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. 2022 Nov 16;10(11):694.
doi: 10.3390/toxics10110694.

Hematotoxic Effect of Respiratory Exposure to PHMG-p and Its Integrated Genetic Analysis

Hwa Jung Sung  1 , Sang Hoon Jeong  2 , Ja Young Kang  2 , Cherry Kim  3 , Yoon Jeong Nam  2 , Jae Young Kim  2 , Jin Young Choi  2 , Hye Jin Lee  2 , Yu Seon Lee  2 , Eun Yeob Kim  2 , Yong Wook Baek  4 , Hong Lee  2 , Ju Han Lee  5
Affiliations

Hematotoxic Effect of Respiratory Exposure to PHMG-p and Its Integrated Genetic Analysis

Hwa Jung Sung et al. Toxics. .

Abstract

Polyhexamethylene guanidine phosphate (PHMG-p), the main ingredient of humidifier disinfectants, circulates systemically through the lungs; however, its toxicological assessment has been primarily limited to pulmonary disease. Herein, we investigated the possible abnormalities in hematopoietic function 20 weeks after intratracheal instillation of PHMG-p in a rat model. Notable abnormalities were found out in the peripheral blood cell count and bone marrow (BM) biopsy, while RNA sequencing of BM tissue revealed markedly altered gene expression. Furthermore, signaling involved in hematopoietic dysfunction was predicted by analyzing candidate genes through Ingenuity Pathway Analysis (IPA) program. Respiratory PHMG-p exposure significantly decreased monocyte and platelet (PLT) counts and total protein, while significantly increasing hemoglobin and hematocrit levels in peripheral blood. Histopathological analysis of the BM revealed a reduced number of megakaryocytes, with no significant differences in spleen and liver weight to body weight. Moreover, PHMG-p exposure significantly activated estrogen receptor signaling and RHOA signaling, and inhibited RHOGDI signaling. In IPA analysis, candidate genes were found to be strongly related to 'hematological system development and function' and 'hematological disease.' Accordingly, our results suggest that PHMG-p could affect hematopoiesis, which participates in monocyte differentiation and PLT production, and may induce hematologic diseases via the respiratory tract.

Keywords: Ingenuity Pathway Analysis (IPA); bone marrow (BM); hematopoietic toxic effect; polyhexamethylene guanidine phosphate (PHMG-p); respiratory exposure.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
BM tissue with stained megakaryocytes (400×). (A) Control BM stained with hematoxylin and eosin, (B) control BM with megakaryocyte cytoplasm immunostained with integrin β3, (C) PHMG-p exposed BM stained with hematoxylin and eosin, and (D) PHMG-p-exposed BM with the cytoplasm of megakaryocytes immunostained with integrin β3. BM, bone marrow; PHMG-p, polyhexamethylene guanidine phosphate.
Figure 2
Figure 2
Top canonical pathways elicited by PHMG-p exposure. Pathway candidates selected using IPA core analysis. All canonical pathways registered on the IPA dataset were automatically matched and analyzed for candidate genes. The length of bars is indicated based on the p-value of Fisher’s exact test. IPA, Ingenuity Pathway Analysis; PHMG-p, polyhexamethylene guanidine phosphate.
Figure 3
Figure 3
Core signaling pathways related to hematopoiesis. Twenty weeks after intratracheal instillation of PHMG-p, molecules associated with candidate genes analyzed in the bone marrow are schematized as a hematopoietic signaling pathway. PHMG-p, polyhexamethylene guanidine phosphate.
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