Long-Term Exposure to Concentrated Ambient PM
            <sub>2.5</sub>
            Increases Mouse Blood Pressure through Abnormal Activation of the Sympathetic Nervous System: A Role for Hypothalamic Inflammation

Zhao, Ying; Xu, Xiaohua; Bai, Yuntao; Zhong, Jixin; Chen, Minjie; Liang, Yijia; Zhao, Jingang; Liu, Dongyao; Morishita, Masako; Sun, Qinghua; Spino, Catherine; Brook, Robert D.; Harkema, Jack R.; Rajagopalan, Sanjay

doi:10.1289/ehp.1307151

Cited by 181 publications

(127 citation statements)

References 43 publications

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“…[8][9][10] Animal studies further implicated PM 2.5 as a stressor to the central nervous system that might induce a cascade of neuroendocrine responses. 11,12 These provocative findings warrant mechanistic investigations in humans.…”

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confidence: 98%

Particulate Matter Exposure and Stress Hormone Levels

et al. 2017

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BACKGROUND:Exposure to ambient particulate matter (PM) is associated with a number of adverse health outcomes, but potential mechanisms are largely unknown. Metabolomics represents a powerful approach to study global metabolic changes in response to environmental exposures. We therefore conducted this study to investigate changes in serum metabolites in response to the reduction of PM exposure among healthy college students. METHODS:We conducted a randomized, double-blind crossover trial in 55 healthy college students in Shanghai, China. Real and sham air purifiers were placed in participants' dormitories in random order for 9 days with a 12-day washout period. Serum metabolites were quantified by using gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-mass spectrometry. Between-treatment differences in metabolites were examined using orthogonal partial least square-discriminant analysis and mixed-effect models. Secondary outcomes include blood pressure, corticotropin-releasing hormone, adrenocorticotropic hormone, insulin resistance, and biomarkers of oxidative stress and inflammation. RESULTS:The average personal exposure to PMs with aerodynamic diameters ≤2.5 μm was 24.3 μg/m 3 during the real purification and 53.1 μg/m 3 during the sham purification. Metabolomics analysis showed that higher exposure to PMs with aerodynamic diameters ≤2.5 μm led to significant increases in cortisol, cortisone, epinephrine, and norepinephrine. Between-treatment differences were also observed for glucose, amino acids, fatty acids, and lipids. We found significantly higher blood pressure, hormones, insulin resistance, and biomarkers of oxidative stress and inflammation among individuals exposed to higher PMs with aerodynamic diameters ≤2.5 μm. CONCLUSIONS:This study suggests that higher PM may induce metabolic alterations that are consistent with activations of the hypothalamuspituitary-adrenal and sympathetic-adrenal-medullary axes, adding potential mechanistic insights into the adverse health outcomes associated with PM. Furthermore, our study demonstrated short-term reductions in stress hormone following indoor air purification. ORIGINAL RESEARCH ARTICLE C onvincing epidemiological evidence suggests that exposure to higher levels of ambient particulate matters (PMs), especially fine PMs with aerodynamic diameters ≤2.5 μm (PM 2.5 ), may have adverse cardiovascular and metabolic consequences such as hypertension, coronary heart disease, stroke, and diabetes mellitus. CLINICAL TRIAL REGISTRATION:1-4 Although potential biological mechanisms for these adverse health effects are yet to be fully ascertained, inflammation and oxidative stress are likely to be involved. [5][6][7] In addition, several studies have reported an association between PM exposure and dysfunction of the automatic nervous system, which is known to increase cardiovascular risk. [8][9][10] Animal studies further implicated PM 2.5 as a stressor to the central nervous system that might induce a cascade of neuroendocrine responses...

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confidence: 98%

Particulate Matter Exposure and Stress Hormone Levels

et al. 2017

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“…5J shows that CAP exposure did not impact the expression of SOCS3 in WT controls, but significantly increased its expression in KO mice, further supporting the central leptin resistance in CAP-exposed TNF/LT KO mice. CAP exposure has been shown to cause hypothalamic inflammation that may play a role in the pathogenesis of central leptin resistance (Ying et al, 2014). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Age-matched wildtype (C57BL/6J) mice were purchased from the Jackson Laboratories (Stock #000664) and were allowed to acclimate for two weeks in animal facilities at UMB before beginning inhalation exposure protocols. Animal exposure and the monitoring of exposure atmosphere and ambient aerosol were performed as previously described using a versatile aerosol concentration enrichment system that was modified for long-term exposures (Ying et al, 2014). Briefly, 10-week-old WT and KO mice were randomly grouped ( N = 7–8/group, male only) and subjected to filtered air (FA) or CAP exposure from October 2015 to March 2016.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5

Chen

Zhou

et al. 2017

Toxicology

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Background Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFα), lymphotoxin α (LTα), and lymphotoxin β (LTβ) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. Methods and results LTα/TNFα/LTβ triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. Conclusion The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.

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“…In animal models, longer-term exposures elicit elevations in BP via sympathetic activation induced by hypothalamic inflammation and/or by endothelial dysfunction favouring vasoconstriction (e.g. rho kinase activation) [25,26]. Although we have shown that the inhalation of very high levels of airborne particles [20,24] can raise BP within hours, the fact that the pro-hypertensive response was delayed by a few days (which accords with many prior studies) [6] supports the contention that slower mechanistic pathways (e.g.…”

Section: Potential Mechanismsmentioning

confidence: 99%