Background Northern residents predominantly rely on coal-fired heating during winter, leading to severe air pollution. Polycyclic aromatic hydrocarbons (PAHs) adsorbed on atmospheric particulate matter pose significant health risks. Among PAHs, dibenz[a, h]anthracene (DahA), though present at lower environmental concentrations compared to other PAHs, exhibits a carcinogenic potency that is 10 or more times greater than benzo[a]pyrene (BaP), underscoring its potential harm. Despite reports on DahA's multiple toxic effects, its impact on metabolic networks remains poorly understood.Methods Based on the respiratory volume of adult rats and the concentration of PM2.5-bound DahA in heavily polluted cities of northern China, adult Sprague-Dawley rats were treated with DahA (0.07 μg/kg and 0.2 μg/kg) twice weekly for four weeks via intratracheal instillation. Metabolomic profiling of serum was performed using rapid resolution liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (RRLC/Q-TOF-MS) to elucidate metabolic disruptions caused by DahA exposure.Results DahA exposure induced significant oxidative stress and inflammatory responses in rats, accompanied by notable alterations in the serum metabolome. A total of 11 metabolites were found to be decreased, and 2 metabolites were increased, with disruptions observed in folate biosynthesis, glycerophospholipid metabolism, and nitrogen metabolism pathways. Additionally, metabolic dysregulation may interfere with the tricarboxylic acid cycle and compromise nucleotide homeostasis.Conclusion These findings enhance our understanding of the toxicological effects of DahA exposure and its role in lung damage. The results suggest that metabolic disturbances caused by DahA may contribute to the exacerbation of respiratory diseases associated with particulate matter-bound PAH pollution during the heating season in cold regions.
Northern China experiences a longer winter and lower average temperatures. Residents primarily rely on coal-fired heating, which contributes to frequent regional haze. Ambient PM2.5-bound polycyclic aromatic hydrocarbons (PAHs), known for their high content and toxicity, have garnered significant attention. PAHs, predominantly generated from the combustion of organic materials and gasoline exhaust, are widely distributed atmospheric pollutants[1]. During the heating season, PAHs adsorbed onto atmospheric particulate matter have been associated with increased morbidity related to respiratory and cardiovascular diseases, as well as impairments in cognitive development and immune function[2-4].
In previous studies, PAHs have been identified as classic persistent organic environmental pollutants with mutagenic and carcinogenic properties, which can increase the risk of lung cancer, skin cancer, breast cancer, and oral cancer in the population[5-6]. Additionally, PAHs such as benz[a]anthracene (BaA), benzo[a]pyrene (BaP), benzo[b]fluoranthene (BbFA), and benzo[k]fluoranthene (BkFA) have been shown to exhibit embryotoxicity in both in vivo and in vitro experiments. Maternal exposure to BbFA disrupted the expression of steroidogenesis-related genes, and testicular apoptosis mediators were significantly upregulated in young adult F1 mice[7]. Furthermore, BaA and BkFA were found to reduce the expression of estrogen receptor α in luminal epithelium, glandular epithelium, and stromal cells[8].
PAHs are mixtures; however, the responses elicited by each chemical component are distinct. Currently, most research on environmental PAHs has focused on BaP, with comparatively less attention given to fully characterizing the effects of dibenz[a, h] anthracene (DahA). DahA is also a component of PAH complexes and has been designated as a probable human carcinogen by IRIS[9]. A previous study found that ambient PM2.5-bound DahA levels were correlated with small airway dysfunction in primary schoolchildren in northeast China[10]. Meanwhile, another study demonstrated that sub-chronic oral treatment with DahA resulted in the formation of fewer DNA adducts than BaP at the same dose, but with similar mutation induction[11]. Although the exposure concentrations of DahA in the air are much lower than those of other PAHs, animal studies indicate that the carcinogenic potency of DahA is 10 times (or more) greater than that of BaP[12]. Therefore, the potential harm of DahA should not be overlooked.
Currently, the metabolic mechanisms underlying DahA toxicity remain unclear. Previous studies have explored the metabolic impacts of water-soluble or insoluble components of PM2.5 exposure in rats, identifying disrupted metabolic pathways, including lipid metabolism, amino acid metabolism, energy metabolism, stress hormone metabolites, and altered circadian rhythm biomarkers[13-15]. Despite these efforts, the metabolic mechanisms of individual PAHs, such as DahA, are still largely unknown, and limited research has been conducted on rat intratracheal instillation models for DahA toxicity exposure.
It is hypothesized that the level of Reactive Oxygen Species (ROS) may be increased by exogenous compounds, and in turn, pro-inflammatory cytokines and chemokines may be stimulated by the production of ROS and Reactive Nitrogen Species (RNS), leading to tissue damage[16-17]. Metabolites, as the terminal products of gene expression, play a critical role in cellular communication processes[18]. While metabolomics has been widely applied in lung-related clinical studies, its application in understanding PAH-induced lung toxicity remains limited. Therefore, the purpose of this study was to investigate oxidative stress and inflammation responses caused by the intratracheal instillation of DahA. A metabolomics approach based on rapid resolution liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (RRLC/Q-TOF/MS) was used to explore disruptions in serum metabolic profiles in rats. In conclusion, these findings enhance our understanding of the toxic effects of DahA exposure in the development of lung damage and provide insights into the mechanisms of environmental toxicity caused by PAHs.
2.
Methods and materials
2.1
Chemicals
The chemical products used in this study included DahA (CAS 50-70-3), purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), with a purity of > 98%. Assay kits for alkaline phosphatase (AKP), lactate dehydrogenase (LDH), total protein (TP), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide synthase (iNOS, eNOS), and nitric oxide (NO) were obtained from Nanjing Jiancheng Bio-technology and Science Inc. (Nanjing, China). Kits for interleukin (IL-6) and tumor necrosis factor (TNF)-α were purchased from Boster Biological Technology Ltd. (Wuhan, China), and all reagents were used according to the manufacturer's protocols.
2.2
Animal care
Prior to the study initiation, the experimental protocol was reviewed and approved by the Committee on Animal Research and Ethics of Harbin Medical University (2015010). Twenty-four male Sprague-Dawley rats (6 weeks old, weighing 180-200 g) were purchased from Beijing WTLH Laboratory Animal Co., Ltd. (Beijing, China). After 1 week of acclimatization, the rats were randomly assigned to three groups (N = 8/group): the low-dose DahA-exposed (DL) group, high-dose DahA-exposed (DH) group, and the control group. The rats were exposed to DahA by intratracheal instillation twice a week for 4 weeks. The respiratory volume of adult rats was 0.105 m3/day[16]. For heavily polluted northern Chinese cities, the reported levels of PM2.5-bound DahA were approximately 6.49 ng/m3. Taking into account the interspecies uncertainty factor (10-fold), the low-dose concentration of 0.07 μg/kg·bw was chosen, with a high-dose concentration set at 3 times this amount (0.2 μg/kg·bw).
2.3
Sample collection and preparation
After the final exposure, the rats were anesthetized with chloral hydrate. Blood was collected via the abdominal aorta, and serum samples were obtained by centrifugation (3500 g, 10 min at 4℃). The left bronchus was temporarily closed with a hemostatic clamp, and the right lung was lavaged with 3 mL of bronchoalveolar lavage fluid (BALF) three times. An aliquot of the recovered lavage fluid was then centrifuged (1500 rpm for 10 min at 4℃). Subsequently, a portion of the left lung was excised, fixed in 4% paraformaldehyde in PBS, and paraffin-embedded for Hematoxylin and Eosin (HE) staining analysis.
Before RRLC/Q-TOF/MS analysis, 1000 µL of acetonitrile was added to 200 µL of serum. After vortexing vigorously for 2 minutes, the mixture was allowed to settle at 20℃ for 15 minutes and then centrifuged at 14, 000 g for 15 minutes at 4℃. The supernatant was dried under nitrogen at 37℃. The residue was then dissolved in 300 µL of acetonitrile-water (3:1, v/v), vortex-mixed for 60 seconds, kept at 20℃ for 10 minutes, and centrifuged again at 14, 000 g for 15 minutes at 4℃. The supernatant was then transferred into a sample vial for RRLC/Q-TOF/MS analysis.
2.4
Chromatography and mass spectrometry
Chromatography and mass spectrometry analysis, biomarker identification, and potential target metabolic pathway analysis using MetaboAnalyst 3.0 were performed as previously described[19]. The raw RRLC-QTOF/MS ESI+ data were transformed into mzData files using MassHunter Qualitative Analysis Software (Agilent Technologies, USA), and these files were then imported into the XCMS package in R for preprocessing.
2.5
Data analysis
Statistical analysis was performed using SPSS (version 17.0; Beijing Stats Data Mining Co., Ltd., Beijing, China). Data are presented as mean ± Standard Deviation (SD). Differences between groups were analyzed using one-way analysis of variance (ANOVA). All P-values were two-tailed, and a P value < 0.05 was considered significant. The normalized data were exported to SIMCA-P (version 14.0; Umetrics AB, Umeå, Sweden) for multivariate data analysis.
3.
Results
3.1
Physiological conditions
Body weights showed a normal increasing trend over the 4-week exposure period. Therefore, the body weight of the exposed groups was not significantly different from that of the control group at any time point (P > 0.05) (Table 1).
Table
1.
The fundamental variables between the control group and the DahA exposure group during the experiment
Control (N= 8)
DL(N=8)
DH(N=8)
Body weight (g)
304.5 ± 15.7
298.4 ± 18.8
296.0 ± 23.4
Cytotoxicity and inflammation cytokine in BALF
LDH (U/L)
121.51 ± 25.92
165.55 ± 70.02*
180.06 ± 61.27*
AKP (U/100mL)
3.48 ± 1.27
4.16 ± 1.18
7.08 ± 2.10*
TP (mg/L)
158.27 ± 59.60
190.47 ± 85.81*
242.05 ± 57.68*
IL-6 (pg/mL)
101.06 ± 28.57
126.15 ± 73.21
154.10 ± 42.51*
TNF-α (pg/mL)
28.15 ±8.47
45.12 ±10.59*
40.71 ±18.81
Inflammatory and oxidant stress cytokine levels in serum
SOD (mg/mL)
32.59 ±3.65
21.74 ±4.67*
17.55 ±3.94*
MDA (mg/mL)
1.03 ± 0.30
1.17 ± 0.38
1.27 ± 0.38
IL-6 (pg/mL)
32.68 ±14.52
47.27 ±15.37
53.88 ±18.66*
TNF-α (pg/mL)
22.14 ±9.28
26.07 ±11.34
27.46 ±8.85
Markers of oxidative stress in rat lung tissue
SOD (U/mg prot)
82.72 ±18.84
60.53 ±17.49*
55.47 ±19.95*
MDA (nmol/mg prot)
1.51 ± 0.52
2.47 ± 0.55*
2.03 ± 0.46
i-NOS (U/mg prot)
0.58 ± 0.31
0.83 ± 0.32
1.21 ± 0.76*
e-NOS (U/mg prot)
2.13 ± 1.06
1.58 ± 0.85
1.37 ± 0.45
NO (nmol/mg prot)
1.71 ± 0.41
2.37 ± 0.53
2.91 ± 0.67*
DL: low-dose DahA-exposed; DH: high-dose DahA-exposed; BALF: bronchoalveolar lavage fluid; LDH: lactate dehydrogenase; AKP: alkaline phosphatase; TP: total protein; IL: Interleukin; TNF: tumor necrosis factor; SOD: Superoxide dismutase; MDA: malondialdehyde; NOS: nitric oxide synthase; NO: nitric oxide. *P value < 0.05 was considered significantly compared with the control group.
Morphological alterations in the lungs were observed through HE staining, as shown in Fig. 1. Lung structures were nearly normal, with only slight lung inflammation in the control group (Fig. 1A). In contrast, pathological changes were more pronounced in the exposure groups. Inflammatory cell infiltration (Fig. 1B, C), thickened alveolar walls, and proliferation of fibrous tissue (Fig. 1C) were observed and are indicated by the arrows in the exposed groups.
Figure
1.
Photomicrographs of rat lungs (HE staining)
(A) Control group: Lung structures appeared nearly normal with only slight inflammation; (B) DL group: Lung structures remained nearly normal, but inflammatory cell infiltration was more pronounced compared to the control group, as indicated by the arrows; (C) DH group: Compared with the control group, thickened alveolar walls and proliferation of fibrous tissue were observed, as indicated by the arrows in the exposed groups. Original magnification: ×200; small window in exposed group: ×400.
3.3
Cytotoxic and proinflammatory cytokines in BALF
The mean values of cytotoxicity and inflammatory cytokines in BALF are shown in Table 1. To examine lung injury, cytotoxicity markers (LDH, AKP, TP) and proinflammatory factors (IL-6, TNF-α) in BALF were measured. The results showed that the levels of cytotoxicity markers (LDH, TP) in BALF were significantly increased in the exposure groups, and the level of AKP in the DH group was significantly higher compared to the control group (P < 0.05). Furthermore, the level of IL-6 in BALF was significantly upregulated in the DH group, and the level of TNF-α in BALF was significantly upregulated in the DL group compared to the control group (P < 0.05).
3.4
Serum levels of proinflammatory cytokines and oxidant stress
The effects on the inflammatory and oxidative parameters in the serum of rats treated with DahA are presented in Table 1. After intratracheal instillation for 4 weeks, the serum activity of SOD showed a significant decrease in the exposed groups, and the level of serum IL-6 was significantly upregulated in the DH group compared to the control group (P < 0.05). Meanwhile, the levels of serum MDA and TNF-α were also upregulated, although not significantly, in the exposure groups (P > 0.05).
3.5
Oxidants and anti-oxidants in rat lung tissue
As shown in Table 1, compared with the control group, the levels of iNOS and NO in the DH group and MDA in the DL group in the lungs of rats were significantly increased (P < 0.05), while SOD activity was markedly inhibited in the exposed groups (P < 0.05). Additionally, the level of eNOS in the exposed groups was not statistically significantly different compared with the control group (P < 0.05).
3.6
RRLC/Q-TOF-MS fingerprinting and multivariate analysis
The PLS-DA score plot showed that the variation in R2Y was 99.1%, while the variation in Q2 was 87.0% in ESI+ mode, indicating that the model had good fitting and prediction ability. A permutation test with 800 permutations was performed, which showed that the R2 and Q2 values were lower than the original points to the right, and the Q2 regression line had a negative intercept, confirming that the PLS-DA model was valid (Fig. 2).
Figure
2.
Score plot with PLS-DA and permutation test of serum metabolites in control (CON) and exposure groups
Panel (A) shows the score plot derived from PLS-DA analysis, while panel (B) presents the results of the permutation test, comparing the serum metabolite profiles between the CON and exposure groups.
This study indicated that DahA exposure disrupted the pulmonary metabolome in rats, and 13 differential metabolites were identified as biomarkers (Table 2). The upregulated clusters included Prolyl-Tryptophan and Docosahexaenoic acid (DHA). The downregulated cluster included LysoPC (22 ∶6), LysoPE (0 ∶0/20 ∶0), phosphatidylethanolamine (PE)-NMe (18∶1), phosphatidic acid (PA) (i-13∶0/i-12∶0), 3-O-Sulfogalactosylceramide, sphingomyelin (SM) (d18 ∶ 0/20∶ 0), Carbamoyl phosphate (CP), Dihydrofolic acid, Choline, Glutamylglycine, and Isoleucyl-Glutamate (Fig. 3).
Table
2.
Important metabolites in RRLC/Q-TOF-MS positive ion modes (ESI+)
Figure
3.
Trends in alterations of different metabolites in serum comparing DahA exposed groups with the control group
The horizontal axis represents the ratio of the metabolite in the exposure group compared with the control group, calculated as (Cexposed-Ccontrol) / Ccontrol. This plot illustrates the changes in metabolite levels following DahA exposure.
The potential target metabolic pathway analysis using MetaboAnalyst 3.0 revealed that three metabolic pathways—folate biosynthesis, glycerophospholipid metabolism, and nitrogen metabolism—were the most significant pathways (Fig. 4).
Figure
4.
Pathway analysis of biomarkers using MetaboAnalyst 3.0
(1) Folate biosynthesis; (2) Glycerophospholipid metabolism; (3) Nitrogen me-tabolism; (4) Sphingolipid metabolism. The analysis highlights key metabolic pathways impacted by DahA exposure, identifying potential biomarkers associ-ated with pulmonary toxicity.
The results showed that cytotoxicity markers (LDH, AKP, TP) in BALF significantly increased. Moreover, inflammatory cell infiltration and proliferation of fibrous tissue were observed in the lungs of the exposure groups. Thus, it can be concluded that the toxicity of DahA may cause acute lung injury in treated rats. It is well known that under stress conditions, the activities of antioxidative enzymes such as SOD may be inhibited, while excessive ROS can damage the cell membrane and form MDA[18]. Additionally, excessive NO, regulated by iNOS, may generate more toxic peroxynitrite anions[20], causing oxidative damage and cytotoxicity[21]. Therefore, we examined the concentrations of SOD, MDA, iNOS, eNOS, and NO in rat lung tissue and serum. The results of this study demonstrated that exposure to DahA may induce oxidative stress by inhibiting SOD activity and elevating iNOS activity as well as the levels of MDA and NO. The generation of ROS/RNS, in turn, may induce the release of proinflammatory cytokines and chemokines, leading to lung injury. Furthermore, we examined the concentrations of TNF-α and IL-6 in rat serum and BALF, and the results indicated that lung inflammatory injury was induced, accompanied by increased levels of pro-inflammatory cytokines such as IL-6. Therefore, the metabolic changes associated with early damage caused by DahA toxicity must be elucidated in future studies on the toxicity mechanisms of PAHs in the environment.
In the present study, serum metabolomics of DahA exposure were analyzed using RRLC/Q-TOF-MS. Thirteen principal serum metabolites were identified as contributors to the clusters. The serum metabolomic changes indicated that exposure to DahA can affect inflammatory responses and oxidative stress factors in the lung by disrupting folate biosynthesis, lipid metabolism, nitrogen metabolism, and amino acid metabolism. The flow diagram illustrates the main pathways and toxic effects of metabolic changes caused by DahA exposure (Fig. 5).
Figure
5.
Toxic effects of metabolic changes induced by DahA exposure
The serum metabolomic changes reveal that exposure to DahA disrupts key metabolic pathways, including folate biosynthesis, lipid metabolism, nitrogen metabolism, and amino acid metabolism. These disruptions contribute to heightened inflammatory responses and oxidative stress in the lungs, providing insight into the mechanisms underlying DahA-induced pulmonary toxicity.
This study demonstrated that DahA exposure could trigger an increase in oxidized phospholipids, mediating a systemic inflammatory response. Abnormal lipid metabolism is closely associated with the activation of oxidative and inflammatory pathways[22]. Metabolic disorders of glycerophospholipids and sphingomyelins were revealed in this study. Surfactant phospholipids, such as PA and PE, are essential components of cell membranes, which serve as critical structures for regulating the intercellular exchange of exogenous compounds[23]. Previous studies have shown that phospholipid metabolism plays a significant role in the pathogenesis of various diseases[18]. In inflamed lungs, lysophospholipids (lysoPC and lysoPE) are produced through the hydrolysis of phospholipids, leading to surfactant dysfunction[24]. LysoPC facilitates the entry of long-chain fatty acids, such as DHA, into mitochondria for fatty acid oxidation, producing acetyl-CoA, which participates in the tricarboxylic acid (TCA) cycle. This process can generate excessive ROS and impair antioxidant defenses[25].
Sphingolipids, essential components of membrane lipids, are involved in numerous cellular signaling pathways and play critical roles in cell death and survival[26]. SM, a primary sphingolipid component, plays a pivotal role in cellular responses to oxidative stress[13]. The observed reduction in serum SM and 3-O-sulfogalactosylceramide levels suggests that DahA exposure disrupts the membrane distribution of these components. SM is hydrolyzed into sphingosine, which is phosphorylated by sphingosine kinase and can mitigate tissue oxidative injury[27]. Results from KEGG pathway analyses further suggest that the decreased levels of 3-O-sulfogalactosylceramide and SM are indicative of lung-related disease progression, driven by inhibited sphingosine kinase activity and aggravated oxidative tissue damage. Taken together, the observed alterations in the serum glycerophospholipid and sphingolipid profiles in this study suggest that DahA exposure disrupts lipid metabolism, playing a crucial role in the pathogenesis of inflammatory diseases.
Plasma concentrations of glutamate, dihydrofolic acid, CP, and dehydroascorbic acid were lower in the exposure groups compared to the control group, indicating that nitrogen metabolism and folate biosynthesis pathways were disrupted. By examining metabolic pathways in HMDB and KEGG, we identified glutamate as a crucial intermediate. Glutamate is produced from glutamine through the action of phosphate-dependent glutaminase. It is known to possess antioxidant activity, regulate body weight, and modulate hormone release[28]. Additionally, glutamate serves as a precursor for tetrahydrofolate synthesis. Tetrahydrofolate is converted into dihydrofolate by dihydrofolate reductase, a process critical for the transfer of one-carbon units involved in DNA methylation and nucleotide synthesis[29]. Thus, the observed decrease in dihydrofolic acid levels in this study may impair nucleotide homeostasis. Furthermore, glutamine is metabolized in mitochondria into ammonia and glutamate. Ammonia, along with bicarbonate, contributes to the synthesis of CP in mitochondria[30]. CP plays a vital role in pyrimidine and purine synthesis, and its reduction can interfere with nucleotide synthesis, compromise S-phase progression, and lead to DNA damage. Additionally, CP serves as a substrate for the synthesis of arginine and urea during de novo pyrimidine synthesis in the mammalian liver[31]. Thus, a reduction in CP concentration not only affects nucleotide homeostasis but also disrupts the urea cycle. This study suggests that the disruption of folate biosynthesis and nitrogen metabolism impairs the activity of metabolic kinases and affects nucleotide homeostasis, ultimately promoting disease development.
Amino acid metabolism provides the material basis for protein synthesis and energy metabolism. In the current study, we observed significantly higher serum levels of prolyl-tryptophan, while glutamylglycine and isoleucyl-glutamate were significantly lower in the exposure groups compared to the control group. Using HMDB and KEGG pathway analyses, we identified glycine as a key metabolite promoting glutathione (GSH) synthesis and playing a critical role in antioxidant defense during liver damage[32]. The observed decrease in glycine levels in this study suggests a weakened antioxidant system. Additionally, glutamate is known to mitigate inflammation induced by oxidative stress and enhance the TCA cycle, particularly in lipid and glucose metabolism[33]. Tryptophan, on the other hand, is integral to T-cell-mediated inflammation, and previous studies have shown that changes in serum tryptophan concentrations can trigger systemic inflammatory responses[34]. In this study, DahA exposure disrupted amino acid metabolism, which contributed to inflammation and oxidative stress.
To the best of our knowledge, this is the first report evaluating metabolic changes and exploring the mechanisms of DahA-induced pulmonary injury in rats using metabolomics techniques following intratracheal instillation. However, our study has some limitations. While intratracheal instillation is a widely accepted method in toxicological studies, it represents a non-physiological route of exposure, leading to nonuniform distribution of the instilled material. Therefore, the potential biomarkers identified in this study require further validation in future research.
5.
Conclusions
In summary, our results suggest that DahA exposure induces pulmonary injury in rats following intratracheal instillation, potentially disrupting key metabolic pathways such as folate biosynthesis, glycerophospholipid metabolism, and nitrogen metabolism. Furthermore, these metabolic disorders may interfere with the TCA cycle and compromise nucleotide homeostasis, leading to heightened inflammatory responses and oxidative stress. These findings highlight a possible mechanism by which atmospheric particulate matter-bound PAHs exacerbate respiratory diseases, particularly during the heating season in cold regions. Although this was a preliminary study, we believe it is the first to identify potential biomarkers associated with DahA exposure and its toxicity, providing a foundation for further research into the health impacts of PAHs in environmental pollution.
Acknowledgments:
Not applicable.
Research ethics
Prior to the study initiation, the experimental protocol was reviewed and approved by the Committee on Animal Research and Ethics of Harbin Medical University (2015010).
Informed consent
Not applicable.
Author contributions
Kang Z, Wang C, Na X L conceived and designed the study. Kang Z, Hong Q Q, Bai Y N and Yu T Y performed the experiments and data collection. Kang Z, Yan F and Liu X B analysed the data. Kang Z wrote and compiled the manuscript. All authors read and approved the final version of the manuscript.
Use of Large Language Models, AI and Machine Learning Tools
None declared.
Conflict of interest
The authors declare no competing interest in this study.
Data availability
Data supporting the findings of this study are available from the corresponding author upon reasonable request.
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