Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice

Tomoyo Kawakubo-Yasukochi, Masahiko Morioka, Kenji Ohe, Atsushi Yasukochi, Yasuhiko Ozaki, Mai Hazekawa, Takuya Nishinakagawa, Kazuhiko Ono, Seiji Nakamura, Manabu Nakashima

Research output: Contribution to journalArticle

Abstract

Gestational nutrition is widely recognized to affect an offspring's future risk of lifestyle-related diseases, suggesting the involvement of epigenetic mechanisms. As folic acid (FA) is a nutrient essential for modulating DNA methylation, we sought to determine how maternal FA intake during early pregnancy might influence tumor sensitivity in an offspring. Dams were maintained on a FA-depleted (FA(-)) or normal (2 mg FA/kg; FA(+)) diet from 2 to 3 days before mating to 7 days post-conception, and their offspring were challenged with chemical tumorigenesis using 7,12-dimethylbenz[a)anthracene and phorbol 12-myristate 13-acetate for skin and 4-nitroquinoline N-oxide for tongue. In both squamous tissues, tumorigenesis was more progressive in the offspring from FA(-) than FA(+) dams. Notably, in the skin of FA(-) offspring, the expression and activity of cylindromatosis (Cyld) were decreased due to the altered DNA methylation status in its promoter region, which contributed to increased tumorigenesis coupled with inflammation in the FA(-) offspring. Thus, we conclude that maternal FA insufficiency during early pregnancy is able to promote neoplasm progression in the offspring through modulating DNA methylation, such as Cyld. Moreover, we propose, for the first time, "innate" utero nutrition as the third cause of tumorigenesis besides the known causes - hereditary predisposition and acquired environmental factors.

Original languageEnglish
JournalJournal of Developmental Origins of Health and Disease
DOIs
Publication statusPublished - Jan 1 2019

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Folic Acid
Mothers
Pregnancy
Neoplasms
Carcinogenesis
DNA Methylation
4-Nitroquinoline-1-oxide
Skin
Tongue
Genetic Promoter Regions
Epigenomics
Life Style
Acetates
Diet
Inflammation
Food

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)

Cite this

Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice. / Kawakubo-Yasukochi, Tomoyo; Morioka, Masahiko; Ohe, Kenji; Yasukochi, Atsushi; Ozaki, Yasuhiko; Hazekawa, Mai; Nishinakagawa, Takuya; Ono, Kazuhiko; Nakamura, Seiji; Nakashima, Manabu.

In: Journal of Developmental Origins of Health and Disease, 01.01.2019.

Research output: Contribution to journalArticle

Kawakubo-Yasukochi, Tomoyo ; Morioka, Masahiko ; Ohe, Kenji ; Yasukochi, Atsushi ; Ozaki, Yasuhiko ; Hazekawa, Mai ; Nishinakagawa, Takuya ; Ono, Kazuhiko ; Nakamura, Seiji ; Nakashima, Manabu. / Maternal folic acid depletion during early pregnancy increases sensitivity to squamous tumor formation in the offspring in mice. In: Journal of Developmental Origins of Health and Disease. 2019.
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