Superfund Research Program
Superfund Chemicals, Nutrition, and Multi-Organ Cardiovascular Risk
Final Progress Reports
Studies and Results
Contaminant remediation and biological modulation of environmentally persistent pollutants are two crucial means of reducing the human health risks of Superfund chemicals/toxicants and related hazardous materials. Although complete remediation of a hazardous site may continue to be an ultimate goal of human exposure risk reduction, it is important to design and implement other biologically relevant means of buffering against toxicant exposure before, during, and after remediation activities. Dr. Hennig and his research team's data implicate the importance of an individual's nutritional status and the use of protective bioactive food components to decrease the overall toxicity of environmental pollutants to biological systems. Their research is based on the paradigm that nutrition can modulate environmental insults.
A major accomplishment was the completion of the research team's in vivo study, where the team demonstrated that feeding a green tea-enriched diet can decrease PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes. Much time was spent to develop toxicological data profiles using the coplanar PCB 126, which is more persistent than PCB 77 and which is a stronger AhR ligand. Following a dose-dependent study with PCB 126, the team of researchers found that gavaging 5 µmol of PCB 126 per kg mouse is optimal to induce vascular inflammation without other signs of compromised health. Utilizing in vitro settings, the research team has provided extensive evidence that selective bioactive food components such as flavonoids can ameliorate PCB toxicity. They now show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the up-regulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low-fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 µmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-isoprostanes and F2-isoprostane metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited five-fold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both messenger RNA and protein analyses, and it was determined that many genes transcriptionally controlled by aryl hydrocarbon receptor and nuclear factor (erythroid-derived 2)-like 2 proteins were up-regulated in PCB-exposed mice fed the green tea-supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126, which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants.
Much work still needs to be done with regard to the understanding of proinflammatory mechanisms associated with the toxicity of coplanar PCBs. The team of researchers continues to test the hypothesis that PCB toxicity to vascular endothelial cells is regulated in part through caveolae signaling. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in endothelial cells. Caveolae may be a critical platform regulating inflammatory signaling pathways induced by PCBs that can be modulated by bioactive compounds (e.g., flavonoids) as well as the cellular lipid milieu. The team of researchers now has preliminary data indicating that adaptive and protective cell responses may be linked to crosstalk between caveolae and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. Cav-1 was silenced in vascular endothelial cells, resulting in a decreased PCB-induced inflammatory response. Cav-1 silencing (siRNA treatment) also increased levels of Nrf2-ARE transcriptional binding, resulting in higher mRNA levels of the antioxidant genes glutathione s-transferase and NADPH dehydrogenase quinone-1 in both vehicle and PCB-treated systems. The researchers's preliminary data demonstrate novel cross-talk mechanisms between Cav-1 and Nrf2 and implicate the reduction of Cav-1 as a protective mechanism for PCB-induced cellular dysfunction and inflammation.
An important objective of this study included a joint project with Dr. Bhattacharyya's group (of the environmental science chloro-organic degradation by nanosized metallic systems and by chelate-modified hydroxyl radical reaction project), where the team discovered that dechlorination of PCB 77 reduced its toxic potency in their biological systems. Due to the difficulty of complete dechlorination in a real world context, this work focused on characterizing and evaluating the biological effects of PCB 77 dechlorination intermediates. The research team analyzed the toxic effects of PCB congener mixtures produced at multiple time points during the dechlorination of PCB 77 to biphenyl. Compared with pure PCB 77, exposing endothelial cells to lower chlorinated PCB byproducts led to improved cellular viability, decreased superoxide production, and decreased nuclear factor kappa B (NF-?B) activation based on duration of remediation. Presence of the parent compound, PCB 77, led to significant increases in mRNA and protein inflammatory marker expression. These data implicate that PCB dechlorination reduces biological toxicity to vascular endothelial cells.
Finally, an exciting study was initiated by one of Hennig's doctoral students to test the hypothesis that, in addition to nutrition, exercise also can modulate the vulnerability to environmental insults. This study was initiated in collaboration with Dr. Kevin Pearson. Preliminary results from this study provide novel findings suggesting that regular physical activity could be utilized as a therapeutic approach for the prevention of adverse cardiovascular health effects induced by environmental pollutants such as PCBs.
The team's research has significance for human health, because life-style changes such as healthy nutrition and an increase in physical activity can markedly alter human vulnerability to chemical stressors (such as PCBs). The research team's work has translational significance as well and is rather cost-effective: healthy life-style changes reduce disease risks associated with exposure to Superfund pollutants. Most of all, the team's research is highly applicable to advance risk assessments. They propose that nutrition can modulate disease risks associated with exposure to Superfund pollutants throughout one's life span and that life-style choices that include healthy nutrition can reduce health risks associated with hazardous substances, which clearly fits within the paradigm of risk assessment.