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
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.
Friedman School of Nutrition Science and Policy at Tufts University, Boston, Massachusetts, United States of America.
PLoS One. 2016 Mar 11;11(3):e0151579. doi: 10.1371/journal.pone.0151579. eCollection 2016.
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.
母体营养对后代健康和疾病风险的重要性已得到充分证实。新出现的证据表明，父亲的饮食也可能影响后代健康。
在本研究中，我们试图确定孕前调节父亲的B族维生素摄入量是否会改变后代肠道肿瘤的形成。此外，我们试图通过分析肝脏基因表达和脂质含量来确定观察到的后代体重差异的潜在机制。
雄性Apc1638N小鼠（易患肠道肿瘤）在与对照喂养的野生型雌性小鼠交配前8周，分别喂食含有充足（对照，CTRL）、轻度缺乏（DEF）或补充（SUPP）量的维生素B2、B6、B12和叶酸的饮食。野生型后代在断奶时安乐死，并分析肝脏基因表达。Apc1638N后代喂食充足饮食，并在28周龄时安乐死以评估肿瘤负荷。
不同父本饮食组的雄性Apc1638N后代在肠道肿瘤发生率或肿瘤负荷方面没有差异。虽然雌性Apc1638N后代在肿瘤发生率或多发性方面没有差异，但随着父本B族维生素摄入量的增加，肿瘤体积呈逐步增加。有趣的是，SUPP和DEF组父亲的雌性后代体重明显低于CTRL组父亲的雌性后代。此外，SUPP组父亲的成年雌性后代肝脏甘油三酯和胆固醇升高了3倍。同一组父亲的断奶后代显示出几个关键脂质代谢基因的表达改变。在父本精子中，针对DEF和SUPP饮食鉴定出数百个差异甲基化区域。除了包括Igf2在内的少数基因外，精子中差异甲基化的基因与后代中差异表达的基因之间几乎没有重叠。
在这个动物模型中，交配前调节父本的B族维生素摄入量会以性别特异性方式改变后代的体重增加、脂质代谢和肿瘤生长。这些结果凸显了更好地确定父本营养如何影响后代健康的必要性。
