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Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo

Title
Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo
Authors
Kim S.Park G.-Y.Yoo Y.J.Jeong J.S.Nam K.T.Jee S.-H.Lim K.-M.Lee Y.-S.
Ewha Authors
이윤실임경민
SCOPUS Author ID
이윤실scopus; 임경민scopus
Issue Date
2019
Journal Title
Food and Chemical Toxicology
ISSN
0278-6915JCR Link
Citation
Food and Chemical Toxicology vol. 124, pp. 265 - 272
Keywords
Di-(2-ethylhexyl) phthalate (DEHP)DNA damagePhthalatesProliferationThyroidThyrotropin receptor (TSH)
Publisher
Elsevier Ltd
Indexed
SCI; SCIE; SCOPUS scopus
Document Type
Article
Abstract
Phthalates are being suggested to be associated with altered thyroid function and proliferative changes, but detailed mechanisms remain unclear. Here, we examined the effects of di-(2-ethylhexyl) phthalate (DEHP) on DNA damage and proliferation in thyroid using thyroid carcinoma cell line, 8505C, in vitro and the rats orally treated with DEHP at 0, 0.3, 3, 30 and 150 mg/kg for 90 days from post-natal day 9 in vivo. Exposure to DHEP (1–50 μM) induced cellular proliferation, as evidenced by increased cell viability and DNA synthesis. Activation of γH2AX, a sensitive biomarker for DNA damage was observed following the exposure to DHEP (from 5 to 50 μM) with increased comet tail moment (5–100 μM) in comet assay, reflecting that DNA damage also occurred. When upstream signaling was examined, both thyrotropin receptor (TSHR)-ERK1/2 axis and TSHR-AKT axis were activated with upregulation of Pax8, a master transcriptional factor for thyroid differentiation and proliferation. Thyroid tissue from juvenile rats orally exposed to DEHP also confirmed DNA damage responses and the activation of TSHR signaling, which was evident from 0.3 to 3 mg/kg respectively. Notably, deletion of TSHR through siRNA attenuated these DEHP-induced events in vitro. Collectively these results suggest that DEHP induces DNA damage and cellular proliferation in thyroid, which appears to be from TSHR activation, providing an important insight into endocrine disrupting activities of phthalates on thyroid. © 2018 Elsevier Ltd
DOI
10.1016/j.fct.2018.12.010
Appears in Collections:
약학대학 > 약학과 > Journal papers
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