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

Seoyoung Kim, Ga Young Park, Young Jo Yoo, Ji Seong Jeong, KiTaek Nam, Sun Ha Jee, Kyung Min Lim, Yun Sil Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)265-272
Number of pages8
JournalFood and Chemical Toxicology
Volume124
DOIs
Publication statusPublished - 2019 Feb 1

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Diethylhexyl Phthalate
Thyrotropin Receptors
phthalates
Cell proliferation
DNA damage
DNA Damage
cell proliferation
Thyroid Gland
Cell Proliferation
DNA
Chemical activation
Rats
Cells
thyroid function
Comet Assay
rats
Biomarkers
small interfering RNA
In Vitro Techniques
phthalic acid

All Science Journal Classification (ASJC) codes

  • Food Science
  • Toxicology

Cite this

Kim, Seoyoung ; Park, Ga Young ; Yoo, Young Jo ; Jeong, Ji Seong ; Nam, KiTaek ; Jee, Sun Ha ; Lim, Kyung Min ; Lee, Yun Sil. / Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo. In: Food and Chemical Toxicology. 2019 ; Vol. 124. pp. 265-272.
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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. / Kim, Seoyoung; Park, Ga Young; Yoo, Young Jo; Jeong, Ji Seong; Nam, KiTaek; Jee, Sun Ha; Lim, Kyung Min; Lee, Yun Sil.

In: Food and Chemical Toxicology, Vol. 124, 01.02.2019, p. 265-272.

Research output: Contribution to journalArticle

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