Association between serum periostin levels and the severity of arsenic-induced skin lesions

Abstract

Arsenic is a potent environmental toxicant and human carcinogen. Skin lesions are the most common manifestations of chronic exposure to arsenic. Advanced-stage skin lesions, particularly hyperkeratosis have been recognized as precancerous diseases. However, the underlying mechanism of arsenic-induced skin lesions remains unknown. Periostin, a matricellular protein, is implicated in the pathogenesis of many forms of skin lesions. The objective of this study was to examine whether periostin is associated with arsenic-induced skin lesions. A total of 442 individuals from low- (n = 123) and high-arsenic exposure areas (n = 319) in rural Bangladesh were evaluated for the presence of arsenic-induced skin lesions (Yes/No). Participants with skin lesions were further categorized into two groups: early-stage skin lesions (melanosis and keratosis) and advanced-stage skin lesions (hyperkeratosis). Drinking water, hair, and nail arsenic concentrations were considered as the participants' exposure levels. The higher levels of arsenic and serum periostin were significantly associated with skin lesions. Causal mediation analysis revealed the significant effect of arsenic on skin lesions through the mediator, periostin, suggesting that periostin contributes to the development of skin lesions. When skin lesion was used as a three-category outcome (none, early-stage, and advanced-stage skin lesions), higher serum periostin levels were significantly associated with both early-stage and advanced-stage skin lesions. Median (IQR) periostin levels were progressively increased with the increasing severity of skin lesions. Furthermore, there were general trends in increasing serum type 2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and immunoglobulin E (IgE) levels with the progression of the disease. The median (IQR) of IL-4, IL-5, IL-13, eotaxin, and IgE levels were significantly higher in the early-and advanced-stage skin lesions compared to the group of participants without skin lesions. The results of this study suggest that periostin is implicated in the pathogenesis and progression of arsenic-induced skin lesions through the dysregulation of type 2 immune response.

Fig 1. Representative photographs of arsenic-induced skin lesions.

A. Leucomelanosis on the back, B. Diffuse pigmentation on the chest, C. Severe hyperkeratosis (large nodular keratosis) on the palms, and D. Severe hyperkeratosis on the soles.

Fig 2. Comparisons of arsenic exposure levels between the groups of participants with and without skin lesions using box and whisker plots.

Comparisons of water (A), hair (B), and nail (C) arsenic levels between the groups of participants with and without skin lesions. The center line indicates the median value, the box contains the 25th to 75th percentiles of the dataset. The whiskers mark the minimum and maximum values. The dots show the individual data points. Mean rank differences were assessed by using the Mann-Whitney U test between each skin lesions group. ***p < 0.001.

Fig 3. Comparison of the distribution patterns of serum periostin in the different stages of skin lesions using box and whisker plots.

(A) Comparison between the groups of participants with and without skin lesions (B) Comparison among the participants without, early- and advanced-stage skin lesions groups. The center line indicates the median value, the box contains the 25th to 75th percentiles of the dataset. The whiskers mark the minimum and maximum values. The dots show the individual data points. Mean rank differences were assessed by using the Mann-Whitney U test (A), and the Kruskal-Wallis test followed by Dunn-Bonferroni post hoc test (B) between each skin lesions group. ***p < 0.001; *p < 0.05.

Fig 4. Comparisons of the levels of type 2 cytokines and IgE in the different stages of skin lesions using box and whisker plots.

Comparisons of IL-4 (A), IL-5 (B), IL-13 (C), eotaxin (D), and IgE (E) levels between the groups of participants with and without skin lesions. The center line indicates the median value, the box contains the 25th to 75th percentiles of the dataset. The whiskers mark the minimum and maximum values. The dots show the individual data points. Mean rank differences were assessed by the Kruskal-Wallis test followed by Dunn-Bonferroni post hoc test between each skin lesions group. ***p < 0.001; **p < 0.01; ^‡p = 0.075.