Biomedical subjects
Hisahiko Hiroi
Publications and source records attributed to Hisahiko Hiroi.
Images in reproductive medicine. A case of giant cystic adenomyosis.
We describe a 37-year-old woman with giant cystic adenomyosis who underwent a hysterectomy, providing magnetic resonance imaging and gross and microscopic images.
Regulation of transcription of the steroidogenic acute regulatory protein (StAR) gene: temporal and spatial changes in transcription factor binding and histone modification.
We examined the binding of transcription factors and histone modifications associated with induction of expression of the steroidogenic acute regulatory protein (StAR) gene in MA-10 cells using a quantitative chromatin immunoprecipitation (ChIP) assay. GATA-4, SF-1/Ad4BP, and cyclic AMP response element binding protein binding protein (CBP) bind rapidly to the StAR proximal promoter, but in different patterns following 8-Br-cAMP stimulation. Concomitantly, histone modifications occur in a spatial and temporal sequence including increased association of acetylated histone H3 with the proximal promoter region, increased association of dimethylated lysine 4 histone H3 with exonic sequences, a modification that marks actively transcribed regions, and reduced association of a marker linked to gene silencing (lysine 9 dimethylated histone H3). Our findings demonstrate that transcription factors and coactivators are rapidly associated with the StAR proximal promoter, that the patterns of binding differ which has implications for postulated direct interactions among these factors, and that multiple histone modifications are demonstrable in a spatially- and temporally-specific pattern along the StAR gene. These observations suggest that a combinatorial code of transcription factors including reciprocal changes in histone modifications associated with active transcription and gene silencing control StAR gene expression.
Temporal and spatial changes in transcription factor binding and histone modifications at the steroidogenic acute regulatory protein (stAR) locus associated with stAR transcription.
We investigated the binding of transcription factors and histone modifications associated with expression of the steroidogenic acute regulatory protein (StAR) gene in cultured MA-10 Leydig cells and in granulosa cells isolated from mouse periovulatory follicles before and after in vivo human chorionic gonadotropin administration. Quantitative chromatin immunoprecipitation assays were employed to prove association of specific transcription factors (GATA-4, steroidogenic factor 1/adrenal-4 binding protein, CCAAT/enhancer-binding protein beta, cAMP response element binding protein/cAMP response element modulator) and a coactivator (cAMP response element binding protein-binding protein) with the promoter, to define patterns of binding to test hypotheses regarding interactions among these factors, and to correlate changes in histone modification at the StAR locus with transcription. Although each of the transcription factors bound to the StAR proximal promoter, we observed cell-specific binding patterns for individual factors. From these findings we infer that associations among some of the factors can be more complex than can be explained by simple models of stable protein-protein interactions. Histone modifications were also found to exhibit cell-specific, temporal and spatial differences across the StAR locus. In MA-10 cells, these modifications included increased acetylation of histone H3, increased dimethylation of lysine 4 on histone H3 in exonic/intronic sequences (a modification that marks transcriptionally permissive chromatin), and reduced dimethylation of lysine 9 on histone H3 (a modification linked with gene silencing). In mouse granulosa cells, we observed no change in histone H3 or H4 acetylation, but a rapid loss of the dimethyl K9 histone H3 mark. Our findings demonstrate that increased StAR transcription can occur in the context of different patterns of transcription factor binding and histone modification.
Differences in serum bisphenol a concentrations in premenopausal normal women and women with endometrial hyperplasia.
Exposure to endocrine disrupting chemicals (EDCs) has been raised in relation to its potential for adverse health outcomes. Bisphenol A (BPA) is an estrogenic EDC widely found in plastic products. We determined BPA concentrations in premenopausal women by an enzyme-linked immunosorbent assay and evaluated possible linkage between its contamination levels and endometrial hyperplasia, an estrogen-related disorder of the uterus. It has been implied that higher levels of BPA, which binds to estrogen receptor and plays estrogenic roles may, enhance endometrial hyperplasia. Serum BPA was detectable in all subjects and its concentrations in healthy controls with normal endometrium were 2.5 +/- 1.5 ng/ml (mean +/- SD). BPA levels in patients with simple endometrial hyperplasia with benign nature were 2.9 +/- 2.0 ng/ml and were not significantly different from the controls. Unexpectedly, BPA levels in patients with complex endometrial hyperplasia with malignant potential were 1.4 +/- 0.4 ng/ml and significantly lower compared to both control and simple endometrial hyperplasia groups. In addition, we measured the serum BPA levels in postmenopausal endometrial cancer patient (1.4 +/- 0.5 ng/ml), which were also significantly lower than control and simple endometrial hyperplasia groups. These findings suggest the presence of associations between BPA exposure and complex endometrial hyperplasia and endometrial cancer. The mode of action of BPA may be more complex than expected and the contradictory results may serve as a clue to addressing the mechanisms of linkage between occurrence of estrogen-dependent diseases and endocrine disruption.
START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells.
The intracellular trafficking of cholesterol in steroidogenic cells plays an important role in the regulation of hormone synthesis. Recent evidence indicates that a family of proteins related to the steroidogenic acute regulatory protein (StAR) perform critical functions in moving the sterol substrate to the mitochondrial inner membrane where the first committed step in steroid hormone synthesis occurs. StAR, the prototype of the family, is known to promote the translocation of cholesterol from the outer to the inner mitochondrial membrane. Mutations in StAR cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenocortical steroid hormones is severely impaired, and the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets. The StAR-related lipid transfer (START) domain consists of an approximately 210 amino acid residue sequence that forms a compact alpha/beta structure, a helix-grip fold, with a hydrophobic tunnel that can accommodate a sterol molecule. START domains can bind sterol, facilitate the transfer of cholesterol from sterol-rich unilammelar liposomes to acceptor membranes, and stimulate steroidogenesis when expressed in cells co-expressing the cholesterol side-chain cleavage system or when added to isolated steroidogenic mitochondria. Sixteen human START domain proteins have been identified to date. Of these, StAR and MLN64 consist of one subfamily and newly described proteins named StarD4, StarD5, and StarD6 represent a closely related second subfamily. MLN64 is incorporated into the late endosomal compartment and is involved in the movement of cholesterol acquired from endocytosed LDL out of these vesicles. Expression of a dominant negative form of MLN64 causes accumulation of free cholesterol in lysosomes. The roles of StarD4, StarD5, and StarD6 in sterol movement remain to be determined. These genes have tissue-specific patterns of expression that may predict specialized roles.
A case of estrogen-producing Brenner tumor with a stromal component as a potential source for estrogen.
BACKGROUND: Although Brenner tumors with endocrine activities have been reported, the source or mechanisms for hormone production is poorly known at present. CASE REPORT: A 66-year-old Japanese woman presented with atypical vaginal bleeding. A left ovarian tumor was detected on ultrasonography and CT scanning. Her serum estradiol level was elevated (73.5 pg/ml). We performed total hysterectomy, bilateral salpingo-oophorectomy and partial omentectomy. The ovarian tumor was diagnosed as a benign Brenner tumor associated with simple hyperplasia of the endometrium. Postoperatively, the serum estradiol level decreased. Immunoreactivity of cytochrome P-450 aromatase was detected in stromal cells. CONCLUSION: Stromal contribution to the secretion of estrogen was shown in this case. Considering the known source of estrogen production being tumor cells in certain cases of Brenner tumor, there seem to be two types of estrogen-producing Brenner tumors depending on the source of estrogen, i.e. tumor cells or stromal cells.
The activity of bisphenol A depends on both the estrogen receptor subtype and the cell type.
Bisphenol A (BPA), a monomer of plastic used in consumer products, is abundant in the environment and enters the body by ingestion or adsorption. In order to characterize the estrogenic effect of BPA, we performed luciferase assay on three independent cell lines derived from different tissues transfected with either human ERalpha cDNA or ERbeta cDNA. The estrogenic activities of BPA were detectable in all cell lines via both ERalpha and ERbeta. In 293T cells and Hec-1 cells, the estrogenic activities were significantly decreased when cells expressing ERalpha were incubated with 10(-6) M BPA in the presence of 10(-8) M 17beta-estradiol (E2) while the activities via ERbeta were essentially unchanged in the same conditions. Interestingly, no reduction of estrogenic activity was detected in HOS-TE85 cells via either ERalpha or ERbeta. Our results indicate that BPA only acts as an agonist of estrogen via ERbeta whereas it has dual actions as an agonist and antagonist in some types of cells via ERalpha. Thus, the activity of BPA may depend on the ER subtype and the tissue involved.