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Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism

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...

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Autores principales: Padmanabhan, Nisha, Rakoczy, Joanna, Kondratowicz, Monika, Menelaou, Katerina, Blake, Georgina E T, Watson, Erica D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804557/
https://www.ncbi.nlm.nih.gov/pubmed/29492317
http://dx.doi.org/10.1093/eep/dvx014
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author Padmanabhan, Nisha
Rakoczy, Joanna
Kondratowicz, Monika
Menelaou, Katerina
Blake, Georgina E T
Watson, Erica D
author_facet Padmanabhan, Nisha
Rakoczy, Joanna
Kondratowicz, Monika
Menelaou, Katerina
Blake, Georgina E T
Watson, Erica D
author_sort Padmanabhan, Nisha
collection PubMed
description 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 Mtrr(gt) 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 wild-type 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.
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spelling pubmed-58045572018-02-28 Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism Padmanabhan, Nisha Rakoczy, Joanna Kondratowicz, Monika Menelaou, Katerina Blake, Georgina E T Watson, Erica D Environ Epigenet Research Article 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 Mtrr(gt) 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 wild-type 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. Oxford University Press 2017-11-03 /pmc/articles/PMC5804557/ /pubmed/29492317 http://dx.doi.org/10.1093/eep/dvx014 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Padmanabhan, Nisha
Rakoczy, Joanna
Kondratowicz, Monika
Menelaou, Katerina
Blake, Georgina E T
Watson, Erica D
Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title_full Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title_fullStr Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title_full_unstemmed Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title_short Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
title_sort multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804557/
https://www.ncbi.nlm.nih.gov/pubmed/29492317
http://dx.doi.org/10.1093/eep/dvx014
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