To assess the role of environmental chemicals in the etiology of type 2 diabetes development, we will examine a birth cohort of 1022 subjects born in 1986-1987 at the Faroe Islands, where an unusually wide range of exposures to environmental chemicals has been documented. Cohort members will now be invited at age 27 years for clinical examination, including oral glucose tolerance test, to assess glucose metabolism, hepatic insulin sensitivity, metabolic flexibility, and clinical signs of metabolic syndrome development. Data on chemical exposures, body weight and other covariates were obtained at birth and at previous clinical examinations at ages 7, 14, and 22 years. Existing exposure data include methylmercury, PCB, and DDE, and they will now be complemented by analyses of perfluorinated compounds in cord blood and postnatal samples. All of these substances are suspected of being diabetogenic, possibly through developmental programming of glucose metabolism. To establish an epigenetic signature for these exposures we will conduct a genome-wide epigenetic mapping using DNA extracted from whole blood from cohort members. We will examine CpG islands and shores, CpG outside islands, non-CpG methylated sites identified in human cancer stem cells, miRNA promoter regions and disease-associated regions identified through GWAS. The total and site-specific DNA methylations will be linked to exposures to environmental chemicals at birth and postnatally and to clinical indicators of glucose metabolism and metabolic flexibility. We will determine if exposures to the pollutants are associated with subclinical changes related to type 2 diabetes, whether these changes are mediated by DNA methylation, and whether they are affected by changes in body weight. These results will therefore contribute to our understanding of developmental programming effects of environmental chemicals, as indicated by DNA methylation, and their role in type 2 diabetes pathogenesis.

Public Health Relevance

Because of the increasing prevalence of type 2 diabetes and metabolic syndrome, the proposed research will examine the possible etiologic role of environmental chemicals that appear to be diabetogenic in experimental studies and epidemiological studies, most of which are cross-sectional. We will extend up to age 27 years our follow-up of a Faroese birth cohort with unusually wide ranges of exposures to suspected chemicals and link prenatal and postnatal exposures to glucose metabolism, metabolic flexibility, and body composition as indicators of early development of type 2 diabetes and metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES021477-05
Application #
9185316
Study Section
Kidney, Nutrition, Obesity and Diabetes Study Section (KNOD)
Program Officer
Mcallister, Kimberly A
Project Start
2013-02-01
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2018-10-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Leung, Yuet-Kin; Ouyang, Bin; Niu, Liang et al. (2018) Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort. Epigenetics 13:290-300
Audouze, Karine; Taboureau, Olivier; Grandjean, Philippe (2018) A systems biology approach to predictive developmental neurotoxicity of a larvicide used in the prevention of Zika virus transmission. Toxicol Appl Pharmacol 354:56-63
Manzano-Salgado, Cyntia B; Casas, Maribel; Lopez-Espinosa, Maria-Jose et al. (2017) Prenatal Exposure to Perfluoroalkyl Substances and Cardiometabolic Risk in Children from the Spanish INMA Birth Cohort Study. Environ Health Perspect 125:097018
Valvi, Damaskini; Oulhote, Youssef; Weihe, Pal et al. (2017) Gestational diabetes and offspring birth size at elevated environmental pollutant exposures. Environ Int 107:205-215
Zong, Geng; Grandjean, Philippe; Wang, Xiaobin et al. (2016) Lactation history, serum concentrations of persistent organic pollutants, and maternal risk of diabetes. Environ Res 150:282-288
Grandjean, Philippe (2016) Paracelsus Revisited: The Dose Concept in a Complex World. Basic Clin Pharmacol Toxicol 119:126-32
Jensen, Tina K; Timmermann, Amalie G; Rossing, Laura I et al. (2014) Polychlorinated biphenyl exposure and glucose metabolism in 9-year-old Danish children. J Clin Endocrinol Metab 99:E2643-51
Audouze, Karine; Brunak, Søren; Grandjean, Philippe (2013) A computational approach to chemical etiologies of diabetes. Sci Rep 3:2712