Diabetes Metab J.  2022 Jul;46(4):592-604. 10.4093/dmj.2021.0132.

Effect of Low-Dose Persistent Organic Pollutants on Mitochondrial Function: Human and in Vitro Evidence

• Kim SA
• Lee H
• Park SM
• Kim MJ
• Lee YM
• Yoon YR
• Lee HK
• Moon HB
• Lee IK
• Lee DH

• KMID: 2531963
• DOI: http://doi.org/10.4093/dmj.2021.0132

Abstract

Background
Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells.
Methods
Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, β-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells.
Results
The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/μg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/μg according to the PCB quintiles of summary measure (P trend <0.001), and this inverse association was consistently observed in all subgroups stratified by age, sex, obesity, type 2 diabetes mellitus, and hypertension, respectively. In vitro experimental studies have also demonstrated that chronic exposure to low-dose POPs could decrease OCR levels.
Conclusion
The findings from human and in vitro studies suggest that chronic exposure to low-dose POPs can induce mitochondrial dysfunction by impairing oxidative phosphorylation.

Keyword

Mitochondria; Oxygen consumption; Persistent organic pollutants; Pesticides; Polychlorinated biphenyls

Figure

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  Fig. 1 (A) Comparison between summary measures of organochlorine pesticides (OCPs) and body mass index (BMI) on the relationships with basal oxygen consumption rate (OCR) of platelets. (B) Comparison between summary measures of polychlorinated biphenyls (PCBs) and BMI on the relationships with basal OCR of peripheral blood mononuclear cells (PBMCs). All results were adjusted for age, sex, hypertension, type 2 diabetes, smoking, alcohol consumption, and exercise. ∑OCPs, rank sum of 4 OCPs (β-hexachlorocyclohexane, p,p′-dichlorodiphenyldichloroethylene, p,p′-DDT, and trans-nonachlor); ∑PCBs, rank sum of five PCBs (PCB118, PCB138, PCB153, PCB180, and PCB187).

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  Fig. 2 Effect of three individual compounds (Arochlor-1254, β-hexachlorocyclohexane [HCH], and p,p′-dichlorodi-phenyltrichloroethane [DDT]) on basal and maximal oxygen consumption rate (OCR) of (A) human platelets, (B) human peripheral blood mononucle ar cells (PBMCs), and (C) Jurkat T-cells. O, oligomycin; CCCP, carbonyl cyanide 3-chlorophenylhydrazone; R, rotenone. aP<0.05 and bP<0.01, respectively, compared to the vehicle group.

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Reference

1. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016; 61:654–66.

2. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012; 12:685–98.

3. Feve B, Bastard JP. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009; 5:305–11.

4. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009; 106:14670–5.

5. Koopman M, Michels H, Dancy BM, Kamble R, Mouchiroud L, Auwerx J, et al. A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans. Nat Protoc. 2016; 11:1798–816.

6. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011; 435:297–312.

7. Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers. Redox Biol. 2014; 2:206–10.

8. Cardenes N, Corey C, Geary L, Jain S, Zharikov S, Barge S, et al. Platelet bioenergetic screen in sickle cell patients reveals mitochondrial complex V inhibition, which contributes to platelet activation. Blood. 2014; 123:2864–72.

9. Malinow AM, Schuh RA, Alyamani O, Kim J, Bharadwaj S, Crimmins SD, et al. Platelets in preeclamptic pregnancies fail to exhibit the decrease in mitochondrial oxygen consumption rate seen in normal pregnancies. Biosci Rep. 2018; 38:BSR20180286.

10. Kramer PA, Chacko BK, George DJ, Zhi D, Wei CC, Dell’Italia LJ, et al. Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients. Biosci Rep. 2015; 35:e00237.

11. Weiss SL, Selak MA, Tuluc F, Perales Villarroel J, Nadkarni VM, Deutschman CS, et al. Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock. Pediatr Crit Care Med. 2015; 16:e4–12.

12. McDowell RE, Aulak KS, Almoushref A, Melillo CA, Brauer BE, Newman JE, et al. Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2020; 318:L562–9.

13. Morton JC, Armstrong JA, Sud A, Tepikin AV, Sutton R, Criddle DN. Altered bioenergetics of blood cell sub-populations in acute pancreatitis patients. J Clin Med. 2019; 8:2201.

14. Meyer JN, Leung MC, Rooney JP, Sendoel A, Hengartner MO, Kisby GE, et al. Mitochondria as a target of environmental toxicants. Toxicol Sci. 2013; 134:1–17.

15. Liu Q, Wang Q, Xu C, Shao W, Zhang C, Liu H, et al. Organochloride pesticides impaired mitochondrial function in hepatocytes and aggravated disorders of fatty acid metabolism. Sci Rep. 2017; 7:46339.

16. Ruzzin J, Petersen R, Meugnier E, Madsen L, Lock EJ, Lillefosse H, et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect. 2010; 118:465–71.

17. Lee DH, Porta M, Lind L, Lind PM, Jacobs DR Jr. Neurotoxic chemicals in adipose tissue: a role in puzzling findings on obesity and dementia. Neurology. 2018; 90:176–82.

18. Lee YM, Jacobs DR Jr, Lee DH. Persistent organic pollutants and type 2 diabetes: a critical review of review articles. Front Endocrinol (Lausanne). 2018; 9:712.

19. Kramer PA, Chacko BK, Ravi S, Johnson MS, Mitchell T, Darley-Usmar VM. Bioenergetics and the oxidative burst: protocols for the isolation and evaluation of human leukocytes and platelets. J Vis Exp. 2014; (85):51301.

20. Wallace KB. Multiple targets for drug-induced mitochondrial toxicity. Curr Med Chem. 2015; 22:2488–92.

21. Brunst KJ, Baccarelli AA, Wright RJ. Integrating mitochondriomics in children’s environmental health. J Appl Toxicol. 2015; 35:976–91.

22. Attene-Ramos MS, Huang R, Michael S, Witt KL, Richard A, Tice RR, et al. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect. 2015; 123:49–56.

23. Chandel NS. Evolution of mitochondria as signaling organelles. Cell Metab. 2015; 22:204–6.

24. Lee YM, Lee DH. Mitochondrial toxins and healthy lifestyle meet at the crossroad of hormesis. Diabetes Metab J. 2019; 43:568–77.

25. Meyer JN, Leuthner TC, Luz AL. Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology. 2017; 391:42–53.

26. Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, et al. Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev. 2017; 117:10043–120.

27. Sundar IK, Maremanda KP, Rahman I. Mitochondrial dysfunction is associated with Miro1 reduction in lung epithelial cells by cigarette smoke. Toxicol Lett. 2019; 317:92–101.

28. Hojlund K, Mogensen M, Sahlin K, Beck-Nielsen H. Mitochondrial dysfunction in type 2 diabetes and obesity. Endocrinol Metab Clin North Am. 2008; 37:713–31.

29. Lahera V, de Las Heras N, Lopez-Farre A, Manucha W, Ferder L. Role of mitochondrial dysfunction in hypertension and obesity. Curr Hypertens Rep. 2017; 19:11.

30. Chacko BK, Smith MR, Johnson MS, Benavides G, Culp ML, Pilli J, et al. Mitochondria in precision medicine: linking bioenergetics and metabolomics in platelets. Redox Biol. 2019; 22:101165.

31. Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013; 123:951–7.

32. Pence BD, Yarbro JR. Aging impairs mitochondrial respiratory capacity in classical monocytes. Exp Gerontol. 2018; 108:112–7.

33. Pearson AG, Zawari M, Pearson JF, Hampton MB. Quantifying mitochondrial respiration in human lymphocytes and monocytes challenged with hydrogen peroxide. Free Radic Res. 2020; 54:271–9.

34. Sjovall F, Ehinger JK, Marelsson SE, Morota S, Frostner EA, Uchino H, et al. Mitochondrial respiration in human viable platelets: methodology and influence of gender, age and storage. Mitochondrion. 2013; 13:7–14.

35. Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell. 2012; 11:801–9.

36. Porter C, Hurren NM, Cotter MV, Bhattarai N, Reidy PT, Dillon EL, et al. Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. Am J Physiol Endocrinol Metab. 2015; 309:E224–32.

37. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A. 2005; 102:5618–23.