NORA Manufacturing Sector Strategic Goals
927ZJFR - PFOA and PFOS-induced oxidative stressStart Date: 10/1/2009
End Date: 9/30/2013
Principal Investigator (PI)Name: Yong Qian
Funded By: NIOSH
Primary Goal Addressed9.0
Secondary Goal Addressed
Attributed to Manufacturing
Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) are widely known man-made fluorocarbon based acids, which have been used in various industrial processes in the aircraft, automotive, chemical, building material, and personal care products industries. They are non-biodegradable and persistent in the human body and environment. Surveillance data suggests that PFOA and PFOS may cause adverse health effects, but no consistent association between exposure and health effects has been proven. This study will use a mouse model as well as human cells to detect and identify an oxidative stress response as a result of exposure to PFOA and PFOS. Isolating this type of response may help identify potential health effects of exposure. This study will contribute to NIOSH research goals for creating new knowledge related to emerging risks in manufacturing as well as the goal of contributing to the identification of agents that may pose hazards to occupational safety or health in manufacturing. This will potentially result in presentations at scientific conferences and publications in peer reviewed scientific journals that influence the direction of science related to evaluating the health effects of exposure to PFOA and PFOS as well as data from this project being disseminated through NIOSH, EPA, and OSHA to support the development of prevention strategies.
PFOA and PFOS are used in the production of fluorocarbon-based industrial surfactants in aircraft production processes, automotive production processes, chemical products, building products, electronic products, and personal care products. Surveillance studies have suggested an association between PFC exposure and the adverse health effects. However, confounding factors have weakened determination of causality and mechanistic information is lacking.
The central hypothesis of this proposal is that exposure to PFOA and PFOS induces an oxidative stress response, which leads to dysfunction of the vascular permeability barrier. The overall objective of this proposal is to test this hypothesis at three different levels: cells, mice, and human serum specimens. To accomplish the objective of this proposal, four specific aims are proposed.
Specific Aim 1 will detect and identify ROS generation in human microvascular endothelial cells (HMVECs) exposed to PFOA and PFOS in vitro. The hypothesis of this specific aim is that PFOA and PFOS exposure produces ROS in HMVECs, which may be through NADPH oxidase activation. We will use electron spin resonance (ESR) spin trapping, confocal microcopy, flow cytometry, ELISA, and other molecular techniques to detect the ROS production. Antioxidant enzyme overexpression, protein deletion, and various specific antioxidant inhibitors will be used to identify the mechanisms of PFOA and PFOS-induced ROS production.
Specific Aim 2 will detect PFOA and PFOS-induced oxidative stress response in mice. The hypothesis of this specific aim is that PFOA and PFOS exposure induces both oxidative stress and antioxidant defense response in mice. Mice will be exposed to PFOA and PFOS through drinking water. First, we will perform the following measurements to detect the oxidative stress in mice: a) total ROS production using chemiluminescence in whole blood, b) lipid peroxidation in serum, c) protein oxidation in serum, and d) DNA damage by measuring 8-OHdG in serum. Then, we will measure PFOA and PFOS-induced antioxidant defense adaption in mice serum, including total antioxidant status, manganese superoxide dismutase activities, catalase activities, and glutathione peroxidase activities.
Specific Aim 3 will determine the role of ROS production in PFOA and PFOS-induced endothelial permeability in vitro and in vivo. The hypothesis of this specific aim is that ROS production is important in PFOA and PFOS-induced endothelial permeability both in vitro and in vivo. Both the cell-based in vitro assays and the in vivo mice assays will be performed to determine the involvement of ROS production in PFOA and PFOS-induced endothelial permeability. The changes in monolayer HMVEC permeability will be determined by measuring transendothelial electrical resistance (TER) using an electric cell-substrate impedance sensor (ECIS) and analyzing cell morphology uses a confocal microscopy. The changes in vascular permeability in mice will be determined by a rhodamine-conjugated dextran vassal permeability assay.
Specific Aim 4 will determine the association between the PFOA and PFOS concentrations and markers of oxidative stress in human serum samples. The hypothesis of this specific aim is that the exposure concentrations of PFOA and PFOS in serum correlate with the intensity of oxidative stress in humans. Data for PFOA and PFOS levels in banked serum samples are available through collaborators at West Virginia University. We will perform the following measurements to detect the oxidative stress in human serum specimens: a) lipid peroxidation, b) protein oxidation, and c) DNA damage by measuring 8-OHdG in serum.
This study will provide a fundamental understanding concerning the adverse health effects of PFOA and PFOS exposure. It is anticipated that results of this study will be used by West Virginia University Health Sciences Center, NIOSH, OSHA, EPA, and public health systems in developing prevention strategies for PFOA and PFOS, as well as other members of PFAA. Workers impacted by this research project will be those involved in the synthesis of PFOA and PFOS and their use in manufacturing new products.
The new research project will provide the information about PFOA and PFOS-induced toxicity in cells, mice, and humans, which will lead to developing an in vitro screening model for assessing the potential vascular toxicity of other members of the PFAA family and will provide a basis for recommendations and guidance on the safe handling of PFOA and PFOS as well as other members of perfluorooctanoic acids (PFAAs). The information obtained from this research can be used by NIOSH, OSHA, and EPA in developing protective strategies for PFAAs in face of little epidemiology data. Workers impacted by this research will be those involved in the synthesis of PFOA and PFOS and their use in manufacturing new products. Success of the project will be determined by publications in reputable journals in the field, impact on the field as indicated by citations and use of data by NIOSH, OSHA, and EPA to develop prevention strategies.
Perfluorinated chemicals (PFC) are man-made chemicals with a backbone 4-14 carbons in length and a charged functional moiety (mainly carboxylate, sulfonate, or phosphonate). Perfluoroalkyl acids (PFAA) are a member of the PFC family.
Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are the two most widely known PFAAs, which contain an eight-carbon backbone. They are man-made fluorocarbon based acids that have been used in various industrial processes, such as aircraft production processes, automotive production processes, chemical products, building products, electronic products, and personal care products. They are non-biodegradable and persistent in the human body and environment. They are released directly from industrial processes, as well as from the use in manufacturing of new products. Human occupational and environmental exposure to PFOA and PFOS occurs globally. Accumulating surveillance data suggest that exposure to PFOA and PFOS may pose adverse effects on human health. However, no consistent association between their exposures and the adverse health effects has yet been proven. The Center for Disease Control and Prevention (CDC) has recently established biomonitoring for several members of PFAAs in its National Health and Nutrition Examination Survey (NHANES). Therefore, data are needed to demonstrate a cause and effect relationship.
Surveillance Information: National Health and Nutrition Examination Survey (NHANES)
The central hypothesis of this proposal is that exposure to PFOA and PFOS induces an oxidative stress response, which leads to dysfunction of the vascular permeability barrier. We will apply various laboratory techniques to detect and identify the production of ROS upon PFOA and PFOS stimulation in cultures of human microvascular endothelial cells (HMVECs) and a mouse model.
We will also utilize several molecular biological approaches to determine oxidative stress response in mice and humans using serum samples. Finally, we will examine the role of ROS production in PFOA and PFOS-induced vascular permeability changes in vitro and in vivo.
We believe that at the completion of this proposed study, we will have more information about PFOA and PFOS-induced toxicity in cells, and mice models which can be applied to humans. Results will lead to development of an in vitro screening assay for evaluating the potential toxicity of other members of the PFAA family. Results will also provide a basis for recommendations and guidance on the safe handling of PFAAs.
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