scholarly journals 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

Endocrinology ◽  
2005 ◽  
Vol 146 (2) ◽  
pp. 607-612 ◽  
Author(s):  
R. Thomas Zoeller ◽  
Ruby Bansal ◽  
Colleen Parris
Keyword(s):  
Thyroid Hormone ◽  
Bisphenol A ◽  
Thyroid Hormone Receptor ◽  
Dietary Exposure ◽  
The United States ◽  
Maternal Serum ◽  
Environmental Chemicals ◽  
Production Volume ◽  
Sprague Dawley

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 β-TR, which mediates the negative feedback effect of TH on the pituitary gland, but that BPA is less effective at antagonizing TH on the α-TR, leaving TRα-mediated events to respond to elevated T4.

scholarly journals Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

2021 ◽  
Vol 22 (11) ◽  
pp. 5534
Author(s):  
Elin Engdahl ◽  
Maarten van Schijndel ◽  
Dimitrios Voulgaris ◽  
Michela Di Criscio ◽  
Kerry Ramsbottom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bisphenol A ◽  
Blood Brain Barrier ◽  
Breast Cancer Resistance Protein ◽  
Brain Barrier ◽  
Production Volume ◽  
Cancer Resistance ◽  
Blood Brain ◽  
Resistance Protein

The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment.

Prenatal iodine deficiency results in structurally and functionally immature lungs in neonatal rats

2012 ◽  
Vol 302 (10) ◽  
pp. L1037-L1043 ◽  
Author(s):  
Madan M. Godbole ◽  
Geeta Rao ◽  
B. N. Paul ◽  
Vishwa Mohan ◽  
Preeti Singh ◽  
...  
Keyword(s):  
Drinking Water ◽  
Thyroid Hormone ◽  
Respiratory Distress ◽  
Lung Development ◽  
Thyroid Hormone Receptor ◽  
Alveolar Epithelium ◽  
Lung Compliance ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Deficient Diet

Maternal hypothyroidism affects postnatal lung structure. High prevalence of hypothyroxinemia (low T4, normal T3) in iodine-deficient pregnant women and associated risk for neuropsychological development along with high infant/neonatal mortality ascribed to respiratory distress prompted us to study the effects of maternal hypothyroxinemia on postnatal lung development. Female Sprague Dawley rats were given a low-iodine diet (LID) with 1% KClO4in drinking water for 10 days, to minimize thyroid hormone differences. Half of these rats were continued on iodine-deficient diet; ID (LID with 0.005% KClO4) for 3 mo, whereas the rest were switched to an iodine-sufficient diet; IS [LID + potassium iodide (10 μg iodine/20 g of diet + normal drinking water)]. Pups born to ID mothers were compared with age-matched pups from IS mothers at postnatal days 8 (P8) and 16 (P16) ( n = 6–8/group). ID pups had normal circulating T3 but significantly low T4 levels ( P < 0.05) and concomitantly approximately sixfold higher thyroid hormone receptor-β mRNA in alveolar epithelium. Lung histology revealed larger and irregularly shaped alveoli in ID pups relative to controls. Lung function was assessed at P16 using a double-chambered plethysmograph and observed reduced tidal volume, peak inspiratory and expiratory flow, and dynamic lung compliance in ID pups compared with IS pups. Significant lowering of surfactant protein (SP)-B and SP-C mRNA and protein found in ID pups at P16. ID pups had 16-fold lower matrix metalloproteinase-9 mRNA levels in their alveolar epithelium. In addition, mRNA levels of thyroid transcription factor-1 and SP-D were significantly higher (3-fold) compared with IS pups. At P16, significantly lower levels of SP-B and SP-C found in ID pups may be responsible for immature lung development and reduced lung compliance. Our data suggest that maternal hypothyroxinemia may result in the development of immature lungs that, through respiratory distress, could contribute to the observed high infant mortality in ID neonates.

scholarly journals Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

2001 ◽  
pp. 59-64 ◽  
Author(s):  
F Bogazzi ◽  
L Bartalena ◽  
S Brogioni ◽  
A Burelli ◽  
F Raggi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Molecular Level ◽  
Inhibitory Effect ◽  
Mobility Shift ◽  
Down Regulation ◽  
Nih3t3 Cells ◽  
Peripheral Tissues

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

scholarly journals Bisphenol A Altersβ-hCG and MIF Release by Human Placenta: AnIn VitroStudy to Understand the Role of Endometrial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
C. Mannelli ◽  
F. Ietta ◽  
C. Carotenuto ◽  
R. Romagnoli ◽  
A. Z. Szostek ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Conditioned Medium ◽  
Human Placenta ◽  
Environmental Chemicals ◽  
Endometrial Cells ◽  
Direct Exposure ◽  
And Control ◽  
Cell Conditioned Medium

A proper fetomaternal immune-endocrine cross-talk in pregnancy is fundamental for reproductive success. This might be unbalanced by exposure to environmental chemicals, such as bisphenol A (BPA). As fetoplacental contamination with BPA originates from the maternal compartment, this study investigated the role of the endometrium in BPA effects on the placenta. To this end,in vitrodecidualized stromal cells were exposed to BPA 1 nM, and their conditioned medium (diluted 1 : 2) was used on chorionic villous explants from human placenta. Parallel cultures of placental explants were directly exposed to 0.5 nM BPA while, control cultures were exposed to the vehicle (EtOH 0.1%). After 24–48 h, culture medium from BPA-treated and control cultures was assayed for concentration of hormone human Chorionic Gonadotropin (β-hCG) and cytokine Macrophage Migration Inhibitory Factor (MIF). The results showed that direct exposure to BPA stimulated the release of both MIF andβ-hCG. These effects were abolished/diminished in placental cultures exposed to endometrial cell-conditioned medium. GM-MS analysis revealed that endometrial cells retain BPA, thus reducing the availability of this chemical for the placenta. The data obtained highlight the importance ofin vitromodels including the maternal component in reproducing the effects of environmental chemicals on human fetus/placenta.

Role of thyroxine on postnatal development of ileal active bile salt transport

1986 ◽  
Vol 251 (2) ◽  
pp. G237-G242 ◽  
Author(s):  
J. E. Heubi
Keyword(s):  
Thyroid Hormone ◽  
Postnatal Development ◽  
Active Transport ◽  
Salt Transport ◽  
Maximal Velocity ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Taurocholate Transport

The role of thyroid hormone on the postnatal development of ileal active taurocholate transport uptake was measured by an in vitro incubation technique in Sprague-Dawley rats. In 16-day-old rats treated with pharmacological doses of L-thyroxine (50 micrograms X 100 g body wt-1 X day-1 on days 10-13), ileal active transport appeared precociously whose Km was 1.60 +/- 0.48 mM and Vapp (apparent maximal velocity) was 8.09 +/- 1.14 nmol X min-1 X mg dry wt-1, while age-matched shams had only passive diffusion of taurocholate. To determine whether enhanced endogenous secretion of thyroxine was capable of stimulating development of ileal active taurocholate transport, thyrotrophic stimulating hormone (TSH) (0.5 U/100 g body wt twice daily) was given on days 10-13, with uptake measured on day 16. Following TSH treatment, only passive transport for taurocholate was observed in the ileum; uptake rates were consistently higher than those for untreated controls at each study concentration. Thyroidectomy performed at age 14 days with uptake measured at age 21 days did not ablate development of ileal active transport but resulted in a significant reduction (P less than 0.001) in the Vapp (7.39 +/- 1.10 nmol X min-1 X mg dry wt-1) and a significant increase (P less than 0.014) in Km (1.72 +/- 0.53 mM) compared with age-matched controls. Thyroid hormone does not appear to be obligatory for the postnatal development of ileal active taurocholate transport.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Vol 116 (45) ◽  
pp. 22754-22763 ◽  
Author(s):  
Teresa G. Krieger ◽  
Carla M. Moran ◽  
Alberto Frangini ◽  
W. Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

scholarly journals Human body burdens of chemicals used in plastic manufacture

2009 ◽  
Vol 364 (1526) ◽  
pp. 2063-2078 ◽  
Author(s):  
Holger M. Koch ◽  
Antonia M. Calafat
Keyword(s):  
Analytical Chemistry ◽  
Bisphenol A ◽  
The United States ◽  
Environmental Chemicals ◽  
Biological Matrices ◽  
Relevant Research ◽  
Biomarkers Of Exposure ◽  
Accuracy And Precision ◽  
High Degree ◽  
Selection Of

In the last decades, the availability of sophisticated analytical chemistry techniques has facilitated measuring trace levels of multiple environmental chemicals in human biological matrices (i.e. biomonitoring) with a high degree of accuracy and precision. As biomonitoring data have become readily available, interest in their interpretation has increased. We present an overview on the use of biomonitoring in exposure and risk assessment using phthalates and bisphenol A as examples of chemicals used in the manufacture of plastic goods. We present and review the most relevant research on biomarkers of exposure for phthalates and bisphenol A, including novel and most comprehensive biomonitoring data from Germany and the United States. We discuss several factors relevant for interpreting and understanding biomonitoring data, including selection of both biomarkers of exposure and human matrices, and toxicokinetic information.

Fatty Acyl-CoAs Are Potent Inhibitors of the Nuclear Thyroid Hormone Receptor In Vitro

1990 ◽  
Vol 107 (5) ◽  
pp. 699-702 ◽  
Author(s):  
Qiulin Li ◽  
Naoki Yamamoto ◽  
Akira Inoue ◽  
Seiji Morisawa
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Fatty Acyl

scholarly journals CLARITY-BPA: Bisphenol A or Propylthiouracil on Thyroid Function and Effects in the Developing Male and Female Rat Brain

Endocrinology ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1771-1785 ◽  
Author(s):  
Ruby Bansal ◽  
R Thomas Zoeller
Keyword(s):  
Thyroid Hormone ◽  
Bisphenol A ◽  
Ethinyl Estradiol ◽  
Elevated Serum ◽  
Developing Brain ◽  
Female Rat ◽  
Sprague Dawley ◽  
Negative Effects ◽  
End Points ◽  
Environmental Health Sciences

Abstract The CLARITY-BPA experiment, a large collaboration between the National Institute of Environmental Health Sciences, the National Toxicology Program, and the US Food and Drug Administration, is designed to test the effects of bisphenol A (BPA) on a variety of endocrine systems and end points. The specific aim of this subproject was to test the effect of BPA exposure on thyroid functions and thyroid hormone action in the developing brain. Timed-pregnant National Center for Toxicological Research Sprague-Dawley rats (strain code 23) were dosed by gavage with vehicle control (0.3% carboxymethylcellulose) or one of five doses of BPA [2.5, 25, 250, 2500, or 25,000 µg/kg body weight (bw) per day] or ethinyl estradiol (EE) at 0.05 or 0.50 µg/kg bw/d (n = 8 for each group) beginning on gestational day 6. Beginning on postnatal day (PND) 1 (day of birth is PND 0), the pups were directly gavaged with the same dose of vehicle, BPA, or EE. We also obtained a group of animals treated with 3 ppm propylthiouracil in the drinking water and an equal number of concordant controls. Neither BPA nor EE affected serum thyroid hormones or thyroid hormone‒sensitive end points in the developing brain at PND 15. In contrast, propylthiouracil (PTU) reduced serum T4 to the expected degree (80% reduction) and elevated serum TSH. Few effects of PTU were observed in the male brain and none in the female brain. As a result, it is difficult to interpret the negative effects of BPA on the thyroid in this rat strain because the thyroid system appears to respond differently from that of other rat strains.

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