Abstract
Hexavalent chromium (Cr(VI)) is widely used in many industries but can induce contact dermatitis especially in cement industries. Many cement workers suffer from Cr(VI)-induced allergic contact dermatitis (ACD), and prevention and therapeutic strategies are still lacking. Pterostilbene (PT) is a natural compound predominantly found in blueberries. Studies indicate the potential use of PT as an effective anti-oxidative and anti-inflammatory agent. Herein, we investigated the possible mechanisms involved and whether chromium-induced ACD could be effectively inhibited by treating PT. In our in vivo study, epidermal Cr(VI) administration causes cutaneous inflammation in mice ear skin, and the pro-inflammatory cytokines, TNF-α and IL-1β, were found in the epidermis, presenting the level of increase after Cr(VI) treatment. Meanwhile, the results of our in vitro experiment showed that apoptosis and endoplasmic reticulum (ER) stress were induced after treatment with different concentrations of Cr(VI) in HaCaT cells (human keratinocyte). Cr(VI) also induced TNF-α and IL-1β mRNA expressions, through the activation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) pathway. Notably, the severity of the skin reactions in the epicutaneous elicitation test significantly diminished when the mouse was treated with PT. Likewise, PT intervention also ameliorated the inflammation and apoptosis of HaCaT cells in vitro. Furthermore, our current findings demonstrated that the NLRP3 inflammasome could be involved in the Cr(VI)-mediated inflammation and apoptosis of ACD. Thus, interrupting this mechanism with proper nontoxic agents, such as PT, could be a new option to improve occupational chromium toxicity and hypersensitivity.
Highlights
Allergic contact dermatitis (ACD) is an important occupational disease caused mainly by topical exposure to hexavalent chromium (Cr(VI)), an impurity of cement manufacture
Reactive oxygen species (ROS) activation was proposed as the initial event, as it leads to the activation of transcriptional factors and signaling pathways, including NF-κB and p38 mitogen-activated protein kinase (MAPK) pathway, which leads to the release of pro-inflammatory cytokines such as TNF-α and IL-1β [5,6,7]
It usually takes months to years for cement workers to become sensitized to Cr(VI) [28], and it is difficult to observe the effects of preventative agents that might benefit cement workers in a short period of time
Summary
Allergic contact dermatitis (ACD) is an important occupational disease caused mainly by topical exposure to hexavalent chromium (Cr(VI)), an impurity of cement manufacture. Due to its high prevalence, ACD exerts an important occupational health impact on those workers. Disruption of MK2 signaling leads to a significant reduction in the level of several pro-inflammatory cytokine production [8]. ROS are involved in the activation of the NLRP3 inflammasome, which is required to direct the proteolytic maturation of inflammatory cytokines, such as IL-1β and IL-18. Recent studies have indicated that the NLRP3 inflammasome is often wrongly activated by environmental irritants, resulting in cutaneous inflammatory diseases [9]. The intracellular reduction of Cr(VI) is associated with the production of ROS, leading to dermal toxicity, cytokine excretion and skin hypersensitivity [1]
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