Paternal B vitamin intake is a determinant of growth, hepatic lipid metabolism and intestinal tumor volume in female Apc1638N mouse offspring

Authors: SABET, JULIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PARK, LARA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; IYER, LAKSHMANAN - Tufts University; TAI, ALBERT - Tufts University; KOH, GAR YEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PFALZER, ANNA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Parnell, Laurence; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, ZHENHUA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BYUN, ALEXANDER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CROTT, JIMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2016
Publication Date: 3/11/2016
Citation: Sabet, J.A., Park, L.K., Iyer, L.K., Tai, A.K., Koh, G., Pfalzer, A., Parnell, L.D., Mason, J.B., Liu, Z., Byun, A.J., Crott, J.W. 2016. Paternal B vitamin intake is a determinant of growth, hepatic lipid metabolism and intestinal tumor volume in female Apc1638N mouse offspring. PLoS One. 11(3):e0151579. https://doi.org/10.1371/journal.pone.0151579.

Interpretive Summary: It is well accepted that a mother's diet can affect various aspects of offspring health, from obesity to cancer risk. In contrast, very little is known about how a father's diet, or intake of specific nutrients, can affect the health of his offspring. We tested whether altering a male's intake of B vitamins would alter the risk of cancer in his offspring using a mouse model of colorectal cancer. Offspring cancer risk was not altered. However, female offspring of fathers who had received supplemental levels of B vitamins weighed significantly less than their counterparts despite having a significant accumulation of fat in their liver. These results show that paternal B vitamin intake can affect offspring metabolism.

Technical Abstract: Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.