Fathers' nutritional legacy

Michael K Skinner

doi:10.1038/467922a

A female can develop a diabetes-like disease due to a high fat content in her father's diet before she was conceived. Epigenetic modifications of the father's sperm DNA might underlie this peculiar observation. See Letter p.963 On page 963 of this issue, Ng et al. 1 report one of the first observations that a father's diet can affect his daughters' health. When the authors fed male rats a highfat diet, the outcome was not surprising: the animals' body weight and body fat increased, and they exhibited glucose intolerance and resistance to the hormone insulin. Unexpectedly, however, although these males' daughters did not show altered body weight or body fat, in adulthood they developed a diabeteslike condition of impaired glucose tolerance and insulin secretion. Ng and colleagues also found that the gene-expression profile of the insulin-secreting pancreatic islet cells obtained from the daughters was abnormal, affecting several gene networks and cellular pathways. This indicates that the fathers' high-fat diets altered the development of their sperm, which then promoted an adult-onset disease in the daughters. Although diet undoubtedly influences many somatic (non-germ) cells and disease states (obesity and diabetes), none of the somatic-cell effects can be transmitted to the next generation 2. For environmental factors such as diet to exert the type of generational effects that Ng et al. describe, the process of sperm formation in the testis and molecular programming of the germ line must be affected. Previous studies 3–6 have shown that genetic abnormalities in sperm caused by chemotherapeutic drugs and environmental factors can be transmitted to the next (F 1) generation. But such genetic effects are random and occur at extremely low frequency — and thus cannot explain the high frequency and reproducibility of Ng and co-workers' observations. An alternative explanation could be that sperm and its precursors undergo alterations in epigenetic programming (this is mediated by molecular factors around DNA that alter gene expression independently of the DNA sequence). This could lead to reproducible traits (phenotypes) at high frequency. Among epigenetic modifications, DNA methylation patterns are predominantly altered in — and transmitted through — the germ line 2. Transgenerational transmission of adult-onset disease affecting the prostate, kidney, testis and mammary gland through alterations in the sperm's DNA-methylation patterns has been documented 2,7. Alterations in the small percentage of DNA-associated histone proteins that sperm retain could also play a part, but the functional role of sperm histones remains unclear 8. Ng and colleagues' finding that a large number of genes have altered expression in HHS Public Access

Fathers' nutritional legacy

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