Effects of In Utero Exposure to Perfluorinated Compounds on Placental Functions and Early Development of Pancreatic Islets

The prevalence of metabolic diseases is on an uprising trend. Although susceptible genetic background, over-nutrition and physical inactivity are identified as major risk factors contributing to the development of the diseases, they alone are not sufficient to account for the high prevalence. Over the last 20 years, converging epidemiological and experimental data have pointed out that the risk of developing metabolic syndrome is associated with early exposure to endocrine-disrupting chemicals (EDCs) in life. Seemingly, EDC-elicited suboptimal maternal-intrauterine environment which perturbs early metabolic programming, thereby increasing the susceptibility to the development of metabolic diseases (i.e. obesity, type-2 diabetes) in adulthood. Although the risk of EDC exposure during fetal development is highest, the underlying effects are not clearly documented. Previous studies confirmed that placenta and pancreatic islets both plays critical roles in fetal metabolic programming, therefore any perturbations in placental function and malprogramming of islets would seemingly predispose the offspring to a greater risk of developing obesity and diabetes later in life.

Perfluorinated compounds (PFCs) are EDCs that could alter fetal metabolic programming by targeting on nuclear receptors (the metabolic sensors in energy homeostasis) using its fatty-acid-like chemical structure. There is considerable amount of human data that correlates PFC exposure to the risk of metabolic diseases. Unfortunately, prospective evidence on both causality and mechanisms is lacking. Although laboratory studies provided mechanistic insight to underline the effects of PFC exposure on insulin secretion, dysglycemia and dyslipidemia, major informational gap still exists between the observed functional disorders and the mechanistic effects upon exposure in utero.

In this proposal, we hypothesized that early PFC exposure perturbs maternal metabolic status which alters placental function and fetal nutrient supply. The nutritional disturbances in turn affects the growth and function of pancreatic islets in the fetuses. Using maternal-fetal mouse model, we will analyze the changes in hormones and metabolites in the maternal environment during gestational PFOS (perfluorooctane sulfonate) exposure. Molecular and biochemical approaches will be adopted to measure the responses in (i) nutrient-transport function of placenta, (ii) growth and maturation of islets and (iii) nutrient sensing pathways (mTOR signaling) with respect to the changes in maternal-intrauterine environment and early neonatal growth. This will be an integrated approach to decipher the mechanisms underlying the metabolic perturbations in pregnant dams and adult offspring, thus providing valuable insights to aid in the disease management in humans.