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Epigenetics and development

By Amos Esty

Corina Lesseur and Carmen Marsit are intrigued by the effects of epigenetics on the development of infants

A close look at the hormone leptin has revealed a connection between methylation of the leptin gene and the development of male infants. The study, which was led by Geisel associate professor of pharmacology and toxicology Carmen Marsit and former graduate student Corina Lesseur, both confirms earlier findings made in studies of mice and offers a potential mechanism to explain differences by sex in environmental effects on development. The research was published in the journal Psychoneuroendocrinology.

Leptin is commonly known for its role in regulating appetite and weight, but it is also involved in fetal development, including the development of the brain. Methylation can prevent expression of the leptin gene (LEP), leading to lower levels of the hormone and potentially affecting development.

Marsit, Lesseur, and colleagues analyzed the methylation of LEP in 444 placental samples and measured the expression of leptin in a subset of those samples. They found that a 10 percent increase in LEP methylation was associated with a 90 percent increase in the risk that an infant would display signs of delayed development, such as low muscle tone and lethargy.

The study is part of Marsit's ongoing work in the field of epigenetics, which focuses on heritable changes in gene expression rather than on the DNA sequence itself. "You're born with some genetics, but that alone doesn't tell you what your outcome is," Marsit explains. "Your genetics are not everything."

Marsit and Lesseur were excited by the findings because they parallel other research in mice that found a similar relationship between leptin and development. "It's really translation," Marsit says of the new study. "It's taking what has been found in a very basic model . . . and showing that in people you can see similar behavior."

Your genetics are not everything.

Lesseur, who earned a medical degree in her native Venezuela before coming to the U.S. to study at Dartmouth, has long been interested in how leptin—and, more generally, obesity—affect early development. She graduated last spring and is now a postdoctoral fellow at the prestigious International Agency for Research on Cancer in Lyon, France.

Although the study involved both male and female infants, the effect of leptin methylation on development was seen only in males. Even more intriguing, Marsit says, is that even in females with high levels of methylation, the leptin gene was still expressed. So the difference wasn't just the result of differences in methylation but of differing effects of methylation.

Lesseur says that many studies have now found sex-specific effects of epigenetic factors, which might help to explain differences in health and disease by sex. "We're looking at a mechanism now," Marsit says. "What we're getting at are potential mechanisms behind these differences. That could start to explain some of these findings that people have seen for years and never understood."

The researchers are continuing this line of research by studying other hormones related to metabolism and how the metabolic status of the mothers affect methylation levels. "What you experience in utero can set you up for very different outcomes," Marsit says.

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Geisel School of Medicine at DartmouthDartmouth-Hitchcock Medical CenterWhite River Junction VAMCNorris Cotton Cancer CenterDartmouth College