Bisphenol-A, an Environmental Contaminant that Acts as a Thyroid Hormone Receptor Antagonist in Vitro, Increases Serum Thyroxine, and Alters RC3/Neurogranin Expression in the Developing Rat Brain

Abstract

Considering the importance of thyroid hormone (TH) in brain development, it is of potential concern that a wide variety of environmental chemicals can interfere with thyroid function or, perhaps of greater concern, with TH action at its receptor (TR). Recently bisphenol-A (BPA, 4,4' isopropylidenediphenol) was reported to bind to the rat TR and act as an antagonist in vitro. BPA is a high production volume chemical, with more than 800 million kg of BPA produced annually in the United States alone. It is detectable in serum of pregnant women and cord serum taken at birth; is 5-fold higher in amniotic fluid at 15-18 wk gestation, compared with maternal serum; and was found in concentrations of up to 100 ng/g in placenta. Thus, the human population is widely exposed to BPA and it appears to accumulate in the fetus. We now report that dietary exposure to BPA of Sprague Dawley rats during pregnancy and lactation causes an increase in serum total T4 in pups on postnatal d 15, but serum TSH was not different from controls. The expression of the TH-responsive gene RC3/neurogranin, measured by in situ hybridization, was significantly up-regulated by BPA in the dentate gyrus. These findings suggest that BPA acts as a TH antagonist on the beta-TR, which mediates the negative feedback effect of TH on the pituitary gland, but that BPA is less effective at antagonizing TH on the alpha-TR, leaving TRalpha-mediated events to respond to elevated T4.

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…Zoeller et al (2005), supported in part by NIH, examined the effect of bisphenol A exposure on the thyroid of developing rats. Sprague-Dawley rats were housed in plastic cages.…”

Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism

“…However, other studies have been unable to duplicate these results, finding that BPA does not competitively inhibit the binding of labeled T3 to the TR or induce TH-dependent production of growth hormone (GH) in GH3 cells (Kitamura et al, 2002(Kitamura et al, , 2005a. In vivo studies examining the effects of low dose BPA on TH signaling have suggested that perinatally exposed rats have elevated T4 levels on postnatal day (PND) 15 and up-regulation of a TH responsive gene in the brain (Zoeller et al, 2005). Furthermore, perinatal exposure to low dose BPA in rats has been implicated in the abnormal brain development, characterized by hyperactivity and impaired cognition (Carr et al, 2003;Kubo et al, 2001).…”

Maternal bisphenol-A levels at delivery: a looming problem?

“…12 There is long-standing evidence that BPA can bind to the estrogen receptor and induce estrogen receptor-mediated gene expression [13][14][15] although recent evidence suggests that BPA can also bind to the thyroid receptor and affect thyroid hormone signaling. 16 BPA does not bind to plasma estrogen-binding proteins that normally limit the bioavailability of estradiol. 17 Accumulation of BPA appears to occur in pregnant adult female subjects, 3 more likely in fat and other tissues.…”