04/05/2023
Formaldehyde Hazards
Formaldehyde Exposure Immunosuppressive Actions and Related Mechanisms
Modern people spend most of their time indoors, an average of 21.6 hours a day. According to a report by the US Environmental Protection Agency (EPA), the damage caused by indoor air pollution is more than 10 times greater than that caused by outdoor air pollution. According to a report by the World Health Organization (WHO), indoor air pollution causes 4.3 million deaths worldwide, accounting for more than half of air pollution deaths. Formaldehyde is a representative substance among indoor air pollutants and is emitted from various products in daily life such as interior materials, plastics, and pharmaceuticals. In particular, formaldehyde is emitted in large amounts from concrete, furniture, and wallpaper, and is continuously exposed to the human body through inhalation and skin contact. According to the U.S. Environmental Protection Agency, human health hazards from inhalation of formaldehyde include 1) sensory stimulation 2) airway inflammation 3) lung function reduction 4) asthma and atopy induction 5) immune dysfunction 6) neurological and behavioral toxicity 7) developmental and reproductive toxicity this is reported In addition, many studies are being conducted on the relationship between formaldehyde exposure and various diseases, and recently, studies on the effect of formaldehyde on the immune system mediated by T cells have been actively conducted. It has been reported that indoor formaldehyde exposure increases the risk of asthma and atopy in children, and that formaldehyde exposure increases T cell-related cytokines and proteins in rodent models. In addition, it has been reported that formaldehyde causes various effects on the differentiation of T cells and B cells, which are representative cells of the immune response, depending on the exposure concentration, exposure period, exposure period, and experimental model. there is. However, no studies have been reported on the role and effects of regulatory T cells in regulating formaldehyde-induced immune responses. Therefore, this study aimed to investigate the effect and related mechanisms of formaldehyde exposure on the immune response mediated by regulatory T cells. Exposure concentrations were 1.38 mg/m3 and 5.36 mg/m3 by referring to the formaldehyde guidelines of various international organizations and OECD SIDS Initial Assessment Report for SIAM 14: Formaldehyde (Mice NOAEC: 2.46 mg/m3, LOAEC: 5.04 mg/m3) , and repeated whole-body exposure was carried out for 4 hours a day for 10 days. To investigate the effect of this on the immune system, protein expression and mRNA expression of cytokines involved in differentiation of helper T cells, distribution of helper T cells and regulatory T cells, and related induction mechanisms were investigated. As reported in the existing literature, even in this experimental condition, a significant weight loss was observed compared to the control group by exposure to 5.36 mg/m3 formaldehyde, and no significant weight change was observed in the 1.38 mg/m3 exposure group. To investigate the effect of formaldehyde exposure on the lungs, histopathological examination of lung tissue was performed using hematoxylin and eosin (H&E) staining using lung samples obtained after autopsy. As a result, in the 5.36 mg/m3 formaldehyde exposure group, A slight local inflammatory cell infiltration was observed. However, no significant changes were observed in the total white blood cell count and white blood cell differential test of bronchial lavage fluid. This result suggests that the formaldehyde exposure conditions used in this study induce only a slight inflammatory response in the lung tissue of some individuals, but do not cause direct lung damage. Nevertheless, various literatures have reported that formaldehyde can cause lung damage and immune-related diseases, so immunological changes in the spleen, one of the representative immune organs, were investigated under formaldehyde exposure conditions that do not directly affect the lungs. . The spleen is a lymphoid tissue organ where the acquired immune response starts, and it is an immune organ where helper T cells are activated and differentiated into effector T cells (Th1, Th2, and Th17) and regulatory T cells. It has been reported that such differentiation is regulated together with the expression of related cytokines and mRNAs. To investigate the effect of formaldehyde exposure on the differentiation of helper T cells, the levels of protein expression and mRNA expression of related cytokines were compared and analyzed. Expression analysis of Th2 (IL-4, IL-5, and IL-13), Th1 (INF-γ), and Th17 (IL-17A and IL-22) was performed using the Multiplex Luminex System, and mRNA expression analysis was performed using qRT-PCR As a result, all effector T cell-related cytokine protein expression in the spleen was decreased by formaldehyde exposure in a concentration-dependent manner compared to the control group, and a significant decrease was observed in the 5.36 mg/m3 exposure group. It was confirmed that the mRNA expression of these cytokines was also decreased by formaldehyde exposure. Therefore, it can be assumed that formaldehyde exposure inhibits the activity of effector T cells, resulting in a decrease in T cell cytokine secretion and mRNA expression. Regulatory T cells regulate effector T cells and maintain the homeostasis of the immune system, playing an important role in protecting the body from chronic inflammation and autoimmune diseases. However, it has been reported that overexpressed regulatory T cells induce immunosuppression and, as a result, increase the incidence of opportunistic infections and diseases such as cancer. In order to determine whether the decrease in cytokine secretion and mRNA expression caused by formaldehyde exposure was related to regulatory T cells, the distribution of helper T cells and regulatory T cells was measured by flow cytometry, and related mechanisms were analyzed by Western blot technique. . As a result, the distribution of regulatory T cells in the spleen increased by formaldehyde exposure in a concentration-dependent manner compared to the control group, and in particular, a significant increase of about 20% was observed in the 5.36 mg/m3 exposure group. In contrast, no significant changes in helper T cells were observed. A typical induction mechanism related to regulatory T cells is the T cell receptor (TCR) signaling pathway, and recent studies have reported that the TCR signaling pathway involving calcineurin-NFAT plays an important role in the expression, maintenance, and suppression of regulatory T cells. NFAT is dephosphorylated by activated calcinuerin and moves into the nucleus. Then, transcription of NFAT-mediated genes takes place. NFAT1 protein expression plays an important role in increasing the expression of Forkhead box P3 (Foxp3), a representative transcription factor of regulatory T cells, and inhibiting effector T cells. Conversely, NFAT2 protein expression plays an important role in effector T cell proliferation and related cytokine secretion. The protein expression of Calcinuerin, NFAT1 and NFAT2 was comparatively analyzed through Western blot technique. As a result, the expression of calcineurin and NFAT1 protein was increased in a concentration-dependent manner compared to the control group by formaldehyde exposure, and a significant increase was found in the 5.36 mg/m3 exposure group. Observed. On the other hand, the protein expression of NFAT2 tended to decrease slightly compared to the control group. It can be assumed that formaldehyde exposure induces activation of calcineurin-NFAT signaling by regulating the expression of NFAT 1 and 2 differently, thereby increasing regulatory T cells and suppressing the activity of effector T cells. Taken together, these findings suggest that formaldehyde exposure may suppress the activity of effector T cells by increasing the distribution of regulatory T cells through calcineurin-NFAT signaling and, as a result, create an immunosuppressive environment. It is thought that formaldehyde-induced immunosuppression may increase susceptibility to various chemicals or opportunistic infections or diseases such as cancer.
