Raising gestational choline intake alters gene expression in DMBA‐evoked mammary tumors and prolongs survival

Abstract

Choline is an essential nutrient that serves as a donor of metabolic methyl groups used during gestation to establish the epigenetic DNA methylation patterns that modulate tissue-specific gene expression. Because the mammary gland begins its development prenatally, we hypothesized that choline availability in utero may affect the gland's susceptibility to cancer. During gestational days 11-17, pregnant rats were fed a control, choline-supplemented, or choline-deficient diet (8, 36, and 0 mmol/kg of choline, respectively). On postnatal day 65, the female offspring received 25 mg/kg of a carcinogen 7,12-dimethylbenz[alpha]anthracene. Approximately 70% of the rats developed mammary adenocarcinomas; prenatal diet did not affect tumor latency, incidence, size, and multiplicity. Tumor growth rate was inversely related to choline content in the prenatal diet, resulting in 50% longer survival until euthanasia, determined by tumor size, of the prenatally choline-supplemented rats compared with the prenatally choline-deficient rats. This was accompanied by distinct expression patterns of approximately 70 genes in tumors derived from the three dietary groups. Tumors from the prenatally choline-supplemented rats overexpressed genes that confer favorable prognosis in human cancers (Klf6, Klf9, Nid2, Ntn4, Per1, and Txnip) and underexpressed those associated with aggressive disease (Bcar3, Cldn12, Csf1, Jag1, Lgals3, Lypd3, Nme1, Ptges2, Ptgs1, and Smarcb1). DNA methylation within the tumor suppressor gene, stratifin (Sfn, 14-3-3sigma), was proportional to the prenatal choline supply and correlated inversely with the expression of its mRNA and protein in tumors, suggesting that an epigenetic mechanism may underlie the altered molecular phenotype and tumor growth. Our results suggest a role for adequate maternal choline nutrition during pregnancy in prevention/alleviation of breast cancer in daughters.

Gestational Choline Supply Regulates Methylation of Histone H3, Expression of Histone Methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA Methylation of Their Genes in Rat Fetal Liver and Brain

“…In addition to the well documented role of the adequate supply of choline in utero for the development and functioning of the adult rat brain (see above), we recently found that high E11-17 choline intake slows the growth of mammary tumors evoked by treatment with a carcinogen 7,12-dimethylbenz[␣]anthracene in adulthood, and alters gene expression, and DNA methylation patterns within these tumors (82). These data pointed to the heretofore unanticipated role of adequate choline nutrition during pregnancy in prevention and/or amelioration of breast cancer in adult offspring.…”

The Impact of Traditional Food and Lifestyle Behavior on Epigenetic Burden of Chronic Disease

“…) of choline in diet) supplementation from day 12 to 17 of pregnancy [107,108,111,[121][122][123] Improved age-related memory in choline supplemented group www.global-challenges.com [109] Offsprings of choline supplemented group had increased levels of hippocampal BDNF, NGF, and IGF-1. Choline supplementation also caused less seizure-induced hippocampal neurodegeneration, dentate cell proliferation, hippocampal GFAP mRNA expression levels, prevented the loss of hippocampal GAD65 protein and mRNA expression, and altered growth factor expression patterns Rat Third trimester ethanol (5.25-6 g kg…”

Dietary cholesterol, heart disease risk and cognitive dissonance

“…Another study (50) reported data from a casecontrol study of breast cancer incidence showing that egg consumption was significantly inversely associated with risk of breast cancer. The epigenetic effects of choline availability during prenatal and postnatal development are just beginning to be investigated (51,52) . Eggs also provide highly bioavailable forms of the xanthophylls lutein and zeaxanthin, which are related to lower risks for age-related macular degeneration and cataracts (53)(54)(55)(56) as well as some types of cancer (57)(58)(59) and carotid artery atherosclerosis (60) .…”