Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
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Padmanabhan, N., Rakoczy, J., Kondratowicz, M., Menelaou, K., Blake, G., & Watson, E. (2017). Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism. Environmental Epigenetics, 3 (4)https://doi.org/10.1093/eep/dvx014
The exposure to adverse environmental conditions (e.g., poor nutrition) may lead to increased disease risk in an individual and their descendants. In some cases, the results may be sexually dimorphic. A range of phenotypes has been associated with deficiency in or defective metabolism of the vitamin folate. However, the molecular mechanism linking folate metabolism to development is still not well defined nor is it clear whether phenotypes are sex-specific. The enzyme methionine synthase reductase (MTRR) is required for the progression of folate metabolism and the utilization of methyl groups from the folate cycle. Previously, we showed that the hypomorphic Mtrrgt mutation in mice results in metabolic disruption, epigenetic instability, and a wide spectrum of developmental phenotypes (e.g., growth defects, congenital malformations) at midgestation that appear in subsequent wildtype generations. This transgenerational effect only occurs through the maternal lineage. Here, we explore whether the phenotypes that result from either intrinsic or ancestral Mtrr deficiency are sexually dimorphic. We found that no sexual dimorphism is apparent in either situation when the phenotypes were broadly or specifically defined. However, when we focused on the group of phenotypically normal conceptuses derived from maternal grandparental Mtrr deficiency, we observed an apparent increase in placental efficiency in each subsequent generation leading to F4 generation female embryos that weigh more than controls. These data suggest that ancestral abnormal folate metabolism may lead to male grandprogeny that are less able to adapt or female grandprogeny that are programmed to become more sensitive to folate availability in subsequent generations.
folic acid, MTRR, sexual dimorphism, developmental phenotypes, intrauterine growth restriction, congenital malformations, placenta, transgenerational epigenetic inheritance
The following support was given: a Centre for Trophoblast Research (CTR) studentship to N.P., a Royal Society Newton International Fellowship to J.R., a Newnham College (Cambridge) studentship to K.M, and a Wellcome Trust 4-year PhD studentship in Developmental Mechanisms to G.E.T.B. This work was funded by a CTR Next Generation Fellowship, a Lister Research Prize, and an Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge joint research grant (to E.D.W.).
Lister Institute of Preventive Medicine ()
Royal Society (NF150004)
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External DOI: https://doi.org/10.1093/eep/dvx014
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267334