Biomol Ther  
Low Dose Exposure to Di-2-Ethylhexylphthalate in Juvenile Rats Alters the Expression of Genes Related with Thyroid Hormone Regulation
Minjeong Kim1,†, Ji Seong Jeong2,†, Hyunji Kim3, Seungwoo Hwang4, Il-Hyun Park5, Byung-Chul Lee5, Sung Il Yoon6, Sun Ha Jee7, Ki Taek Nam3,* and Kyung-Min Lim1,*
1College of Pharmacy, Ewha Womans University, Seoul 03760,
2Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Daejeon 34114,
3Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722,
4Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141,
5GENECAST Co., Seongnam 05838,
6Department of Epidemiology and Health Promotion, and Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 03722,
7Lab frontier Co., Anyang 14042, Republic of Korea
E-mail: kmlim@ewha.ac.kr (Lim KM), kitaek@yuhs.ac (Nam KT)
Tel: +82-2-3277-3055 (Lim KM), +82-2-2228-0754 (Nam KT)
Fax: +82-2-3277-3760 (Lim KM), +82-2-2227-8129 (Nam KT)
The first two authors contributed equally to this work.
Received: April 30, 2018; Revised: June 23, 2018; Accepted: June 26, 2018; Published online: August 2, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Phthalates widely used in the manufacture of plastics have deeply penetrated into our everyday lives. Recently, a concern over the toxicity of phthalates on thyroid, has been raised but in most of cases, the doses employed were unrealistically high. To investigate the effects of phthalates on thyroid, we investigated the effects of the repeated oral exposure to low to high doses (0.3, 3, 30 and 150 mg/kg) di-2-ethylhexylphthalate (DEHP) from weaning to maturity for 90 days in juvenile rats on the thyroid. The histological examination revealed that DEHP significantly induced hyperplasia in the thyroid from the doses of 30 mg/kg, which was confirmed with Ki67 staining. In line with this finding, increased mRNA expression of thyrotropin releasing hormone (Trh) was observed in the thyroid of female at 0.3 mg/kg and 150 mg/kg as determined by RNAseq analysis. Moreover, significantly increased expression of parathyroid hormone (Pth) in the female at 0.3 mg/kg, and thyroglobulin (Tg) and thyroid hormone responsive (Thrsp) in the male at 0.3 mg/kg were noted in the blood, of which changes were substantially attenuated at 150 m/kg, alluding the meaningful effects of low dose DEHP on the thyroid hormone regulation. Urinary excretion of mono-2-ethylhexyl-phthalate (MEHP), a major metabolite of DEHP was determined to be 4.10 and 12.26 ppb in male, 6.65 and 324 ppb in female at 0.3 and 30 mg/kg DEHP, respectively, which fell within reported human urine levels. Collectively, these results suggest a potential adverse effects of low dose phthalates on the thyroid.
Keywords: Phthalate, di-2-ethylhexylphthalate (DEHP), Thyroid, Juvenile toxicity, Thyroid hormone, Proliferation


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