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

Abstract

BackgroundThe 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.ObjectiveIn 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.MethodsMale 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.ResultsNo 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.ConclusionsIn 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.

Folate status and colorectal cancer risk: A 2016 update

“…A single study comparing paternal B vitamin supplementation, repletion and depletion has been conducted in the Apc1638N model in which the endpoint of offspring intestinal tumorigenesis was examined. No overt changes in tumor incidence or multiplicity were observed although mean tumor volume increased in the female offspring in a stepwise fashion with increasing paternal B vitamin intake (Sabet et al, 2016).…”

Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge

“…Environmental factors exert significant effects on gene expression, in some instances through epigenetic mechanisms ( 14 ). Thus, epigenetic marks can be considered “fingerprints” of that communication between the environment and the genome and some experimental evidence indicates that diet-induced epigenetic changes can be transmitted through several generations ( 15 , 16 ). As such, the environment, including habitual diet, may contribute to the health status of the individual and his/her descendants ( 17 ).…”

Effects of altered parental folate and one-carbon nutrient status on offspring growth and metabolism

“…Hepatic transcriptome analyses suggested a disruption of lipid metabolism and subsequent analyses revealed that despite being lighter, female offspring of supplemented sires had an approximately three-fold elevation in hepatic triglyceride content. Sex-specific re-analysis of our RNA-seq data revealed a significant upregulation of three genes (Acaca, Elovl6, Gpam), the products of which are sequentially involved in de novo triglyceride synthesis in the liver (Sabet et al 2016). Thus these data also suggest that paternal on-carbon status may also be a determinant of offspring metabolism, and raise the intriguing possibility of an interaction of maternal and paternal diet in programming offspring health.…”

“…Given the constant production of sperm through adult life, the integrity of the genetic and epigenetic information carried within is constantly at the mercy of an adequate nutrient supply. Indeed, we (Sabet et al 2016) and others (Lambrot et al 2013) have recently demonstrated that altering paternal B vitamin intake can cause widespread changes in the sperm methylome. It remains to be seen which, if any, of these methylation changes escape the widespread demethylation that occurs during embryogenesis -a task that will require single base resolution comparisons of sperm and offspring methylomes.…”