Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A: The role of transmembrane G-protein estrogen receptor 1 and integrin αvβ3

Sheng, Zhenfeng; Wang, Cong; Ren, Fu-Rong; Liu, Yuxiang; Zhu, Ben-Zhan

doi:10.1016/j.jes.2018.05.002

Cited by 38 publications

(21 citation statements)

References 101 publications

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“…We also found a positive correlation between the GPER and THRα. Sheng et al showed that the GPER together with integrin αvβ3 participate in the induction of male germ cell proliferation and thyroid transcription disruption after low-dose Bisphenol A treatment (Sheng et al 2019). Another correlation of our study was found between THRα in the nucleus and the FSH receptor; whereas, the THRα expression in the cytoplasm showed a positive correlation to the LH/hCG receptor.…”

Section: Discussionsupporting

confidence: 68%

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Ditsch

Heublein

Jeschke

et al. 2020

J Cancer Res Clin Oncol

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Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.

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Section: Discussionsupporting

confidence: 68%

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Ditsch

Heublein

Jeschke

et al. 2020

J Cancer Res Clin Oncol

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show abstract

“…We also found a positive correlation between the GPER and THRa. Sheng et al showed that the GPER together with integrin αvβ3 participate in the induction of male germ cell proliferation and thyroid transcription disruption after low-dose Bisphenol A treatment [42]. Another correlation of our study was found between THRa in the nucleus and the FSH receptor, whereas the THRa expression in the cytoplasm showed a positive correlation to the LH/hCG receptor.…”

Section: Discussionsupporting

confidence: 71%

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

Ditsch¹,

Heublein²,

Jeschke³

et al. 2019

Preprint

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Background Ovarian cancer is most lethal in comparison to all other gynecological cancer cases. Within this study, we aimed to investigate the expression of the thyroid hormone receptor alpha and its influence on patient survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and -2 were investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated to clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Patients with clear cell OvCa showed the highest THRα expression and nuclear THRα expression is associated with reduced survival in this group. In contrast, nuclear expressed THRα1 is a positive prognosticator for all OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. Cytoplasmic expression of THRα2 accompanies with reduced OS in all OvCa patients, whereas cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates to gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Thyroid hormones promote ovarian cancer cell proliferation. The further investigation of thyroid hormones and its specific receptors offer the possibility to investigate new endocrine targets against ovarian cancer.

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“…In normal conditions, T3 and thyroxine (T4) induce serine phosphorylation of TR-β1 by binding to αvβ3 and activating mitogen-activated protein kinases (MAPK) and/or c-Src/PI3K pathways [78], which determines the dissociation of N-CoR or SMRT from TR-β1 and consequent activation of transcription. The competitive binding of BPA to αvβ3 antagonizes the serine phosphorylation of TR-β1 leading to the recruitment of N-CoR/SMRT to TR-β1 and suppression of transcription [79].…”

Section: Cell Proliferationmentioning

confidence: 99%

Bisphenols as Environmental Triggers of Thyroid Dysfunction: Clues and Evidence

Gorini

Bustaffa

Coi

et al. 2020

IJERPH

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Bisphenols (BPs), and especially bisphenol A (BPA), are known endocrine disruptors (EDCs), capable of interfering with estrogen and androgen activities, as well as being suspected of other health outcomes. Given the crucial role of thyroid hormones and the increasing incidence of thyroid carcinoma in the last few decades, this review analyzes the effects of BPS on the thyroid, considering original research in vitro, in vivo, and in humans published from January 2000 to October 2019. Both in vitro and in vivo studies reported the ability of BPs to disrupt thyroid function through multiple mechanisms. The antagonism with thyroid receptors (TRs), which affects TR-mediated transcriptional activity, the direct action of BPs on gene expression at the thyroid and the pituitary level, the competitive binding with thyroid transport proteins, and the induction of toxicity in several cell lines are likely the main mechanisms leading to thyroid dysfunction. In humans, results are more contradictory, though some evidence suggests the potential of BPs in increasing the risk of thyroid nodules. A standardized methodology in toxicological studies and prospective epidemiological studies with individual exposure assessments are warranted to evaluate the pathophysiology resulting in the damage and to establish the temporal relationship between markers of exposure and long-term effects.

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Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A: The role of transmembrane G-protein estrogen receptor 1 and integrin αvβ3

Cited by 38 publications

References 101 publications

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

Bisphenols as Environmental Triggers of Thyroid Dysfunction: Clues and Evidence

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