Background and Purpose: Arsenic exposure can lead to skin lesions and multiple organ damage, which are not easily reversible and for which there is no effective therapeutics. Identification of reliable epigenetic markers is essential for early recognition of arsenic poisoning risk. Anomalous DNA methylation of immune homeostasis regulator FOXP3 is a critical mechanism for triggering arsenic poisoning. This study aims to explore the value of FOXP3 methylation in the identification of arsenic poisoning risk. Methods: 88 arsenic poisoning subjects and 41 references were recruited. Urinary arsenic contents and FOXP3 methylation in PBLCs was measured by ICP-MS and pyrosequencing, respectively. Results: The results showed that the elevated FOXP3 methylation in PBLCs were associated with the increased levels of urinary arsenic and were positively associated with the increased risk of arsenic poisoning and its progression. The result of mediation analysis revealed that 24.3% of the effect of arsenic exposure on the risk of arsenic poisoning was mediated by increased FOXP3 methylation. Additionally, we constructed a nomogram model with FOXP3 methylation as an epigenetic predictor to assess the probability of individual arsenic poisoning. The model showed a robust ability in the discrimination of arsenic poisoning risk, with an area under receiver operating characteristics curve of 0.897(0.845–0.949) and more than 70% accuracy. The calibration curves and the Harrell concordance index showed that the consistency rate between the probability predicted by the nomogram model and the actual probability is 89.7%. Conclusions: Taken together, we found the great potential of FOXP3 methylation for the identification of arsenic poisoning risk and provided a new approach to the application of epigenetic markers in accurately quantifying the risk of adverse outcomes.
This study aimed to investigate the effect of N6-methyladenosine (m 6 A) modification in modulating inflammatory homeostasis of arsenic (As)-induced skin lesions. Our bioinformatic analysis revealed abnormal expression of m 6 A RNA methylation regulators and cytokines in the arsenic-exposed population. In human keratinocytes, arsenite increased the levels of m 6 A methylation by upregulating the RNA methyltransferase like 3 (METTL3), mediating the disordered secretion of indicators that reflect inflammatory homeostasis . The indicators reflecting arsenic-induced skin lesions (Krt1 and Krt10) were also significantly elevated, which contributed to the occurrence of skin lesions. Our results also confirmed the association between METTL3 with inflammatory homeostasis and arsenic-induced skin lesions using arsenic-exposed human skin samples. In the arsenic-exposed group, the upregulation of METTL3 exacerbated the increase in cytokine levels (IL-6, IL-17, and IL-10), which was associated with the upregulation of keratins (Krt1 and Krt10). In addition, significant correlations among these factors corroborate the theoretical links. Finally, alteration of the m 6 A levels via knockdown or enhancement of the METTL3 protein could antagonize or aggravate arsenite-induced imbalanced inflammatory homeostasis and human keratinocyte damage in HaCaT cells. Collectively, our study reveals some evidence that regulation of m 6 A modification plays an important role in arsenic-induced skin lesions, which provide a new perspective on the mechanism of arsenite-induced imbalanced inflammatory homeostasis in the field of RNA epigenetics.arsenic, imbalanced inflammatory homeostasis, N 6 -methyladenosine, skin lesions 1 | INTRODUCTION Arsenic (As), a natural element, is widely distributed in the environment. Arsenic exposure occurs primarily through ingestion of contaminated water or food and inhalation of contaminated air. 1,2 Arsenicosis is a multi-systemic disease that involves the digestive, cardiovascular, neural, and cutaneous systems, [3][4][5] which drastically impacts the quality of life and survival of patients and is a worldwide public health priority. A major target organ of As is the skin. The early manifestation of arsenic exposure and toxicity is skin lesions, including hyperkeratosis, hypopigmentation, and hyperpigmentation. 6 Immune dysfunction is an important pathogenesis mechanism of arseniasis. One of the main manifestations is an imbalanced inflammatory homeostasis. 7 Previous studies have confirmed that arsenicexposure can cause injury by triggering imbalanced inflammatory homeostasis in coal-burning As-exposed human and rats. This occurs by interfering with the secretion of pro-inflammatory and anti-inflammatory cytokines (IL-10) to disrupt the differentiation
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.