Di(2-ethylhexyl)phthalate impairs erythropoiesis via inducing Klotho expression and not via bioenergetic reprogramming

Chang-Yi Tsai; Te-Ping Fang; Shuoh-Wen Chen; Hsiao-Wen Chen; Eric Chang-Yi Lin; Ting-An Lin; Der-Cherng Tarng; Yuan-I Chang

Di(2-ethylhexyl)phthalate impairs erythropoiesis via inducing Klotho expression and not via bioenergetic reprogramming

Am J Transl Res. 2022 Feb 15;14(2):1234-1245. eCollection 2022.

Authors

Chang-Yi Tsai¹, Te-Ping Fang¹, Shuoh-Wen Chen¹, Hsiao-Wen Chen¹, Eric Chang-Yi Lin¹, Ting-An Lin^{1

2

3}, Der-Cherng Tarng^{1

4

5

6}, Yuan-I Chang¹

Affiliations

¹ Department and Institute of Physiology, National Yang Ming Chiao Tung University Taipei 112304, Taiwan.
² Department of Internal Medicine, National Yang Ming Chiao Tung University Taipei 112304, Taiwan.
³ Division of Hematology, Department of Medicine, Taipei Veterans General Hospital Taipei 112201, Taiwan.
⁴ Institute of Clinical Medicine, National Yang Ming Chiao Tung University Taipei 112304, Taiwan.
⁵ Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital Taipei 112201, Taiwan.
⁶ Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) Hsinchu 300093, Taiwan.

PMID: 35273725
PMCID: PMC8902563

Abstract

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulated the function of hematopoietic stem and progenitor cells (HSPCs) to influence erythropoiesis, and to explore the associated mechanisms. In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function, but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interfered with erythroid differentiation, we focused on energy metabolism and Klotho expression. DEHP suppressed erythroid differentiation via upregulating Klotho expression, while it did not via modulating cellular bioenergetics. Therefore, our results provided a novel insight into the pathophysiological link between phthalates and dysregulated erythroid differentiation.

Keywords: DEHP; Klotho; bioenergetics; erythroid differentiation; phthalates.