Ambient PM2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation
Introduction
Ambient particulate matter 2.5 (PM2.5) poses a significant risk to public health worldwide and the PM2.5 pollution has been associated with numerous adverse health effects [1]. World Health Organization (WHO) reports that in 2012 around 7 million people died - one in eight of total global deaths - as result of air pollution exposure. According to the WHO global burden of disease (GBD) study, ambient PM2.5 was responsible for 3.2 million premature deaths worldwide annually, and 1.2 million premature deaths in China alone [2]. These data suggest that PM2.5 is now one of the world’s largest environmental health risks. Therefore, the WHO ambient air quality guidelines suggest an annual mean PM2.5 concentration limit of 10 μg/m3 and 25 μg/m3 for the 24-hourly mean to prevent the adverse effects of PM2.5 on public health [3].
Recent study had reported adverse associations between air pollution exposures and the nervous system [4]. Increases in PM2.5 exposure was associated with depression, emotional symptoms and suicide attempts or elevated anxiety [5,6]. Consistent with these findings, time-series studies examining acute associations had reported increased depression-related hospital admissions with increasing pollution levels [[7], [8], [9]]. A significant association between PM2.5 and hospital admission for mental and behavioral disorders was found in Shijiazhuang, as one of the most polluted cities in China [10]. There was association between chronic exposures to PM2.5 and onset of depression among cohorts in the US [11,12].
However, the current insufficient epidemiological evidences are hard to explain the mechanism which would hold back the treatment and prevention of psychological diseases and mental disorders induced by PM2.5 exposure. PM2.5 has complex constituents including heavy metals and PAHs [13], which towards to result in depressive responses and increased hippocampal pro-inflammatory cytokines [14]. The nucleotide-binding domain and leucinerich repeat protein 3 (NLRP3) inflammasome is reported as a central mediator by which psychological and physical stressors could contribute to the development of depression [15].
In the literature, NLRP3 had been associated with oxidative stress [16]. After phagocytosing exogenous particles, macrophages could generate a large amount of reactive oxygen species (ROS) [17], which in turn was known to play an important role in depression [18,19]. Excessive ROS could bind to the inflammasome assembly and finally activated NLRP3 inflammasome [17]. PM2.5 extracts could induce inflammatory responses through NLRP3 inflammasome pathway activating then mediate ROS generation and trigger the following oxidative stress [20].
Nuclear factor E2-related factor-2 (Nrf2) is an essential transcription factor that mediates cellular antioxidant responses. PM2.5 exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes then performed anti-oxidative stress effect [21]. Nrf2-mediated defenses could be activated by PM2.5-induced ROS and many functions as signaling molecules [22]. Though there were evidences of the oxidative stress and inflammation response to depression induced by PM2.5 [23,24], the interaction mechanism of oxidative stress and inflammation regulated by Nrf2 has not been known clearly. Nrf2 signal pathway took responsibility to PM2.5-caused hypothalamus inflammation [25] and its critical proinflammatory effect was mediated by NLRP3inflammasome activation. The NLRP3 inflammasome contains a C-terminal LRR, a central NACHT domain, and an N-terminal pyrin domain (PYD). NLRP3 binds to the adaptor protein, apoptosis speck-like protein, containing a CARD domain (ASC) which in turn recruits and activates Caspase-1. Biochemical analysis revealed that Nrf2 appeared in the ASC-enriched cytosolic compartment after NLRP3 inflammasome activation [26]. Therefore, the Nrf2/ NLRP3 signal regulatory oxidative stress and inflammation interaction mechanism was hypothesized to explain the depressive-like responses induced by sub-chronic PM2.5 exposure.
Here, sub-chronic PM2.5 exposure animal models were established to explore the depression and it’s perhaps mechanism. The evaluation of trace or toxic elements deposition in brain partly explained the direct reason of depressive-like responses in rats. Nrf2 knockout mice were used to study the regulating role of Nrf2/ NLRP3 signaling pathway modulating inflammation on the depression induced by ambient PM2.5. The present study suggested toxic elements deposited in prefrontal cortex after PM2.5 exposure. And PM2.5 exposure triggered Nrf2/ NLRP3 signaling pathway mediating inflammation, then resulting in depressive-like responses.
Section snippets
Whole-body ambient inhalational protocol
Male, pathogen-free Sprague-Dawley rats at 6 weeks of age were purchased from the Animal Experimental Center of Hebei Medical University and acclimated for a week before the commencement of inhalation. The humidity was 50% and the temperature was 25–26 °C in the cages with a 12 h light/dark cycle. Twenty-four rats were divided randomly into 3 groups and exposed to filtered air (FA), unfiltered air (UA) and concentrated PM2.5 air (CA) by real time ambient particulate matter exposed chambers,
PM2.5 concentration and physical characteristics
For exposure week 1–12, the average PM2.5 concentrations were 0, 46.37 ± 27.66, and 305.58 ± 254.22 μg/m3 in the FA, UA and CA chambers, respectively. For exposure week 1–9, the average PM2.5 concentrations were 0.0 and 48.25 ± 24.36 μg/m3 in the FA and UA exposure chambers, respectively. The averages of NO2, SO2 and O3 levels were not significant different among the FA, UA and CA chambers (Table S1).
The depressive behavior of rats induced by PM2.5
The representative traces of rats’ movements by OFT were showed in Fig. 1A. The total distances
Discussion
According to the WHO ambient air quality guidelines, the suggested PM2.5 concentration limit is 25 μg/m3 for the 24-hourly [2], and it is 75 μg/m3 in China [38]. As well, there were some countries setting at 150 μg/m3 which were much higher than the WHO standards. [39]. In the present study, after rats exposed to 305 μg/m3 PM 2.5 for 12 w, the significant depressive symptoms were observed. Even though 46 μg/m3 in this study excesses the limit of WHO (25 μg/m3), it is far less than the
Conclusion
Our study demonstrated the depressive-like responses were caused by ambient PM2.5 dose-dependently in rats and mice, which might partly attribute to the disorders of neurotransmitters as well as the deposition of toxic elements from contaminated air, including Be, Al, Cr, Co, Ni, Se, Cd, Ba, Ti and Pb. After PM2.5 exposure for 9 weeks in mice and 12 weeks in rats, the significant inflammatory changes and oxidative stress had been observed. Though both of oxidative stress and inflammation could
Ethical standards
The animal use protocol has been reviewed and approved by the Laboratory Animal Ethical and Welfare Committee Hebei Medical University, Shijiazhuang, China. Approval No. is IACUC-Hebmu-20170116.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
This work is supported by National Natural Science Foundation of China (91643108, 81573190), National Natural Science Foundation of Hebei Province of China (H2015206326), and National Natural Science Foundation of Education Department of Hebei Province of China (ZD2015008).
We thank for Professor of Haishui Shi Ph.D. (Hebei Medical University) for give us the help in behavior test.
References (70)
- et al.
Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015
Lancet
(2017) - et al.
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012) - et al.
The outdoor air pollution and brain health workshop
Neurotoxicology
(2012) - et al.
Air pollution as a risk factor for depressive episode in patients with cardiovascular disease, diabetes mellitus, or asthma
J. Affect. Disord.
(2014) - et al.
Acute effects of ambient particulate matter pollution on hospital admissions for mental and behavioral disorders: a time-series study in Shijiazhuang, China
Sci. Total Environ.
(2018) - et al.
The inflammasome: pathways linking psychological stress, depression, and systemic illnesses
Brain Behav. Immun.
(2013) - et al.
The inflammasomes
Cell
(2010) - et al.
Effects on IL-1beta signaling activation induced by water and organic extracts of fine particulate matter (PM2.5) in vitro
Environ. Pollut.
(2018) - et al.
Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-kappaB pathway in Nrf2 deficient mice
Free Radic. Biol. Med.
(2016) - et al.
Nuclear factor E2-related Factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation
J. Biol. Chem.
(2014)
Determination of metals, metalloids and non-volatile ions in airborne particulate matter by a new two-step sequential leaching procedure Part B: validation on equivalent real samples
Talanta
The leptin hypothesis of depression: a potential link between mood disorders and obesity?
Curr. Opin. Pharmacol.
Integrated analytical techniques with high sensitivity for studying brain translocation and potential impairment induced by intranasally instilled copper nanoparticles
Toxicol. Lett.
Determination of monoamine and amino acid neurotransmitters and their metabolites in rat brain samples by UFLC-MS/MS for the study of the sedative-hypnotic effects observed during treatment with S. chinensis
J. Pharm. Biomed. Anal.
Highly selective and sensitive determination of several antioxidants in human breast milk using high-performance liquid chromatography based on Ag(III) complex chemiluminescence detection
Food Chem.
Determination of main low molecular weight antioxidants in urinary bladder wall using HPLC with electrochemical detector
Int. J. Pharm.
Are current Chinese national ambient air quality standards on 24-hour averages for particulate matter sufficient to protect public health?
J. Environ. Sci. (China)
Persistence of multiple illnesses in World Trade Center rescue and recovery workers: a cohort study
Lancet
Type II pyrethroid deltamethrin produces antidepressant-like effects in mice
Behav. Brain Res.
Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence
J. Affect. Disord.
Cooking with biomass increases the risk of depression in pre-menopausal women in India
Soc. Sci. Med.
The association of air pollution and depressed mood in 70,928 individuals from four European cohorts
Int. J. Hyg. Environ. Health
Temporal-spatial characteristics and source apportionment of PM2.5 as well as its associated chemical species in the Beijing-Tianjin-Hebei region of China
Environ. Pollut.
PM2.5-bound metal metabolic distribution and coupled lipid abnormality at different developmental windows
Environ. Pollut.
Heavy metals (Pb, Cd, MeHg, As) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in Brain
Environ. Toxicol. Pharmacol.
The role of the innate immune system in psychiatric disorders
Mol. Cell. Neurosci.
Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-κB pathway in Nrf2 deficient mice
Free Radic. Biol. Med.
Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats
Brain Behav. Immun.
A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity
Brain Behav. Immun.
Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor
Biol. Psychiatry
NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases
Redox Biol.
Oxidative stress-induced DNA damage by particulate air pollution
Mutat. Res.
Microglia in the developing brain: a potential target with lifetime effects
Neurotoxicology
How microglia kill neurons
Brain Res.
WHO air quality guidelines for particulate matter, ozone, nitrogen dioxide and sulfur dioxide
Global Update Summary of Risk Assessment
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