Because of the impact that particle-gas exposures may have on public health, identification of host factors that influence susceptibility to airborne pollutants remains an important issue. Particular concern has arisen about potentially sensitive sub-groups such as children, asthmatics, and the elderly. Individuals with cardiopulmonary disease are at particular risk to the effects of exposure. Recent evidence has suggested that some individuals may be genetically predisposed to environmental stressors, including oxidants and particles. Epidemiological studies have also suggested that PM may produce significant changes in cardiovascular function in addition to its pulmonary effects. In ongoing studies, we have began to test the hypothesis that genetic background is an important host factor that contributes to interindividual responsivity to particulate-induced immune dysfunction (an indicator of morbidity) and decreased heart rate (HR) and heart rate variability (HRV). ? ? Reduced HRV and increased resting HR are well established indicators of increased cardiovascular risk. A number of factors have been identified as determinants of HRV that do not fully explain the reported variance in HRV. Importantly, genetic factors may significantly influence HR and HRV, but have not been studied in sufficient detail. The purpose of this study was to assess the genetic contribution to variation in basal HR and HRV and to identify quantitative trait loci (QTLs) that associate with the HR and HRV phenotypes. It is anticipated that identification of genes that control basal heart function will facilitate understanding of the HR and HRV responses to environmental stressors. We have studied thirty male inbred strains of mice (20-30 g) and 29 male BXD Recombinant Inbred (RI) strains. An ETA-F20 radio telemetry transmitter was implanted subcutaneously in all mice for 20 minutes or ECG recording during periods of sleep when breathing rate and depth were consistent. Pulmonary function was assessed using a whole body plethysmograph (Buxco). Statistically significant differences were found in baseline HR and HRV between the inbred strains. The range in mean ( SEM) HRV (ms2/Hz) was 1.39 0.2 (PL/J) to 3.35 0.1 (C3H/HeJ) for the inbred strains. Furthermore, no correlation between baseline HRV and , Vt or f was found between these inbred strains. Mean HR and HRV did not co-segregate (R=0.18) among the strains investigated. That is, HR did not predict HRV, and in the majority of strains a wide range of values for HRV was observed at similar HRs. The most notable exceptions were the CAST and C57L strains. Despite the higher HRs, HRV remained within the range of the other strains suggesting that HR and HRV are independent from one another in these strains. Using the mean HR/HRV data for each of the RI strains, we used MapManager algorithms to identify a significant QTL for HR chromosome 6, 52-56 megabases (Mb) and five suggestive QTLs (chromosomes 2, 4, 5, 6, and 14) for HRV. This study reports a clear genetic influence on HR and HRV using a broad range of inbred mouse strains. However, the influence of genotype on HR, and in particular, HRV appears to be highly complex. This is supported by the continuous distribution of HR and HRV among the strain sets, and the multiple QTLs for each phenotype. This study provides the basis to investigate the precise interaction between genotype and the underlying mechanisms associated with murine heart regulation. ? ? Epidemiological studies have reported changes in heart rate (HR) and HRV during periods of elevated levels of PM, suggesting an effect on the autonomic nervous system. Animal models have supported this notion by demonstrating changes in heart rate. Such changes in HRV are believed to indicate a greater risk of life threatening arrhythmia or the occurrence of fatal CV events in those with pre-existing CV or cardiopulmonary disease. However, there is a paucity of experimental data regarding the possible mechanisms by which PM effects HR and HRV, and little is known about the role of genetics in susceptibility to an adverse response of the heart following exposure to PM. The main purpose of this study was to use positional cloning to identify a genetic component to PM induced changes in HR and HRV using inbred strains of mice. Twelve inbred strains of male mice have been studied. Mice with a subcutaneously implanted telemetry transmitter were aspirated with 50l of sterile saline containing 100g of UF-PM (< 0.1m; from Chapel Hill, NC) or 50l of sterile saline alone. Multiple between-strain differences in HR and HRV suggested a genetic component to the cardiac responses observed following PM exposure. A significant reduction in HR was found in SJL/J mice within the first hour after the bolus exposure to PM and then returned to resting levels after 4 hours. Other strains responded similarly (e.g. NZB/BINJ and BPH/2J), while others did not respond to the PM (e.g. CBA/CaJ and BPN/1J). Furthermore, reductions in HRV were also found in PL/J and BPH/2J within the first few hours after exposure. Interestingly there were no changes in HR in the PL/J mice during this time demonstrating that the two phenotypes did not always respond in concert with one another. Results of these studies provide the basis for further investigation of genetic susceptibility to HR/HRV responses to environmental particulates.? ? We have also initiated a study to investigate the mechanisms of susceptibility to chronic bronchitis phenotypes induced by exposure to the metal vanadium which is known to be an important component of particulates in industrialized cities. Forty-five (45) inbred strains of mice were exposed to two weekly doses of 4 mg/kg V2O5 by oropharyngeal aspiration. One week after the second dose, mice were euthanized. Interestingly, this dosing regime caused strain-dependent distinct phenotypes including fibrosing alveolitis-like phenotypes with focal regions of alveolar inflammation and interstitial fibrosis, bronchitis-like phenotypes featuring peribonchial/perivascular inflammation and mucus cell metaplasia, a combination of both phenotypes, or neither. This novel observation emphasizes the importance of genetic background on host responses to environmental exposures and indicates that V2O5 can be used as a model of pulmonary fibrosis and/or chronic bronchitis. A comparison of strains revealed significant interstrain variation in V2O5-induced lung collagen content (approx. 10-fold difference between lowest and highest responding strains) indicating a significant genetic component for this phenotype. B6 and DBA/2J (D2) mice were identified as fibrosis resistant and susceptible strains, respectively (6-fold difference in collagen levels). Additionally, BXD RIs were used to identify a highly significant QTL for susceptibility to V2O5-induced interstitial fibrosis. In collaboration with Dr. Tim Wiltshire, we have employed a complimentary in silico haplotype mapping approach and have identified 4 additional significant QTLs. We are currently testing candidate genes for the fibrosis phenotype using available KO mice. These studies are the first to systematically investigate the genetic basis of susceptibility to the pulmonary responses to a common metal found in particulate air pollution.
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| Turner, Michael J; Kleeberger, Steven R; Lightfoot, J Timothy (2005) Influence of genetic background on daily running-wheel activity differs with aging. Physiol Genomics 22:76-85 |
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