While we hope that any silly errors and childish pranks of our formative years don´t follow us into adulthood, it now seems that certain experiences during early development are indeed carried into adulthood without our knowledge, where an activating trigger can lead to trouble and strife!
Specifically, exposure to any number of environmental stressors during early development can impact later metabolic function and increase disease risk in organs such as the liver. While recent evidence suggests the involvement of the epigenetic machinery, and we know that epigenetic perturbation during development can induce epigenetic alterations that persist into adulthood, we understand little about the specific targets and pathways linking developmental “insults” to metabolic dysfunction in later life.
In a significant step forward, the always sensible team of researchers led by Cristian Coarfa and Cheryl Lyn Walker (Baylor College of Medicine, Houston, TX, USA) have now demonstrated that neonatal mice exposed to a stressor – the prototypical endocrine disruptor (bisphenol A – BPA) – undergo early epigenetic aging in the liver that can prompt metabolic dysfunction in adulthood following a change in diet.
So how did the perfectly behaved Treviño and colleagues discover this mischievous epigenetic mechanism?
- Short term exposure of rats to “safe” doses of BPA during early development initially prompts minimal phenotypic impact in young adult animals
- Placing the exposed adult animals on a Western-style diet (high in fat, fructose, and cholesterol) increases liver size and reprograms lipid metabolism in male animals
- To understand the mechanism at play, the authors studied histone modification patterns in the liver via ChIP-seq for permissive (H3K4me1, H3K4me3, and H3K27ac) and repressive histone modifications (H3K27me3)
- Alterations to histone modification profiles at promoters and enhancers suggest that BPA-exposure “hijacks” the epigenomic plasticity of the neonatal liver and prompts the accelerated development of an adult histone modification pattern (early epigenetic aging) that persists into adulthood
- RNA-seq analysis explored how early epigenetic aging impacted later gene expression and highlighted the altered expression of genes related to metabolism-associated pathways
- Importantly, Egr1, a transcription factor that responds to diet and stress and controls liver metabolism genes, is highly overexpressed in the liver of BPA-exposed animals fed on a Western-diet
- While the Erg1 regulatory regions suffer from BPA-induced histone modifications, the expression of Egr1 (among others) only increases following exposure to a Western-style diet
- Interestingly, over 60% of affected genes in the liver of BPA-exposed animals fed on a Western-diet are EGR1 targets
- Of the 431 genes differentially expressed after being fed a Western-style diet, 206 suffer from early epigenetic aging, with 158/206 being Egr1 targets
- Metabolomic profiling finally revealed that the production of metabolites related to cholesterol, lipid, and one-carbon pathways significantly contributes to the metabolic disruption in the liver of BPA-exposed animals fed a Western-diet
Overall, the model supported by this study suggests that environmental stressors, such as BPA, prematurely age the liver epigenome during neonatal periods and, when exposed to an unhealthy diet during adulthood, create transcriptional and metabolic alterations.
Co-senior author Cheryl Lyn Walker shares, “We found that even brief exposure to certain chemicals while the liver is developing prematurely aged the liver epigenome. Exposure to these endocrine-disrupting chemicals (EDCs) caused the young liver to acquire an adult epigenomic signature. However, this premature aging of the epigenome did not have an effect on health until later in life and after exposure to a high-fat diet. In a healthy liver we see the epigenome go through a normal aging process. In our study, after exposure to an EDC, we were able to see this process accelerated. So a 6-day old rat had the same epigenome we would normally see in an adult rat. The effect of this change on metabolic function wasn’t immediate; instead, it was like a ticking time bomb, which was only ignited when we switched the animals to a Western-style diet, high in fat, sugar and cholesterol. This study shows us how environmental exposures affect our health, and disease susceptibility, both early and later in life. It also shows us that some people may be more adversely affected by a high-fat diet as adults than others due to environmental exposures they experienced earlier in their life.”
For more on how some experiences during early development can influence epigenetic profiles and impact health later in life, see Nature Communications, May 2020.