adulthood unlock metabolically restricted epigenetic reprogramming to drive metabolic dysfunction.