02.05.07

Transgenerational Epigenetic Modification with Nutritional Supplementation

Posted in commentary, environmental alterations, methylation, research articles at 12:01 am by Trevor

Reader Israel Barrantes recently commented on what he considered to be the “most memorable epigenetic moment of the year” for 2006, which was a groundbreaking paper by Cropley et al. that appeared in Proceedings of the National Academy of Science in November (1). I couldn’t argue with that nomination, so I decided to write about the paper to kick off the week of Just Science.

The paper, titled “Germ-line epigenetic modification of the murine A^vy allele by nutritional supplementation,” uses a mutant mouse strain known as viable yellow agouti, or A^vy. As shown previously, mice carrying the viable yellow agouti allele exhibit yellow fur, obesity, type II diabetes, and predisposition to tumors. Those that carry one A^vy allele and one normal allele (referred to as A^vy/a) exhibit varying degrees of the A^vy phenotype, ranging from fully yellow and obese to lean and fully agouti. In previous studies, it has been shown that pregnant A^vy females that receive a diet supplementation containing folate, choline, betaine, and vitamin B12 from two weeks prior to gestation to birth produce A^vy offspring that are shifted toward the agouti phenotype. This shift was also highly correlated with an increase in cytosine methylation. In other words, nutritional supplementation during gestation seemed to cause an epigenetic alteration in phenotypes of offspring.

The picture below shows samples of the varying degrees of the yellow to agouti mice and their corresponding scores. The scores are used in this study as a quantitative way of determining the degree of tranmission of the A^vy allele, comparing results when the mutant allele is contributed by the male (sire) or female (dam). The authors found that the previously mentioned shift to the agouti phenotype occurred only when the A^vy allele was contributed by the sire, which provides evidence that the male germ line may play a role in transgenerational epigenetic alterations.

The authors then used this evidence of male-specific transmission of the A^vy allele to propose that the altered phenotype could be passed to a subsequent generation without further diet supplementation. Further, they wanted to determine if diet supplementation was required throughout gestation to induce the epigenetic alteration. The authors proposed that supplementation was only critical during the period encompassing the point at which primordial germ cells differentiate and reset epigenetic marks. Therefore, the period of supplementation for pregnant a/a dams mated to A^vy/a sires was set at E8.5 (embryonic day 8.5, or 8.5 days past conception) to E15.5. (Gestation in mice is about 21 days.) Interestingly, this midgestation exposure was very similar to the timepoint used in another study identifying a transgenerational epigenetic effect in mammals (2).

The authors found that when the F1 generation whose mothers received diet supplementation during gestation were mated, the F2 generation exhibited a similar shift in color score as the F1 generation. It is worth emphasizing that the F2 generation embryos were not directly exposed in utero to diet supplementation as the F1 generation embryos were, but the germ line of F2 animals was affected by the diet supplementation given to the previous generation.

This study was groundbreaking in that it provides the first direct evidence of a mechanism in a transgenerational, epigenetic alteration. However, it would be interesting to see if the shift to the agouti phenotype would continue into the F3 and F4 generations, as would be expected if the epigenetic germ line was permanently reprogrammed.

References:

1. Cropley JE, Suter CM, Beckman KB, Martin DIK.
2006. Germ-line epigenetic modification of the murine A^vy allele by nutritional supplementation. Proc Natl Acad Sci USA 103:17308-17312.
doi:10.1073/pnas.0607090103
2. Anway MD, Cupp AS, Uzumcu M, Skinner MK. 2005. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science 308:1466-1469.
doi:10.1126/science.1108190