Approximately 12% of infants in the United States are born with low birthweight, or are born too early, which predisposes them to poorer health outcomes later in life, including impaired neurodevelopment, diabetes, cardiovascular disease, and chronic respiratory conditions. The causative factors influencing fetal growth, and how these outcomes vary by fetal sex, are unclear; however, environmental exposures are hypothesized to play a role. In our prior research, we found that placental tissues associated with male infants accumulated significantly higher concentrations of brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and 2,4,6-tribromophenol (TBP), than placenta tissues from female infants, despite no differences in maternal serum levels based on infant sex. We also found that BFRs concentrate to a significantly higher degree in fetally-derived placental tissues compared to maternally derived placental tissues (2-10X higher), in both human tissues and in a rat model, implicating membrane transporters as a mechanism. In the rat model, thyroid hormone (TH) changes in the placenta were associated with TH changes in the fetuses, in a sex-specific manner. Several placental membrane transporters, including thyroid hormone transporters, were also significantly upregulated upon exposure to BFRs and varied by fetal sex. BFRs are endocrine disrupting chemicals that have been associated with low birth weight and reduced head circumference in several epidemiological studies. In addition, PBDEs are known to interfere with TH regulation via a number of mechanisms and have been shown to be substrates for membrane transporters (organic anion-transporter polypetides) in hepatocytes. Taken together, these preliminary studies suggest placental tissues express membrane transporters in a fetal-sex dependent manner, which influences BFR accumulation and TH regulation. Based on these preliminary data, we hypothesize that fetal sex-specific transporter expression in the placenta influences differential accumulation of BFRs, resulting in sex-specific effects on fetal growth. To test our hypothesis, we propose to analyze newly collected placental tissues from a prospective cohort in which we will uniquely isolate and collect maternal and fetal portions of the placenta for analysis. We will couple this with an in vivo rodent study to examine the mechanism by which BFRs accumulate in the various tissues of the placenta (i.e. roles of various transporters),and interrogate sex-specific differences in transporter expression and regulation across gestation. Using the data collected, we will then construct statistical models to evaluate associations between placental BFR levels and birth outcomes. This innovative study is highly responsive to the NIH interest in the placenta as a driver of children?s health. Through this project we hope to elucidate the impact of contaminant exposures on placenta function (e.g. hormone signaling) based on fetal sex and determine how fetal and infant growth is affected.

Public Health Relevance

Approximately 12% of infants are born with low birthweight or are born prematurely, which predisposes them to poorer health outcomes later in life. Our preliminary data suggests that the placenta modulates accumulation of flame retardants (FRs) in a fetal sex-dependent manner, affecting thyroid regulation, and expression of membrane transporters, which are critical to fetal growth and development. This project will examine the role of membrane transporters in driving sex-specific differences in FR accumulation and thyroid regulation in the placenta, and help elucidate the impacts of exposures on fetal growth and birth outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES031419-01A1
Application #
9989382
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Schug, Thaddeus
Project Start
2020-06-11
Project End
2025-03-31
Budget Start
2020-06-11
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Earth Sciences/Resources
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705