Offspring of prediabetic male mice mated with normal females had impaired glucose tolerance

Males who develop diabetic tendencies by eating too much can pass on an increased susceptibility for the disease to offspring through changes that occur in their sperm, a study carried out in mice suggests.

In research published this week in the Proceedings of the National Academy of Sciences (PNAS), a team of Chinese scientists examined whether overfed male mice could, along with their DNA, also pass on chemically tagged genes to the pups they sired.

There has been growing interest in epigenetics, which deals with how traits change without alterations to genes encoded in the DNA. The tagging of genes with a carbon and three hydrogen atoms, known as a methyl group, is one way that traits are modified. Such methylation typically reduces the amount of protein that cells produce from a tagged gene.

Human studies and animal experiments have indicated that parental diet can act through epigenetic mechanisms and affect their offspring's disease risk.

The PNAS paper demonstrated that such transgenerational inheritance was indeed possible, commented Sanjeev Khosla of the Centre for DNA Fingerprinting and Diagnostics at Hyderabad, who was not involved in the research. A trait acquired by a father — of prediabetes brought on by diet — could, at least in mice, be transmitted to the next generation through changes in the methylation of sperm DNA.

Qing-Yuan Sun of the Institute of Zoology in Beijing and his colleagues fed male mice a high-fat diet and then injected them with a low dose of a drug that affected the insulin-producing cells in the pancreas.

The proof

The mice showed characteristics associated with the development of diabetes, including greater body weight, impaired glucose tolerance and decreased sensitivity to insulin. Mice that received the usual lab diet and were injected with an identical dose of the drug did not develop such prediabetic symptoms.

When prediabetic male mice were mated with normal females, the pups too showed impaired glucose tolerance and decreased insulin sensitivity that worsened as they got older.

Paternal prediabetes was found to have altered the expression of 402 genes in the pups’ insulin-producing pancreatic cells. A large proportion of those genes were associated with insulin and glucose metabolism, Dr. Sun and his colleagues noted. The methylation of many such genes in the pancreatic cells had changed.

The scientists then compared the methylation of genes in sperm from prediabetic mice with those of normal mice. “Of particular interest, we observed that a large proportion of differentially methylated genes identified in sperm overlapped with that of pancreatic islets,” their paper said.

The methylation carried on sperm DNA was typically removed after fertilisation, pointed out Dr. Khosla. “This paper provides strong evidence that something is protecting at least some of this methylation, thereby allowing it to be expressed in the offspring.”

When male progeny of prediabetic fathers were mated with normal female mice, their pups too exhibited impaired glucose tolerance and decreased insulin sensitivity. These second generation mice also had altered methylation patterns.

“These findings may have implications in explaining the prevalence of obesity, type 2 diabetes, and other chronic metabolic diseases,” remarked Dr. Sun and his colleagues in their paper.

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