Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring

• Published in: PloS one Vol. 11; no. 3; p. e0151579
• Main Authors: Sabet, Julia A, Park, Lara K, Iyer, Lakshmanan K, Tai, Albert K, Koh, Gar Yee, Pfalzer, Anna C, Parnell, Laurence D, Mason, Joel B, Liu, Zhenhua, Byun, Alexander J, Crott, Jimmy W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2016; Public Library of Science (PLoS)
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Animals; Biology and Life Sciences; Body weight; Body Weight - drug effects; Cholesterol; Diet; Dietary fiber; DNA Methylation - drug effects; Epigenetics; Fathers; Female; Females; Folic acid; Gene expression; Gene Expression Regulation - drug effects; Genes; Growth and Development - drug effects; Health risk assessment; Health risks; Human nutrition; Humans; Incidence; Insulin-like growth factor II; Intestinal Neoplasms - pathology; Intestine; Lipid metabolism; Lipid Metabolism - drug effects; Liver; Liver - drug effects; Liver - metabolism; Male; Mating; Medicine and Health Sciences; Metabolism; Mice; Mutation; Nutrition; Nutrition research; Offspring; Physical Sciences; Reproduction - drug effects; Risk assessment; Rodents; Sex Characteristics; Spermatozoa - drug effects; Spermatozoa - metabolism; Tumor Burden - drug effects; Vitamin B Complex - blood; Vitamin B Complex - pharmacology; Vitamin B12; Vitamin B6; Vitamin E; Vitamins; Weaning
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151579

The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well. In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content. Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden. No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring. In this animal model, modulation of paternal B vitamin intake prior to mating alters offspring weight gain, lipid metabolism and tumor growth in a sex-specific fashion. These results highlight the need to better define how paternal nutrition affects the health of offspring.