Project Summary / Abstract
Recent research has established that epigenetic information inherited from the father has an impact on the
physiology of his children, and that this information varies depending on environmental exposure and
metabolic status of the father. There is also now a substantial body of evidence that paternally inherited
epigenetic information may contribute to childhood obesity and other significant public health problems,
depending on paternal diet. Mechanistic insights are still scarce, however, and it remains unclear which dietary
factors may be able to modify epigenetic programming of sperm in a way that affects metabolism in the
offspring. Addressing this important problem, this project will test the central hypothesis that reduced paternal
metabolic nicotinamide adenine dinucleotide (NAD+) levels result in heritable sperm-borne epimodifications
that modulate offspring metabolism. NAD+ is a central molecule involved in energy metabolism and it also
serves as a substrate of epigenetic regulators such as sirtuins, including histone deacetylases, and poly(ADP-
ribose) polymerases involved in sperm epigenetic programming and the regulation of energy metabolism.
Vitamin B3 (niacin, nicotinamide) is the main dietary precursor of NAD+ synthesis in humans. This project
proposes to utilize an innovative transgenic mouse model of acquired niacin deficiency (ANDY) that permits for
the first time to study effects of low NAD+ levels, as seen in parts of the human population, in a laboratory
animal. Our preliminary data show that suboptimal levels of NAD+ in ANDY males resulted in progeny with
smaller body size, altered insulin sensitivity, and altered carbohydrate and lipid metabolism, which indicates
that the micronutrient niacin may be of previously unrecognized importance for epigenetic programming of
sperm. The objectives of the proposed work are (1) to characterize the metabolism of NAD+-deficient males
and their F1 progeny, where we expect to identify heritable adaptations of energy metabolism that depend on
paternal nutritional status, (2) to test the hypothesis that low NAD+ levels in males result in elevated sperm
histone acetylation and differential sperm histone positioning, which are expected to include metabolic genes
whose regulation is affected in F1 progeny, and (3) to determine the nature and extent of altered gene
expression profiles in F1 progeny. We further propose to determine the extent to which pharmacological
intervention, e.g. supplementation therapy, can prevent such changes.
We expect that DNA methylation levels will be altered in gene loci in offspring as a consequence of
abnormal sperm histone acetylation in NAD+-deficient sires. In summary, the proposed studies are expected to
establish NAD+ as a molecular link between paternal nutrition and metabolic state, sperm chromatin-mediated
epigenetic inheritance, and the regulation of offspring metabolism, including metabolic disease. The expected
results should be relevant for the future development of avoidance and periconceptional nutritional
supplementation strategies for men with the goal to maximize chances that children are born healthy.
