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Methylation Links Prenatal Famine to Obesity, Metabolic Features in Adulthood

NEW YORK (GenomeWeb) – Prenatal adversity such as exposure to famine in utero can leave long term marks on an individual's genome into adulthood, new research suggests, leading to shifts in DNA methylation that can be detected in adulthood.

Researchers from the Netherlands and the US used array-based DNA methylation profiling to look at interactions between weight, blood metabolic features, and in utero famine exposure in hundreds of individuals who were or were not exposed to prenatal famine. Their results, reported today in Science Advances, highlighted methylation changes in and around genes involved in everything from energy metabolism to pancreatic cell function and lipid metabolism.

"Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health," senior author Bastiaan Heijmans, a molecular epidemiology researcher at the Leiden University Medical Center, and his colleagues wrote, noting that the "specific mechanism awaits elucidation."

Past research suggests individuals who experienced prenatal famine are more prone to adult conditions ranging from schizophrenia to obesity or type 2 diabetes, the team noted. In the Dutch Hunger Winter Families Study — a study of individuals born to mothers who were pregnant during a famine in the western Netherlands at the tail end of World War II — famine in utero was previously linked to increased body mass index, along with riskier blood serum triglyceride, fasting blood glucose, and low-density lipoprotein cholesterol profiles. The famine event is thought to have affected more than 2,400 individuals who were born to underfed mothers-to-be between February 1945 and March 1946.

Heijmans and his colleagues verified the BMI, fasting blood glucose, and serum triglyceride associations with prenatal famine for the first stage of their new study, which focused on 442 Dutch Hunger Winter individuals.

In an effort to explore potential methylation effects of the famine, the team used Illumina Infinium Human Methylation 450k BeadChip arrays to profile methylation marks at hundreds of thousands of CpG sites in the genomes of 348 of the prenatal famine-exposed individuals and 463 non-exposed controls.

The researchers' search for methylation shifts associated with prenatal famine exposure and related traits such as BMI, serum triglyceride levels, or blood glucose concentrations uncovered prenatal famine-associated methylation profiles that appeared to coincide with BMI and triglyceride levels, but were not associated with blood glucose patterns.

Among them: BMI-related DNA methylation near the energy metabolism gene PIM3 and methylated CpGs with ties to serum triglycerides at half a dozen sites in and around genes such as TXNIP and ABCG1 involved in pancreatic beta cell function and lipid metabolism, respectively.

The team noted that altered methylation at the BMI-associated site neighboring PIM3 was linked to altered expression of that cell growth and energy metabolism-related gene in available data for more than 2,000 whole blood samples profiled in the past.

Still other methylation marks shifted depending on the period of gestation in which individuals experienced the in-utero famine. For example, the researchers reported that early gestational exposure to famine tracked with methylation marks near the glycolysis-related gene PFKFB3 and a gene called METTL8 that is implicated in adipogenesis, or fat cell maturation.

Together, they reported, these associations appeared to explain more than 13 percent of the prenatal famine-linked BMI change and some 80 percent of the serum triglyceride effect described in individuals exposed to this form of prenatal adversity.

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