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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

 Seoyoung Kim  ;  Ga-Young Park  ;  Young Jo Yoo  ;  Ji Seong Jeong  ;  Ki Taek Nam  ;  Sun-Ha Jee  ;  Kyung-Min Lim  ;  Yun-Sil Lee 
 FOOD AND CHEMICAL TOXICOLOGY, Vol.124 : 265-272, 2019 
Journal Title
Issue Date
Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; DNA Damage/drug effects* ; Diethylhexyl Phthalate/adverse effects* ; Female ; Histones/metabolism ; Humans ; Male ; Phosphoproteins/metabolism ; Rats, Sprague-Dawley ; Receptors, Thyrotropin/metabolism* ; Signal Transduction/drug effects* ; Thyroid Gland/drug effects* ; Thyroid Gland/pathology
DNA damage ; Di-(2-ethylhexyl) phthalate (DEHP) ; Phthalates ; Proliferation ; Thyroid ; Thyrotropin receptor (TSH)
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.
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Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
Yonsei Authors
Nam, Ki Taek(남기택)
Jee, Sun Ha(지선하) ORCID logo https://orcid.org/0000-0001-9519-3068
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