Obesity and type 2 diabetes (T2D) arise at the interface of genes and environment. It is well-recognized that the intrauterine environment is also an important modifier of this risk, with maternal T2D, obesity, or suboptimal nutrition all promoting increased risk for metabolic syndrome in offspring. Indeed, offspring of female mice exposed to altered nutrition in utero develop glucose intolerance, dysregulated insulin secretion, and obesity as adults - hallmarks of human metabolic syndrome. One novel and unexpected observation made during these studies is that the father's intrauterine exposures can also impact the health of his offspring. First generation male offspring of mothers undernourished (UN) during pregnancy (F1-UN) produce second- (F2) & third-generation (F3) offspring that develop increased adiposity & impaired glucose tolerance as adults. Disease phenotypes in F2/F3 mice indicate F1 males can transmit heritable, non-genetic traits - created by this early in utero exposure - to his offspring & grandoffspring. While mechanisms underlying male germline transmission remain incompletely understood, we recently made the important observation that in utero exposure to UN results in perturbed DNA methylation in sperm of F1-UN males (Science, 2014). Expression of genes adjacent to these differentially methylated regions is altered in F2 embryos, including genes regulating insulin secretion, indicating persistent dysregulation of transcriptional control. The overall aim of this proposal is to identify mechanisms responsible for paternal effects on offspring health. It is important to determine whether differential germ cell DNA methylation is the primary mechanism of altered outcomes in offspring, or is an epigenetic biomarker resulting from additional transcriptional regulatory events, such as altered expression of coding or noncoding RNAs. Moreover, we need to know if epigenetic dysregulation results exclusively from prior exposures or is secondary to current metabolic health of the father. We will use several complementary approaches to dissect contributing factors. First, we will analyze DNA methylation & coding/noncoding RNAs in spermatozoa of males exposed to either in utero UN or overnutrition (ON), and determine genomic overlap with differentially methylated regions already identified. Second, we will examine the impact of interventions shown to improve metabolic health in the F1 father (caloric restriction or exercise) on both epigenetic marks & health of his offspring. This strategy will permit us to determine whether sperm epigenetic marks can be modified or reversed, & whether such interventions can mitigate intergenerational transmission of metabolic disease. Finally, we will identify candidate methylation marks and RNAs and assess their presence in early preimplantation embryos to identify those that persist post-fertilization & thus may play a primary pathogenic role in offspring metabolism and disease risk.

Public Health Relevance

Poor health and nutrition of a mother during pregnancy can increase risk for obesity and diabetes in her children decades later. Using our mouse model, we now show that fathers can also pass along signals through his sperm which increase obesity and diabetes risk in his own children. The overall goal of this project is to understand how these non-genetic ('epigenetic') signals in the father's sperm affect development and increase risk for disease in his own offspring, and to determine whether these signals can be reversed by improving the health of the father (nutrition or exercise) prior to conception.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK106193-01A1
Application #
9106167
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Silva, Corinne M
Project Start
2016-03-05
Project End
2020-02-29
Budget Start
2016-03-05
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
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