Bisphenol-A (4,4'isopropylidenediphenol, BPA) is one of the world's highest-volume chemicals in production today. However, the safety of BPA at current levels of human exposures is intensely debated. BPA is best known as a weak estrogen, but it binds to the thyroid hormone (TH) receptor (TR) with affinity characteristics that are similar to those of the estrogen receptor (ER). Preliminary data from the investigators indicate that BPA inhibits TH negative feedback, driven by the beta TR, causing an increase in serum thyroxine. However, the TH-response gene RC3/Neurogranin, driven by the alpha TR in the developing brain, becomes inappropriately elevated suggesting that BPA is a selective antagonist on the beta TR. Considering the importance of TH signaling during development and in the adult,the investigators propose to collaborate with National Toxicology Program/ National Center for Toxicological Research (NTP/NCTR) scientists to evaluate the ability of BPA to interfere with TH signaling during the life cycle and to characterize potential adverse effects that remain into adulthood. The investigators propose three specific aims to accomplish these goals.
Aim 1 is focused on testing the ability of BPA exposure to interfere with TH signaling in the fetus prior to the onset of fetal thyroid function and in the neonate during the period of peak sensitivity to serum TH. The investigators will evaluate the effect of BPA on serum and tissue TH, TH-regulated gene expression, and TH-dependent development. This will be followed by a focused experiment in a transgenic mouse line to test whether BPA alters the delivery of biologically active T3 to target cells.
Aim 2 is focused on testing the ability of BPA to interfere with TH signaling in the adult. The investigators will evaluate whether developmental BPA exposure produces permanent effects on brain structure and function, and whether current BPA exposure interferes with TH signaling in brain, pituitary, liver and heart.
Aim 3 takes a toxicogenomics approach in collaboration with scientists at Health Canada to determine the degree to which BPA exposure affects TH signaling compared to signaling through the estrogen receptor, and will test whether specific effects that are characterized in aims 1 and 2 are dependent upon the expression of TR? or TR? using well known knock-out mouse models.
The U.S. population exhibits widespread exposure to bisphenol-A (BPA). The ability of BPA to interfere with thyroid hormone signaling in development and in the adult is concerning because thyroid hormone is essential for normal brain development and adult physiology. We propose to comprehensively test whether BPA interferes with TH signaling in development and in the adult.
| Gore, A C; Chappell, V A; Fenton, S E et al. (2015) EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 36:E1-E150 |
