Over the past several decades, the prevalence of gestational diabetes (GDM) has increased 3-fold, with implications for the growing type 2 diabetes (T2DM) epidemic among women with a history of this condition. An increasing body of literature suggests that phthalates, an endocrine disrupting chemical, are associated with increased T2DM risk in non-pregnant women. These chemicals are used in plastics, food packaging, cosmetics, and other consumer products. Phthalates bind to the nuclear receptors, peroxisome proliferator activated receptors (PPAR) alpha and gamma, which may modulate target genes that regulate glucose metabolism. While phthalates have been found to be associated with T2DM risk among non-pregnant women, it remains unclear whether these chemicals are associated with GDM risk. Preliminary data from our research suggest associations between urinary levels of mono-benzyl (MBzP) and mono-(3-carboxypropyl) (MCPP) phthalates and pregnancy-related risk factors of GDM, such as increased pre-pregnancy weight, excessive gestational weight gain, and elevated blood glucose levels during pregnancy among a subset of women (n=350) participating in an ongoing pregnancy cohort study of 4,000 women. Yet, no studies have assessed the association between phthalate levels and GDM risk. In addition, GDM is known to substantially increase future development of T2DM, with over 50% of women with a history of GDM going on to develop T2DM. This increased risk can be seen as early as 6-weeks postpartum, with women with higher fasting and 2-hour blood glucose levels being at substantially higher risk of developing T2DM in the future. However, no studies have evaluated the association between phthalate levels during and after pregnancy to determine whether these chemicals contribute to an increased risk of sustained glucose dysregulation after pregnancy. To this end, we propose conducting a nested case-control study in an established pregnancy cohort to assess the association between 1st and 2nd trimester urinary metabolite levels of mono-benzyl phthalate and mono-(3-carboxypropyl) phthalate and GDM risk, as well as biomarkers associated with GDM risk (i.e. blood glucose levels) among 560 women. We will also conduct a post-pregnancy follow-up study in 866 newly recruited women, including those with GDM, impaired glucose tolerance, and normal glycemia, to evaluate the association of higher pregnancy and post-pregnancy levels of MBzP and MCPP and post-pregnancy glucose, insulin, hemoglobin A1c, and HOMA-IR levels at 6-weeks postpartum as measures of sustained glucose dysregulation after pregnancy. By evaluating the role of phthalate levels and diabetes risk at two sensitive time points-pregnancy and the postpartum, this research will give better understanding for the role of these highly-prevalent endocrine disrupting chemicals on GDM and future T2DM risk, with implications for identifying modifiable risk factors.

Public Health Relevance

While lifestyle factors are assuredly involved in the increasing gestational diabetes and type 2 diabetes epidemics, research has shown an association between higher urinary phthalate concentrations and type 2 diabetes risk in non-pregnant women. Yet, no studies to our knowledge have evaluated this association during the sensitive periods of pregnancy and early postpartum to determine whether higher phthalate concentrations increase the risk of gestational diabetes, with implications for future type 2 diabetes risk. Utilizing an existing pregnancy cohort, we will evaluate pregnancy and postpartum phthalate levels and their association with gestational diabetes and sustained glucose dysregulation postpartum.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES026166-04
Application #
9392167
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Boyles, Abee
Project Start
2016-04-02
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
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
Ertel, Karen A; Huang, Tianyi; Rifas-Shiman, Sheryl L et al. (2017) Perinatal weight and risk of prenatal and postpartum depressive symptoms. Ann Epidemiol 27:695-700.e1
James-Todd, Tamarra; March, Melissa I; Seiglie, Jacqueline et al. (2017) Racial differences in neonatal hypoglycemia among very early preterm births. J Perinatol :
Chiu, Yu-Han; Mínguez-Alarcón, Lidia; Ford, Jennifer B et al. (2017) Trimester-Specific Urinary Bisphenol A Concentrations and Blood Glucose Levels Among Pregnant Women From a Fertility Clinic. J Clin Endocrinol Metab 102:1350-1357
Bellavia, Andrea; Hauser, Russ; Seely, Ellen W et al. (2017) Urinary phthalate metabolite concentrations and maternal weight during early pregnancy. Int J Hyg Environ Health 220:1347-1355
James-Todd, Tamarra M; Meeker, John D; Huang, Tianyi et al. (2016) Pregnancy urinary phthalate metabolite concentrations and gestational diabetes risk factors. Environ Int 96:118-126
James-Todd, Tamarra M; Chiu, Yu-Han; Zota, Ami R (2016) Racial/ethnic disparities in environmental endocrine disrupting chemicals and women's reproductive health outcomes: epidemiological examples across the life course. Curr Epidemiol Rep 3:161-180
James-Todd, Tamarra; Cohen, Allison; Wenger, Julia et al. (2016) Time-specific placental growth factor (PlGF) across pregnancy and infant birth weight in women with preexisting diabetes. Hypertens Pregnancy 35:436-46