In a complex but interesting study, Padmanabhan et al. created transgenic mice with impaired folate metabolism because of heterozygosity for a knock-down allele for Mtrr (encoding methionine synthase reductase, which is necessary in mammals for the activation of methionine synthase). They then interbred these mice with wild-type controls through several generations and evaluated their wild-type progeny and grand-progeny for growth retardation and congenital malformations. They observed that Mtrr deficiency in either maternal grandparent appeared to have deleterious effects, and divided these into two distinct types: 1) growth defects, hypothesized to be due to an atypical uterine environment in the wild-type female progeny of the Mtrr-deficient mouse, causing intrauterine growth retardation in the subsequent generation, and 2) congenital malformations, the increased risk of which persisted for at least four wild-type generations, attributed to epigenetic inheritance via the germline. In support of the inherited epigenetic effects, the authors noted the presence of extensive epigenetic instability in the placentas of the wild-type grand-progeny.
Assuming that these findings can be extrapolated to human populations, and that a genetic perturbation in folate metabolism can be used as a model for dietary folate deficiency, this study addresses fascinating questions about the transgenerational impact of environmental factors via epigenetic mechanisms, which are as yet incompletely understood.
Padmanabhan N et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell. 2013 Sep 26;155(1):81-93.
Posted by: Alina Levtova, MD