NORA Construction Sector Strategic Goals
HELD002 - Oxidative mechanisms of hexavalent chromium induced dermatitis
Principal Investigator (PI)
Primary Goal Addressed
Secondary Goal Addressed
Attributed to Construction
Cr(VI) is known to cause dermaltitis. The long term objectives are to understand the chemical oxidative mechanisms that underlie the toxicology of Cr(VI), especially the early events during Cr(VI) interaction with skin in the absence and presence of FeSO4. Guinea pig skin and cultured human skin will be used in this project. A variety of analytical methods will be developed and applied, including spin-trapping ESR, HPLC, LC/MS, UV/vis, fluorescence and biochemistry methods. We expect that ROS, Cr radical, Cr-complex and lipid peroxidation products will be detected. The radical species that we found in skin will be identified. The effect of FeSO4 can be confirmed. These studies should provide important insight into occupational dermal risk. The results will be helpful to reduce dermal exposure and associated occupational illnesses among construction workers.
ROS can activate both physiologic and pathologic mechanisms. Cr(VI) is capable of inducing the generation of ROS and destroy the dermal defense system leading to skin diseases. The goal of this proposal is to understand the chemical oxidative mechanisms that underlie the toxicology of Cr(VI), especially the early events during interaction of Cr(VI) with skin tissue in the absence and presence of FeSO4.
Although Cr(VI) is a known potent oxidant, itself is relatively un-reactive towards DNA and protein under physiological conditions unless reducing agents are added. Therefore, the capacity of Cr(VI) to damage skin is a result of its interaction with skin component to induce the generation of various reactive intermediates followed by the formation of Cr-complexes that may act as a shuttle to induce further the generation of reactive species. ROS is one of these reactive species and is capable of causing DNA modification, lipid peroxidation, and secretion of inflammatory cytokines. To deal with the harmful effect of oxidative stress, human skin equipped with antioxidant defense mechanisms which prevent oxidative injury of structural lipid and proteins contributing to barrier integrity. Cr(VI) depletes the antioxidant and forms various stable complexes and DNA adducts. Therefore, the oxidative mechanism may be one of Cr(VI) causing dermatitis pathways. To achieve our goal, our specific aims are proposed.
1. 1st to 2nd year, we will investigate the early events during Cr(VI) interaction with skin tissue in the absence and presence of FeSO4, respectively. Cr(VI) will react with skin to form various reactive intermediates species including Cr radicals and ROS. We will detect and identify those primary species using EPR and spin trapping in combination with EPR techniques. Also, we will test the effect of FeSO4 during Cr(VI) interaction with skin. The results may lead to two peer reviewed articles.
2. 2nd to 4th year, we will investigate the effects of antioxidants in Cr(VI) activation. First
we will analyze the antioxidants such as ascorbate, a-tocopherol, ß-carotene, glutathion and cysteine in skin tissue. We will establish a model system with these antioxidants at a similar level existing in skin and determine their reaction rate constants with Cr(VI). The techniques for these assay include chemical kinetics techniques, Fluorescence, EPR, HPLC/DAD/ELSD, LC/MS in combination with EPR. The results will generate at least two peer reviewed areticles.
3. 3rd to 5th year, To characterize the secondary products induced by Cr(VI) in skin tissue. We will determine and identify the Cr(VI) induced complex and adducts of skin component as well as oxidative bio-marker, DNA oxidative product 8-OHdG during the interaction of Cr(VI) with skin tissue using EPR, HPLC/ELSD and LC/MS. We expect that the results will lead to two peer reviewed article.
4. 4th to 5th year, we are going to investigate the lipid composition and study the lipid peroxidation during Cr(VI) interaction with skin tissue. ROS induced by Cr(VI) in skin abstracts a hydrogen atom from PUFAs initiating lipid peroxidation. Lipid peroxidation might be also regarded as indirect evidence for the generation of ROS induced by Cr(VI) in skin tissues. We will determine the lipid composition in Cr(VI) exposed and un-exposed skin in absence and presence of FeSO4, respectively. Also, we will measure the lipid peroxidation product, malonaldehyde (MDA) or 4-hydroxy-2-nonenal using an immune assay or GC/Mass spectrometry. The results will lead to two peer reviewed articles.
The findings of this project will be presented to stakeholders at the conferences focusing on construction safety and health, suggesting that: 1) workers need to reduce their exposure to Cr(VI) by wearing proper protection cloth and gloves; 2) as an intervention workers might take action to decrease free radical production in the skin by applying antioxidants contained cream on the skin; 3) manufacturers may consider additional researches to explore alternate means of reducing Cr(VI) level in their products.