Bisphenol A (BPA), a monomer of polycarbonate plastics, has been shown to possess estrogenic properties and act as an agonist for the estrogen receptors. Although an epidemiologically based investigation has suggested that some chemicals could disrupt thyroid function in animals, the effects on thyroid hormone receptors (TRs) are unknown. We show here that BPA inhibits TR-mediated transcription by acting as an antagonist. In the transient gene expression experiments, BPA suppressed transcriptional activity that is stimulated by thyroid hormone (T(3)) in a dose-dependent manner. The inhibitory effects were observed in the presence of physiological concentrations of T(3). In contrast, in the case of negatively regulated TSHalpha promoter, BPA activated the gene transcription that is suppressed by T(3). To elucidate possible mechanisms of the antagonistic action of BPA, the effects on T(3) binding and cofactor interaction with TR were examined. The K(i) value for BPA was 200 micro M when assessed by inhibition of [(125)I]T(3) binding to rat hepatic nuclear TRs. In a mammalian two-hybrid assay, BPA recruited the nuclear corepressor to the TR. These results suggest that BPA could displace T(3) from the TR and recruit a transcriptional repressor, resulting in gene suppression. This is the first report that BPA can antagonize T(3) action at the transcriptional level. BPA may disrupt the function of various types of nuclear hormone receptors and their cofactors to disturb our internal hormonal environment.

Background: Cofilin is a low-molecular weight actinmodulating protein, and is structurally and functionally conserved in eucaryotes from yeast to mammals. The functions of cofilin appear to be regulated by phosphorylation and dephosphorylation.

Semaphorin 3A is a chemorepulsive axonal guidance molecule that depolymerizes the actin cytoskeleton and collapses growth cones of dorsal root ganglia neurons. Here we investigate the role of LIM-kinase 1, which phosphorylates an actin-depolymerizing protein, cofilin, in semaphorin 3A-induced growth cone collapse. Semaphorin 3A induced phosphorylation and dephosphorylation of cofilin at growth cones sequentially. A synthetic cell-permeable peptide containing a cofilin phosphorylation site inhibited LIM-kinase in vitro and in vivo, and essentially suppressed semaphorin 3A-induced growth cone collapse. A dominant-negative LIM kinase, which could not be activated by PAK or ROCK, suppressed the collapsing activity of semaphorin 3A. Phosphorylation of cofilin by LIM-kinase may be a critical signaling event in growth cone collapse by semaphorin 3A.

Lhx3 and Lhx4 (Gsh4), two closely related LIM homeobox genes, determine formation of the pituitary gland in mice. Rathke's pouch is formed in two steps-first as a rudiment and later as a definitive pouch. Lhx3 and Lhx4 have redundant control over formation of the definitive pouch. Lhx3 controls a subsequent step of pituitary fate commitment. Thereafter, Lhx3 and Lhx4 together regulate proliferation and differentiation of pituitary-specific cell lineages. Thus, Lhx3 and Lhx4 dictate pituitary organ identity by controlling developmental decisions at multiple stages of organogenesis.