Arsenic Toxicity - Heat Shock Response

Heat Shock Response

Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27,60,70,72,90,110 kDa as well as metallotionein, ubiquitin, mitogen-activated kinases, extracellular regulated kinase, c-jun terminal kinases and p38. Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines The effects are largely dependant on the dosing regime and may be as well inversed.

As shown by some experiments reviewed by Del Razo (2001), ROS induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. Thus, taking into account p53’s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.