Type 1 diabetes (T1D) is an organ-specific autoimmune disease that has been showing a disturbing global increase of approximately 3% per year, predominantly in the younger age groups, over the last decades. Parallel increased exposure to endocrine disruptors (EDs) has been noted, resulting in suggestions of possible causality. Two EDs of particular significance due to their abundance are bisphenol A (BPA), used in the construction of polycarbonate plastics as well as epoxy resins found in water bottles, food containers and dental fillings, and genistein (GEN), a prevalent phytoestrogen found in soy food. Growing concerns of altered xenobiotic metabolism and synergistic interaction from combined exposure to soymilk and BPA, including in BPA-laden baby bottles, has warranted the investigation of the interactions between GEN and BPA on development-based postnatal T1D. Dysregulated T cell activity resulting from disturbed thymic central tolerance plays a key role in the T1D epidemic. Discordant T1D incidence among monozygotic twins also suggested a role for epigenetics in its manifestation. BPA and GEN both dysregulate T cell activity and cause inappropriate epigenetic modifications, supporting a possible causal role in increased T1D. The investigators hypothesize that T1D is exacerbated because thymic immune tolerance is disrupted by perinatal BPA ? GEN exposure in genetically susceptible female non-obese diabetic mice and streptozotocin-induced female diabetic C57BL/6 mice. The investigators believe this disruption is through inappropriate epigenetic modifications, which prime the organ for subsequent estrogen-triggering of autoimmunity during peripuberty. The above central hypothesis will be addressed in the experiments of the following two Aims: (1) Determine the exacerbation of T1D in adult female mice following perinatal exposure to GEN and BPA, and its relationship to thymic stromal microenvironment and the expression of interleukin (IL)-17 and Foxp3;and (2) Test the hypothesis that prenatal exposure to GEN and BPA causes histone post-translational modifications at the promoter/enhancer regions of T1D susceptible genes in the medullary thymic epithelial cells, and changes of DNA methylation and histone acetylation in Foxp3 and IL-17 gene loci.
These aims are designed as a focused expansion of the existing BPA and GEN developmental immunotoxicity database, in a manner collectively required to understand how EDs act as "developmental origins of health and disease" compounds to increase risk of later-life T1D. Epigenetic therapy including global DNA demethylating drugs, has translated into improved care for cancer patients, and suggests potential clinical importance of proposed studies for future T1D treatment. This identification of: 1) possible gene targets that are important in increasing risks;2) vulnerable periods in life;and 3) environmental factors which through different mechanisms may be driving the immunological processes that lead to T1D is required to make informed decisions regarding intervention studies and produce potential biomarkers for use in subsequent human surveillance studies.

Public Health Relevance

Type 1 diabetes is a devastating autoimmune disease affecting younger age groups, and is of huge economic importance. In the US, co-exposure to bisphenol A (found in plastics such as water bottles, metal can linings, dental sealants, toys, and other products) and genistein (a prevalent phytoestrogen found in soy food) remains significant and continuous. Elucidation of the key molecular mechanisms underlying the exacerbated type 1 diabetes by these endocrine disruptors will not only help design strategies for improved treatment for affected individuals but also produce potential biomarkers for use in subsequent human surveillance studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES024487-01
Application #
8770595
Study Section
Special Emphasis Panel (ZES1-JAB-J (AU))
Program Officer
Humble, Michael C
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$186,355
Indirect Cost
$61,355
Name
University of Georgia
Department
None
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Guo, Tai L; Wang, Yunbiao; Xiong, Tao et al. (2014) Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet. Toxicol Appl Pharmacol 280:455-66