Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture

Abstract

Thyroid hormones (THs) and oestrogens are crucial in the regulation of cerebellar development. TH receptors (TRs) mediate these hormone effects and are regulated by both hormone families. We reported earlier that THs and oestradiol (E 2 ) determine TR levels in cerebellar cell culture. Here we demonstrate the effects of low concentrations (10 -10 M) of the endocrine disruptor (ED) bisphenol A (BPA) on the hormonal (THs, E 2 ) regulation of TRα,β in rat cerebellar cell culture. Primary cerebellar cell cultures, glia-containing and glia-destroyed, were treated with BPA or a combination of BPA and E 2 and/or THs. Oestrogen receptor and TH receptor mRNA and protein levels were determined by real-time qPCR and Western blot techniques. The results show that BPA alone decreases, while BPA in combination with THs and/or E 2 increases TR mRNA expression. In contrast, BPA alone increased receptor protein expressions, but did not further increase them in combination with THs and/or E 2 . The modulatory effects of BPA were mediated by the glia; however, the degree of changes also depended on the specific hormone ligand used. The results signify the importance of the regulatory mechanisms interposed between transcription and translation and raise the possibility that BPA could act to influence nuclear hormone receptor levels independently of ligand-receptor interaction.Key words: Endocrine disruptors, thyroid receptor, transcription, translation, bisphenol A, rat cerebellum Thyroid hormones (THs) and oestrogens (mostly 17β-oestradiol, E 2 ) play critical roles in the regulation of central nervous system (CNS) development, in-* Corresponding author; Zsarnovszky.Attila@mkk.szie.hu; Phone: 0036 (28) 522-062/1620 (office); 0036 (30) 665-3717 (mobile); Fax: 0036 (28) 522-062

Thyroid function disruptors: from nature to chemicals

“…BPA and several BPA analogs that have recently been introduced in the plastics industry were tested on different TH-responsive cell lines (GH3, FRTL-5 and rat cerebellar cells), and the results showed that they interfered with the expression of genes involved in TH synthesis (Slc5, Tg and Tpo), thyroid cell activity/ proliferation (Tshr, Tshb, Thrb, Thra, Dio1 and Dio2) and thyroid transcriptional regulation (Pax8, Nkx2-1 and FoxE1) (Gentilcore et al 2013, Lee et al 2017. From these results, one can presume that BPA and BPA analogs may affect thyroid function even at low doses, with a possible mechanism being through NF-kB and RAR/RXR pathways (Ghisari & Bonefeld-Jorgensen 2005, Okada et al 2007, Somogyi et al 2016. Phthalate metabolites could affect iodine uptake through the regulation of NIS and of Slc5a5 mRNA expression (Breous et al 2005 and by modulating hormone sulfation (Turan et al 2005).…”

Endocrine Disruptors Induced Distinct Expression of Thyroid and Estrogen Receptors in Rat versus Mouse Primary Cerebellar Cell Cultures

“…Life-long complications (modificational effects) can be induced by exposure if it Based on our studies and the existing literature, a natural balance between estrogen-and thyroid hormones can be disturbed by ED exposure, leading to complex, far-reaching consequences in the targeted organs. These effects are possibly more pervasive than currently believed [34][35][36].…”

“…The absence of estrogen but the presence of T3 dissipates this effect. Understanding the complex interplay between TR and ER regulation in the cells can possibly explain this phenomenon [34,36].…”

“…Available data suggest that estrogens-estrone (E1), 17β-estradiol (E2), and estriol (E3)-and thyroid hormones (THs)-triiodothyronine (T3) and thyroxine (T4)-are equally important regulators of CNS development [31,32]. In the developing cerebellum and possibly in any other brain area, a complex, interconnected effect can be seen between the respective hormones of TRs and ERs, maintaining the physiological levels of these specified receptors [33,34].…”

New EU criteria for endocrine disrupters

“…Although the inhibition of thyroid hormone receptor-β was a consequence of recruitment of N-CoR, BPA acted upstream of the receptor by blocking T3/T4 binding to an integrin cell plasma membrane receptor, necessary for activation of cytoplasmic THR. Primary rat cerebellar cultures +/-glia cells were exposed to 0.1 nM BPA, alone or in combination with E2 (0.12 nM), T3 (0.9 nM), or T4 (65 nM) for 6 h (RT-qPCR) or 18 h (Western blot) [79]. BPA exposure alone suppressed thyroid hormone receptor-α mRNA levels, whereas BPA combined with E2, T3 or T4 synergistically increased thyroid hormone receptor-α mRNA levels in the glia+ cells.…”