title: Disruption of thyroid hormone functions by low dose exposure of tributyltin: an in vitro and in vivo approach.
abstract: Triorganotins, such as tributyltin chloride (TBTCl), are environmental contaminants that are commonly found in the antifouling paints used in ships and other vessels. The importance of TBTCl as an endocrine-disrupting chemical (EDC) in different animal models is well known; however, its adverse effects on the thyroid gland are less understood. Hence, in the present study, we aimed to evaluate the thyroid-disrupting effects of this chemical using both in vitro and in vivo approaches. We used HepG2 hepatocarcinoma cells for the in vitro studies, as they are a thyroid hormone receptor (TR)-positive and thyroid responsive cell line. For the in vivo studies, Swiss albino male mice were exposed to three doses of TBTCl (0.5, 5 and 50μg/kg/day) for 45days. TBTCl showed a hypo-thyroidal effect in vivo. Low-dose treatment of TBTCl exposure markedly decreased the serum thyroid hormone levels via the down-regulation of the thyroid peroxidase (TPO) and thyroglobulin (Tg) genes by 40% and 25%, respectively, while augmenting the thyroid stimulating hormone (TSH) levels. Thyroid-stimulating hormone receptor (TSHR) expression was up-regulated in the thyroid glands of treated mice by 6.6-fold relative to vehicle-treated mice (p<0.05). In the transient transactivation assays, TBTCl suppressed T3 mediated transcriptional activity in a dose-dependent manner. In addition, TBTCl was found to decrease the expression of TR. The present study thus indicates that low concentrations of TBTCl suppress TR transcription by disrupting the physiological concentrations of T3/T4, followed by the recruitment of NCoR to TR, providing a novel insight into the thyroid hormone-disrupting effects of this chemical.
authors.affiliation: Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharan
authors.affiliation: Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Nikhil
authors.affiliation: Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India. Electronic address: paroyfbs@iitr.ernet.in.
authors.forename: Partha
authors.initials: P
authors.lastname: Roy
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D052244:Endocrine Disruptors; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014220:Trialkyltin Compounds; C011559:tributyltin; D007453:Iodide Peroxidase
keywords: Endocrine disruptors; Hypothyroidism; Thyroid disrupting chemical; Tributyltin