High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

Weinhouse, Caren; Perez, Luiza; Ryde, Ian T.; Goodrich, Jaclyn M.; Miranda, J. Jaime; Hsu‐Kim, Heileen; Murphy, Susan K.; Meyer, Joel N.; Pan, William

doi:10.1101/2022.07.05.498896

Cited by 2 publications

(2 citation statements)

References 163 publications

(154 reference statements)

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“…However, we also saw significant interindividual variability in these measures (interestingly, we saw greater interindividual variability in individuals without than with GWI). We similarly saw high interindividual variability in previous studies [ 56 , 87 ]. That this large interindividual variation is biologically real as opposed to technical is supported by two lines of evidence.…”

Section: Discussionsupporting

confidence: 81%

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Meyer,

Pan,

Ryde

et al. 2023

PLoS ONE

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Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

show abstract

Section: Discussionsupporting

confidence: 81%

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Meyer,

Pan,

Ryde

et al. 2023

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, we also saw significant interindividual variability in these measures (interestingly, with greater interindividual variability in individuals without than with GWI). We similarly saw high interindividual variability in previous studies [55,90]. That this large interindividual variation is biologically real as opposed to technical is supported by two lines of evidence.…”

Section: Relationship Of Chemical Exposures To Mitochondrial Parameterssupporting

confidence: 78%

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Meyer

Pan

Ryde

et al. 2023

Preprint

View full text Add to dashboard Cite

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

show abstract

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

Cited by 2 publications

References 163 publications

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

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