Publications by authors named "Heqing Shen"

102 Publications

MiR-939-5p suppresses PM-induced endothelial injury targeting HIF-1α in HAECs.

Nanotoxicology 2021 May 3:1-15. Epub 2021 May 3.

Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, PR China.

Ambient air pollution is a leading cause of non-communicable disease in the world. PM has the potential to change the miRNAs profiles, which in turn causes cardiovascular effects. Hypoxia-inducible factor (HIF)-1 plays a critical role in the development of atherosclerosis. Yet, the possible role of miR-939-5p/HIF-1α in PM-induced endothelial injury remains elusive. Therefore, the study aims to investigate the effects of miR-939-5p and HIF-1α on PM-triggered endothelial injury. The results from immunofluorescence, qRT-PCR, LSCM, and western blot assays demonstrated that PM increased the levels of HIF-1α, inflammation and apoptosis in human aortic endothelial cells (HAECs). Yet, the inflammatory response and mitochondrial-mediated apoptosis pathway were effectively inhibited in HIF-1α knockdown HAECs lines. The expression of miR-939-5p was significantly down-regulated in HAECs after exposed to PM. The luciferase reporter, qRT-PCR and western blot results demonstrated that miR-939-5p could directly targeted HIF-1α. And the miR-939-5p overexpression restricted PM-triggered decreases in cell viability and increases in lactic dehydrogenase (LDH) activity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and inflammation. In addition, miR-939-5p overexpression remarkably suppressed PM-triggered BcL-2/Bax ratio reduction and Cytochrome C, Cleaved Caspase-9 and Cleaved Caspase-3 expression increase, revealed that miR-939-5p hampered PM-induced endothelial apoptosis through mitochondrial-mediated apoptosis pathway. Our results demonstrated that PM increased the expression of HIF-1α followed by a pro-inflammatory and apoptotic response in HAECs. The protective effect of miR-939-5p on PM-triggered endothelial cell injury by negatively regulating HIF-1α. miR-939-5p might present a new therapeutic target for PM induced endothelial injury.
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http://dx.doi.org/10.1080/17435390.2021.1917716DOI Listing
May 2021

Dynamic recovery after acute single fine particulate matter exposure in male mice: Effect on lipid deregulation and cardiovascular alterations.

J Hazard Mater 2021 Feb 24;414:125504. Epub 2021 Feb 24.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China. Electronic address:

Many studies have linked airborne fine particulate matter (PM2.5) exposure to cardiovascular diseases. We performed a time-series analysis to investigate whether the disruption of lipid metabolism recovered or lasted after acute PM2.5 exposure in mice. Targeted lipidomic analysis showed that four major plasma membrane phospholipids along with cholesterol esters (CE) were significantly altered on 7th post-exposure day (PED7), and the alteration reached a peak on PED14. On PED21, the phosphatidylcholine (PC) decrease was more marked than on PED14, and its resurgence was indirectly linked to triglyceride (TG) increase. Homocysteine (HCY), lactate dehydrogenase (LDH), and α-hydroxybutyrate dehydrogenase (α-HBDH) levels increased but glucose levels decreased markedly in a dose- and time-dependent manner throughout the experimental period. Network analysis showed that the lasting lipid deregulation on PED21 correlated to myocardial markers and glucose interruption, during which high-density lipoprotein cholesterol (HDL-C) decreased. The present data implied that the constructional membrane lipids were initially interrupted by PM2.5, and the subsequent rehabilitation resulted in the deregulation of storage lipids; the parallel myocardial and glucose effects may be enhanced by the lasting HDL-C lipid deregulation on PED21. These myocardial and lipidomic events were early indicators of cardiovascular risk, resulting from subsequent exposure to and accumulation of PM2.5.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125504DOI Listing
February 2021

Persistence and reversibility of arsenic-induced gut microbiome and metabolome shifts in male rats after 30-days recovery duration.

Sci Total Environ 2021 Jul 18;776:145972. Epub 2021 Feb 18.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

The metabolites of gut microbiome are important host-health regulating factors and can be interrupted when the host is exposed to environmental pollutant via ingestion route. Arsenic contaminated drinking water is one of the most serious environmental health problems worldwide. Therefore, the arsenic-induced alterations of gut microbiome and metabolome, especially the persistence and reversibility of the alterations after the long-term arsenic exposure will be interesting to know. In this study, we investigated the relationship between gut microbiota and metabolites in male rats both after the 30-days arsenic treatment and 30-days recovery duration. The composition and diversity of gut microbiota were affected significantly by the treatment, but they presented partial improvement in recovery duration. Moreover, arsenic exposure induced the significant changes of 73 metabolites, which involved in the metabolism of glycerophospholipid, linoleic acid, as well as the biosynthesis of phenylalanine, tyrosine and tryptophan. Although it had a persistent effect, the restoration of glycerophospholipid metabolism was observed in the 30-days recovery. Integration analysis further correlated the arsenic impacting microbes with some important differential metabolites. Lactobacillus associated with the decreases of phosphatidylethanolamine(34:1), 16alpha-hydroxydehydroepiandrosterone 3-sulfate, seryltryptophan and alanyltyrosine in recovery duration. Lactobacillus strains have potential to work as protective agents against arsenic toxicity by restoring perturbed glycerophospholipid metabolism. In summary, arsenic significantly disrupted gut microbiome and metabolome, but the disruptions are reversible to some extent after a 30-days recovery.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145972DOI Listing
July 2021

Size-dependent adverse effects of microplastics on intestinal microbiota and metabolic homeostasis in the marine medaka (Oryzias melastigma).

Environ Int 2021 06 24;151:106452. Epub 2021 Feb 24.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

Microplastic (MP) is an emerging environmental pollutant and exposure to MPs has been associated with numerous adverse health outcomes in both wild and laboratory animals. The toxicity of MPs depends on concentration, exposure time, chemical composition and size distribution, but the impacts of particle size remain inconclusive yet. In this study, adult marine medaka (Oryzias melastigma) were exposed to different size of polystyrene MPs (PS-MPs) with concentration of 10 mg/L for 60 days and the growth performance, lipid metabolism, immune parameters and gut microbiome were determined. Results indicated that particle size is a dominant factor causing lipid metabolism disorders and hepatic toxicity in PS-MPs-exposed fish. The bodyweight, adipocyte size and hepatic lipid contents were significantly increased in 200 μm PS-MPs-exposed fish, while 2 and 10 μm PS-MPs-exposed fish exhibited liver injury principally manifested asthepresence oflittlefibrosis and inflammation. Given that larger particles could not enter the circulatory system, the impacts of PS-MPs on intestinal microbial biota homeostasis were further investigated. The results not only showed the characterization of gut microbial communities in Oryzias melastigma, but also indicated that microbial diversity and composition were altered in gut of fish exposed to PS-MPs, in particular 200 μm PS-MPs. The differentially abundant bacterial taxa in PS-MPs-exposed fish mainly belonged to the phylum Verrucomicrobia, Firmicutes and Fusobacteria. And furthermore, increased abundance of Verrucomicrobia and Firmicutes/Bacteroidetes ratio and decreased Fusobacteria were correlated with the increased bodyweight. Intestinal microbiome should play a critical role in regulating host lipid metabolism in fish exposed to lager size of PS-MPs.
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http://dx.doi.org/10.1016/j.envint.2021.106452DOI Listing
June 2021

Meet-in-metabolite analysis: A novel strategy to identify connections between arsenic exposure and male infertility.

Environ Int 2021 02 2;147:106360. Epub 2021 Jan 2.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China; Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China. Electronic address:

Background: Despite a trend in the use of systems epidemiology to fill the knowledge gap between risk-factor exposure and adverse outcomes in the OMICS data, such as the metabolome, seriously hindrances need to be overcome for identifying molecular connections.

Objectives: Using male infertility phenotypes and arsenic exposure, we aimed to identify intermediate biomarkers that reflect both arsenic exposure and male infertility with a meet-in-metabolite analysis (MIMA).

Methods: Urinary arsenic levels and metabolome were measured by using inductively coupled plasma-mass spectrometry (ICP-MS) and HPLC-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS), respectively. To identify arsenic-related metabolic markers (A-MIMA), the intermediate markers were profiled by orthogonal projections to latent structures (OPLS-DA). To detect infertility-related metabolic markers (I-MIMA), the intermediate markers were investigated by weighted gene co-expression network analysis. The key node markers, related to both A-MIMA and I-MIMA, were determined by O2PLS and defined as MIMA markers. Finally, network analysis was used to construct the MIMA-related metabolic network.

Results: Twelve markers each were defined through the significant associations with arsenic exposure (A-MIMA) and/or infertility (I-MIMA), respectively. Seven of them, including acetyl-N-formyl-5-methoxykynurenamine, carnitine, estrone, 2-oxo-4-methylthiobutanoic acid, malonic acid, valine, and LysoPC (10:0), were defined through the associations with both arsenic exposure and male infertility (MIMA markers). These intermediate markers were involved majorly in oxidative stress, one-carbon metabolism, steroid hormone homeostasis, and lipid metabolism pathways. The core correlation network analysis further highlighted that testosterone is a vital link between the effect of arsenic and male infertility.

Conclusions: From arsenic exposure to male infertility, the arsenic methylation that coupled one-carbon metabolism disruption with oxidation stress may have extended its effect to fatty acid oxidation and steroidogenesis dysfunction. Testosterone is at the hub between arsenic exposure and male infertility modules and, along with the related metabolic pathways, may service as a potential surrogate marker in risk assessment for male dysfunction due to arsenic exposure.
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http://dx.doi.org/10.1016/j.envint.2020.106360DOI Listing
February 2021

Environmental doses of arsenic exposure are associated with increased reproductive-age male urinary hormone excretion and in vitro Leydig cell steroidogenesis.

J Hazard Mater 2021 Apr 19;408:124904. Epub 2020 Dec 19.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

Humans are ubiquitously exposed to arsenic from multiple sources, and chronic arsenic exposure may be associated with male reproductive health. Although association regarding arsenic exposure and sex hormone secretion in blood has been reported, sex hormone excretion in urine studies is lacking. Urinary sex hormone excretion has emerged as a complementary strategy to evaluate gonadal function. Herein, we determined the associations between environmental exposure to arsenic and urinary sex hormone elimination and in vitro Leydig cell steroidogenesis. Concentrations of arsenic and testosterone (T), estradiol (E) and progesterone (P) in repeated urine samples were determined among 451 reproductive-age males. Moreover, an in vitro Leydig cell MLTC-1 steroidogenesis experiment was designed to simulate real-world scenarios of low human exposure. Multivariable linear regression models were used to assess the associations of urinary arsenic levels with urinary hormones. Urinary arsenic concentrations were positively associated with urinary sex hormone (T, E, and P) levels. An in vitro test further demonstrated that a population-based environmental exposure range (0.01-5 μM) of arsenic induced Leydig cell steroidogenesis potency. Our results indicate that low-dose arsenic exposure exhibits an endocrine disrupting effect by stimulating Leydig cell steroidogenesis and accelerating urinary steroid excretion, which extends previous knowledge of the inverse association of high-dose arsenic exposure with sexual steroid production that is assumed to be anti-androgen.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124904DOI Listing
April 2021

Arsenic and lead in the indoor residential settings of different socio-economic status; assessment of human health risk via dust exposure.

Environ Sci Pollut Res Int 2021 Mar 11;28(11):13288-13299. Epub 2020 Nov 11.

Family and Community Medicine Department, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

In the present study, occurrence of arsenic (As) and lead (Pb) is reported in rural and urban household dust (floor and AC filter dust) of the Kingdom of Saudi Arabia (KSA). Several studies have found concerning concentrations of these toxic metals in indoor dust from different countries, but data from this region is missing. The association between studied toxic metals and different socioeconomic parameters was investigated. Furthermore, health risk associated with these toxic metals via dust exposure was evaluated for the Saudi population. Mean concentration of Pb was several times higher than As in both types of dust samples. AC filter dust was more contaminated with these metals than floor dust. Levels of Pb were up to 775 ppm in AC filter dust from urban areas, while 167 ppm in rural AC filter dust. Different socioeconomic parameters did not influence much on the presence of studied metals in both AC and floor dust. To estimate health risk from contaminated dust hazardous index (HI), hazardous quotient (HQ), and incremental lifetime cancer risk (ILCR) via dust ingestion, inhalation, and dermal contact was calculate using USEPA equations. The ILCR range for both toxic metals was within the tolerable range of reference values of USEPA (1 × 10 to 5 × 10). Nonetheless, HI was close to 1 for Pb via dust exposure for young urban children, which signifies the risk of non-carcinogenic health problems in studied area. Graphical abstract.
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http://dx.doi.org/10.1007/s11356-020-11546-wDOI Listing
March 2021

Linking emerging contaminants exposure to adverse health effects: Crosstalk between epigenome and environment.

J Appl Toxicol 2021 Jun 28;41(6):878-897. Epub 2020 Oct 28.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.

Environmental epigenetic findings shed new light on the roles of epigenetic regulations in environmental exposure-induced toxicities or disease susceptibilities. Currently, environmental emerging contaminants (ECs) are in focus for further investigation due to the evidence of human exposure in addition to their environmental occurrences. However, the adverse effects of these environmental ECs on health through epigenetic mechanisms are still poorly addressed in many aspects. This review discusses the epigenetic mechanisms (DNA methylation, histone modifications, and microRNA expressions) linking ECs exposure to health outcomes. We emphasized on the recent literature describing how ECs can dysregulate epigenetic mechanisms and lead to downstream health outcomes. These up-to-date research outputs could provide novel insights into the toxicological mechanisms of ECs. However, the field still faces a demand for further studies on the broad spectrum of health effects, synergistic/antagonistic effects, transgenerational epigenetic effects, and epidemiologic and demographic data of ECs.
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http://dx.doi.org/10.1002/jat.4092DOI Listing
June 2021

Infantile phthalate metabolism and toxico/pharmacokinetic implications within the first year of life.

Environ Int 2020 11 18;144:106052. Epub 2020 Aug 18.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, PR China. Electronic address:

Background: Infantile development of phthalate metabolism is crucial for risk assessment of endocrine disruption and has important toxico/pharmacokinetic implications.

Objectives: To characterize temporal variability in urinary phthalate metabolites in infants and to examine their growth-dependent detoxification.

Methods: In this cohort study, urine samples (n = 876) from 155 healthy Chinese infants were collected serially at eight time points from birth to one year old. Free and total (i.e., free plus glucuronide conjugated) phthalate metabolites (PMEs) were measured by LC/MS/MS. Time variability in PMEs and PME metabolism capacity was characterized using intraclass correlation coefficients (ICCs) and linear mixed regression models.

Results: Concentrations of most PMEs changed significantly, with ICCs ranging from 0.213 to 0.318, and trends increased significantly over time (p < 0.001), while MEHP showed fair reproducibility (ICC = 0.480). Glucuronidation increased considerably (ICC ≤ 0.250; p < 0.001) for most PMEs but not for MMP or MEHP. Ester-chain ω-/ω-1-oxidation and α-/β-oxidation patterns of MEHP steeply increased from 3 months to 8 months, where they peaked, resulting in a molar percentage of MEHP in ΣDEHP showing the inversion pattern. MEHP detoxification through oxidation of the hydrophobic ester-chain is apparently a priority for carboxyl glucuronidation in infants.

Conclusions: Infant phthalate exposure is prevalent, but they cannot metabolize or eliminate these compounds as efficiently as adults, especially during the first 6 months of life. From an environmental biomonitoring view, age-dependent phthalate metabolism provides crucial implications for infantile ontogeny and health risk assessment within the first year of life.
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http://dx.doi.org/10.1016/j.envint.2020.106052DOI Listing
November 2020

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle.

Theranostics 2020 23;10(20):9230-9248. Epub 2020 Jul 23.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.

Skeletal muscle insulin resistance is detectable before type 2 diabetes is diagnosed. Exposure to di(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine-disrupting chemical, is a novel risk factor for insulin resistance and type 2 diabetes. This study aimed to explore insulin signaling regulatory pathway in skeletal muscle of the DEHP-induced insulin-resistant mice and to investigate potential therapeutic strategies for treating insulin resistance. C57BL/6J male mice were exposed to 2 mg/kg/day DEHP for 15 weeks. Whole-body glucose homeostasis, oxidative stress and deregulated miRNA-mediated molecular transduction in skeletal muscle were examined. microRNA (miRNA) interventions based on lentiviruses and adeno-associated viruses 9 (AAV9) were performed. Dnmt3a-dependent promoter methylation and lncRNA Malat1-related sponge functions cooperatively downregulated miR-17 in DEHP-exposed skeletal muscle cells. DEHP suppressed miR-17 to disrupt the Keap1-Nrf2 redox system and to activate oxidative stress-responsive Txnip in skeletal muscle. Oxidative stress upregulated miR-200a, which directly targets the 3'UTR of and , leading to hindered insulin signaling and impaired insulin-dependent glucose uptake in skeletal muscle, ultimately promoting the development of insulin resistance. AAV9-induced overexpression of miR-17 and lentivirus-mediated silencing of miR-200a in skeletal muscle ameliorated whole-body insulin resistance in DEHP-exposed mice. The miR-17/Keap1-Nrf2/miR-200a axis contributed to DEHP-induced insulin resistance. miR-17 is a positive regulator, whereas miR-200a is a negative regulator of insulin signaling in skeletal muscle, and both miRNAs have the potential to become therapeutic targets for preventing and treating insulin resistance or type 2 diabetes.
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http://dx.doi.org/10.7150/thno.45253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415800PMC
July 2020

Urinary profiles of selected metals and arsenic and their exposure pathway analysis in four large floodplains of Pakistan.

Sci Total Environ 2020 Oct 21;737:139586. Epub 2020 May 21.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, 361102 Xiamen, China; Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China. Electronic address:

In context of fragile geological conditions and rapid urbanization, element exposure via dietary (food, water) and non-dietary (dust, soil) routes into human population at different land use settings is a major concern in the Indus floodplains (FPs) of Pakistan. In current study, several important trace elements including arsenic (As), chromium (Cr), manganese (Mn), cobalt (Co), cadmium (Cd), nickel (Ni), copper (Cu) and lead (Pb) were analyzed in the paired human urine, food, water and dust samples collected from main FPs of Pakistan. Daily intake estimation and regression analysis were used to evaluate the relationships between internal exposure, exposure routes of studied trace elements and different land use settings. High concentrations of urinary As, Cr, Cu, Mn, and Cd were detected in the general male population of the studied floodplains (FPs). Moreover, the levels (μg/L) of urinary As increased gradually from FP1 (12.8), FP2 (18), FP3 (61) to FP4 (71). Regression analysis showed that As contaminated water was correlated with elevated urinary As concentrations in FP3 and FP4, and water Cr and Mn was significantly associated with urinary Cr and Mn concentrations in FP2. Moreover, the associations of food Mn and urinary Mn were found in FP1. Over all, cumulative estimated daily intake (EDI) values from water, dust and food from all the flood plains showed that Mn had the highest values (6.6, 9.2, 14.4 μg/kg/day) followed by water As (1.98 μg/kg/day), dust Cu (1.5 μg/kg/day) and Pb (1.7 μg/kg/day). Studied floodplains were moderately to highly polluted in terms of studied trace elements (As, Cr, Cu, Mn, and Cd) contamination especially in FP3 and FP4. The results will contribute to improve the knowledge and information on current exposure of Pakistani male adults to the different contaminants.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139586DOI Listing
October 2020

Assessment of carcinogenic and toxic substances in herb.

Toxicol Rep 2020 19;7:468-474. Epub 2020 Mar 19.

Public Health and Environment Division, Department of Biosciences, COMSATS University, Islamabad, 45550, Pakistan.

There has emerged a herb in Zambia called which has unknown chemical composition. The use of herb with unknown chemical composition has brought mixed feelings among many Zambians. This study, therefore, aimed to assess the toxic and carcinogenic substances in herb. herb was purchased from Chipata, Lusaka, Mpika, Mwense, Kitwe, and Solwezi. 5 samples were collected from each of these districts and were thoroughly mixed to give 6 consolidated samples (n = 6). Nicotine and, nitrosamines were analysed using UV spectrometer lambda 35 Perkin Elmer while trace metals were analysed using ICP-MS Inductively Coupled Plasma Mass Spectroscopy (Agilent Technologies, Santa Clara, CA, USA). Nicotine, nitrosamines, and trace metals were detected in high concentrations. The concentrations ranged from 3.87 to 9.83 mg/kg for nitrosamines and 10.94-34.01 mg/kg for nicotine. Hazard Indexes for arsenic, cadmium, chromium, manganese, and copper were greater than one (HI > 1). herb is a potentially toxic and carcinogenic substance because it contains toxic and carcinogenic constituents in high concentrations. These toxic and carcinogenic constituents have been confirmed to cause gastrointestinal disorders, cancers, degenerative, cardiovascular, hematopoietic, neurologic and cognitive problems as well as male infertility.
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http://dx.doi.org/10.1016/j.toxrep.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109397PMC
March 2020

Metabolic linkages between indoor negative air ions, particulate matter and cardiorespiratory function: A randomized, double-blind crossover study among children.

Environ Int 2020 05 20;138:105663. Epub 2020 Mar 20.

Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, Beijing 100191, China.

Background: Ionization air purifiers, which purify particulate matter (PM) by producing vast number of negative air ions (NAI), are widely used. Recent study implied that ionization air purification could bring respiratory benefits but deterioration of heart rate variability (HRV). However, its underlying molecular mechanisms remain unclear.

Objectives: To explore the molecular linkages between indoor NAI, decreased PM and the cardiorespiratory effect after purification.

Methods: Urine samples were collected from 44 healthy children three times of each study period (real and sham purification) in an existing randomized, double-blind crossover study. Ultra-high performance liquid chromatography/mass spectrometry was conducted in metabolomics analysis, the associations between indoor NAI, decreased PM and the cardiorespiratory function were investigated via the meet-in-metabolite approach (MIMA) based on statistical and metabolic pathway analysis. Mixed-effect models were used to establish associations between exposure, health parameters and metabolites.

Results: Twenty-eight and fourteen metabolites were identified with significant correlations to NAI and PM, respectively. Besides, eight and eighteen metabolites were separately associated with respiratory function and HRV. The increased NAI and decreased PM improved respiratory function mainly with eight pathways, promoting energy production, anti-inflammation and anti-oxidation capacity. Decreased PM ameliorated HRV with six main pathways, increasing energy production and anti-inflammation capacity while increased NAI deteriorated HRV with five main pathways, lowering energy generation and anti-oxidation capacity.

Conclusions: Increased NAI and decreased PM ameliorated respiratory function by increasing energy production, improving anti-inflammation and anti-oxidation capacity. Decreased PM improved cardiac autonomic function by increasing energy production and anti-inflammation capacity, while these benefits were overcast by massive NAI via lowering energy generation and anti-oxidation capacity with different metabolic pathways.
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http://dx.doi.org/10.1016/j.envint.2020.105663DOI Listing
May 2020

Combined exposure of fine particulate matter and high-fat diet aggravate the cardiac fibrosis in C57BL/6J mice.

J Hazard Mater 2020 06 30;391:122203. Epub 2020 Jan 30.

Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, People's Republic of China. Electronic address:

Cardiac fibrosis is associated with fine particulate matter (PM) exposure. In addition, whether high-fat diet (HFD) could exacerbate the PM-induced cardiac injury was unevaluated. Thus, this study was aimed to investigate the combined effects of PM and HFD on cardiac fibrosis. The echocardiography and histopathological analysis showed that co-exposure of PM and HFD had a significant deleterious effect on both cardiac systolic and diastolic function accompanied the myofibril disorder and myocardial fibrosis in C57BL/6 J mice than exposed to PM or HFD alone. The augmented oxidative damage and increased α-SMA area percentage were detected in heart tissue of mice exposed to PM and HFD together. PM upregulated the expressions of cardiac fibrosis-related special markers, including collagen-I, collagen-III, TGF-β1, p-Smad3 and total Smad3, which had more pronounced activations in co-exposure group. Meanwhile, the factorial analysis exhibited the synergistic interaction regarded to the combined exposure of PM and HFD. Simultaneously, PM and palmitic acid increased intracellular ROS generation and activated the TGF-β1/Smad3 signaling pathway in cardiomyocytes. While the ROS scavenger NAC had effectively attenuated the ROS level and suppressed the TGF-β1/Smad3 signaling pathway. Taken together, our results demonstrated combined exposure to PM and HFD could aggravate cardiac fibrosis via activating the ROS/TGF-β1/Smad3 signaling pathway.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122203DOI Listing
June 2020

PM-induced inflammation and lipidome alteration associated with the development of atherosclerosis based on a targeted lipidomic analysis.

Environ Int 2020 03 11;136:105444. Epub 2020 Jan 11.

Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China. Electronic address:

Epidemiological studies have confirmed that PM could contribute to the development of atherosclerosis accompanied with lipids dysregulation. However, the lipids biomarkers involved in this progress remain largely unknown. In this study, a targeted lipidomic approach was used to find out the possible lipid biomarkers involved in the development of atherosclerosis after PM exposure or during a recovery period. Also, we assessed the pro-atherosclerosis effects of PM and follow-up influence using pulse wave (PW) Doppler ultrasound, oil red O staining and H&E staining. The vascular stiffness was elevated after 2-month PM exposure and might persist after 1-month recovery. While the lesions mostly concentrated in the aortic arch was significantly increased in 2-month PM exposure group and remained an increasing trend after 1-month recovery. The expressions of pro-inflammatory cytokines detected by Mouse Inflammation Array were elevated after ApoE mice treated with PM for 2-month and restored following 1-month recovery. Yet, IL-10 was significantly decreased during 1-month recovery. Additionally, the targeted lipidomic analysis demonstrated that cholesterol ester (CE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM) were significantly increased while lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), diacylglycerol (DG), triacylglycerol (TG) were reduced after 2-month PM exposure, indicating that PM could disrupt glycerophospholipids, glycerolipids and sphingolipids metabolism. And a persistent impact of PM on glycerophospholipids and glycerolipids metabolism was found after 1-month recovery. Our study demonstrated that PM-induced inflammation response might promote atherosclerotic lesions probably through lipid dysregulation, and the influence probably persisted after 1-month recovery.
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http://dx.doi.org/10.1016/j.envint.2019.105444DOI Listing
March 2020

Environmental exposure pathway analysis of trace elements and autism risk in Pakistani children population.

Sci Total Environ 2020 Apr 7;712:136471. Epub 2020 Jan 7.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

The pursuit of industrialization and urbanization in developing countries disrupt the fragile environment, resulting in biogeochemical extra-emission of the trace elements into human inhabitance causing serious health concerns. We aimed to determine the associations between Autism spectrum disorder (ASD) risk and exposure to trace elements (As, Zn, Ni, Pb, Hg, Cu, Cd, and Co), associations between the internal doses and environmental sources of these elements were also assessed. Genetic susceptibility to toxins was assessed through GSTT1 and GSTM1 null polymorphism analysis. Our results showed that lower BMI in children was significantly associated with ASD (p < 0.05, AOR = 0.86; 95% CI: 0.76, 0.98). As was significantly higher in both hair (p < 0.01, AOR = 18.29; 95% CI: 1.98, 169) and urine (p < 0.01, AOR = 1.04; 95% CI: 1.01, 1.06) samples from children with ASD; urinary Hg (p < 0.05, AOR = 2.90; 95% CI: 1.39, 6.07) and Pb (p < 0.05, AOR = 1.95; 95% CI: 1.01, 3.77) were also positively associated with ASD. Regarding the genetic susceptibility, Cu was significantly associated with GSTM1 positive genotype (p < 0.05, AOR = 1.05; 95% CI: 1.00, 1.10). Children inhabiting the urban areas exposed to significantly higher levels of studied trace elements. The Estimated Daily Intake (EDI) values highlighted that the different land use settings resulted in children's source specific exposure to studied trace elements. The exposure pathway analysis showed that the distal factors of land-use settings associated with children increased exposure risk for most of the investigated elements, noticeably As, Pb and Hg associated with ASD prevalence.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136471DOI Listing
April 2020

Gene-environment interactions between GSTs polymorphisms and targeted epigenetic alterations in hepatocellular carcinoma following organochlorine pesticides (OCPs) exposure.

Environ Int 2020 01 12;134:105313. Epub 2019 Nov 12.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address:

Exposure to environmental pollutant organochlorine pesticides (OCPs) and the role of tumour suppressor GSTs gene polymorphisms as well as epigenetic alterations have all been well reported in hepatocarcinogenesis. However, the interplay between environmental risk factors and polymorphic tumour suppressor genes or epigenetic factors in hepatocellular carcinoma (HCC) development remains ambiguous. Herein, we investigated the relationship of three GSTs polymorphisms (GSTT1 deletion, GSTM1 deletion, GSTP1 rs1695) as well as GSTP1 promoter region DNA methylation and HCC risk with a particular focus on the interaction with OCPs exposure among 90 HCC cases and 99 controls in a Chinese population. Serum samples were analysed for OCPs exposure employing gas chromatography coupled with mass selective detector (GC-MS). GSTs polymorphisms and epigenetic alterations were determined using high-resolution melting PCR (HRM PCR) and DNA sequencing. After adjusting for confounders (HBV infection, smoking, alcohol consumption, BMI, age, gender), OCPs exposure and GSTP1 methylation is significantly associated with elevated risk of HCC, while no significance is observed for GSTs polymorphisms. Moreover, the effects of OCPs exposure on HCC risk are more pronounced amongst GSTP1 (Ile/Val + Val/Val) and GSTP1 promoter methylation subjects than those who were GSTP1 (Ile/Ile) and unmethylated subjects. The interactions between OCPs exposure and GSTP1 genotype as well as GSTP1 epigenetic status are statistically significant. The current study demonstrates the importance of gene-environment interactions in the multifactorial development of HCC.
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http://dx.doi.org/10.1016/j.envint.2019.105313DOI Listing
January 2020

[Metabolomic network analysis of umbilical cord blood of gestational diabetes mellitus patients via liquid chromatography-mass spectrometry].

Se Pu 2019 Aug;37(8):897-903

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China.

The global increase in the prevalence of gestational diabetes mellitus(GDM)in recent years has prompted the study of the effect of GDM on the metabolism between mother and fetus. In this study, the metabolomic investigation of the umbilical cord blood of mothers presenting GDM was performed using liquid chromatography-mass spectrometry (LC-MS), orthogonal projections to latent structures discriminant analysis (OPLS-DA), and network analysis to assess GDM-related metabolic biomarkers. The results showed that arachidonic acid (AA) played an important role in the key metabolic network while further pathway analysis suggested that GDM induced unsaturated fatty acid metabolic disorder. This study provides the underlying metabolic mechanism of GDM-induced metabolic abnormalities between mother and fetus.
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http://dx.doi.org/10.3724/SP.J.1123.2019.02006DOI Listing
August 2019

Seminal plasma metabolites mediate the associations of multiple environmental pollutants with semen quality in Chinese men.

Environ Int 2019 11 6;132:105066. Epub 2019 Aug 6.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China; Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

Environmental exposure to arsenic, phthalate esters (PAEs) and perfluorinated compounds (PFCs) has been associated with human semen quality. However, the epidemiological "black-box" of these associations remains poorly uncovered. In this study, based on the association analysis between arsenic, PAE and PFC exposure and semen quality parameters (i.e., semen volume, sperm concentration, sperm count, progressive motility, total motility and normal morphology) in a Chinese male population, we explored the seminal plasma metabolic signatures that may mediate the exposure-outcome relations by using the meet-in-metabolite-analysis (MIMA) approach. As a result, a negative association was found between DMA and sperm concentration, whereas MEHP and PFHxS were positively associated with sperm count and concentration, respectively. Metabolomics analysis revealed that sixteen and twenty-two seminal plasma metabolites were related to sperm concentration and count, respectively, and they are mainly involved in fatty acid, lipid and amino acid metabolism. Moreover, it was further indicated that eicosatetraenoate, carnitines and DHA may impact the inverse association between DMA and sperm concentration, while eicosatetraenoate, carnitines, DHA, PGB2 and tocotrienol are possible mediators of the positive association between PFHxS and sperm concentration. As these metabolic biomarkers are relevant to antioxidation and fatty acid β-oxidation, we suggest that redox balance and energy generation shifts in seminal plasma are involved in the association of human semen quality with environmental DMA and PFHxS exposure.
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http://dx.doi.org/10.1016/j.envint.2019.105066DOI Listing
November 2019

Phthalate side-chain structures and hydrolysis metabolism associated with steroidogenic effects in MLTC-1 Leydig cells.

Toxicol Lett 2019 Jun 29;308:56-64. Epub 2019 Mar 29.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

Although it is well acknowledged that the anti-androgenic phthalate diesters can be readily hydrolysed into their monoester counterparts, their metabolites' toxicology remains obscure. Herein, we tested the hypothesis that hydrolysis of one of the two ester bonds can mediate phthalate diesters' potential endocrine effects in MLTC-1 Leydig cells, in line with their ability to disrupt androgen secretion in humans. Five diesters (DMP, DEP, DBP, DBzP and DEHP) and five monoesters (MMP, MEP, MBP, MBzP and MEHP) phthalates as mixtures or individually were applied to cell lines to investigate differences in phthalates' hydrolysis associated with varying side-chain structures and steroidogenic effects. Short-chain diesters DMP, DEP and DBP are more readily hydrolysed compared to the long-chain DEHP, while aromatic alkyl chain DBzP cannot be metabolized completely in vitro. When the hydrolysis processes are interrupted, the diester phthalates' steroidogenic effects can be influenced via regulating related steroidogenic pathway genes. With 10-100 μM treatment exposures, androgenic effects were observed only with DMP or DEP but not for MMP or MEP; while the phthalate diesters DBP, DBzP or DEHP generally exhibited more complex steroidogenic effects than their corresponding monoester counterparts (i.e., biphasic androgen and anti-androgen effects for diesters but monotonic androgen effects for monoesters were observed). DBP elicited hydrolysis-related steroidogenic modulation, in which the anti-androgenic effects of diester DBP reversed into the androgenic effects of monoester MBP at 100 μM. Phthalate metabolites appear to exert different effects at an endocrine level compared to parent compounds, and deeper insights into how the hydrolytic process is related to this alternating toxicity would improve our understanding of a risk assessment for these widespread contaminants in male reproduction.
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http://dx.doi.org/10.1016/j.toxlet.2019.03.013DOI Listing
June 2019

Phthalate exposure and cumulative risk in a Chinese newborn population.

Environ Sci Pollut Res Int 2019 Mar 23;26(8):7763-7771. Epub 2019 Jan 23.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China.

Phthalates have been attracted as a considerable attention in toxicological research as well as public health context due to their ubiquitous occurrence and potential adverse health effects. Newborns are susceptible to the environmental risk factors; however, data are still limited on newborn phthalate exposure and risk assessment worldwide, especially in China. This study was nested in a cross-sectional retrospective study of 1359 pregnant women recruited in Xiamen Maternity and Child Care Hospital, China, during June to July 2012. All urine samples from newborn were collected using disposal diapers during the first two postnatal days, and seven phthalate metabolites were measured by LC-ESI-MS/MS. Phthalate exposure and accumulation risk were evaluated based on the measured newborn urinary internal doses. The detection rate (96.5%) and the median concentration (17.5 ng/mL) of mono-n-butyl phthalate (MBP) were the highest, while monobenzyl phthalate (MBzP) concentration was the lowest with a detection rate (1.50%). By estimating the daily intakes of the parent phthalates, their EDI were 0.04, 0.10, 0.32, 0.00, and 0.12 μg/kg-bw/day for dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalates (DBP), benzyl butyl phthalate (BBzP), and di-(2-ethylhexyl) phthalate (DEHP), respectively. The newborns were commonly exposed to phthalates but no one exceeds the regulated tolerable daily intake (TDI) values in this large newborn population.
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http://dx.doi.org/10.1007/s11356-019-04216-zDOI Listing
March 2019

Positive association of low-level environmental phthalate exposure with sperm motility was mediated by DNA methylation: A pilot study.

Chemosphere 2019 Apr 21;220:459-467. Epub 2018 Dec 21.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China. Electronic address:

Accumulating evidence indicates that phthalate exposures may affect human semen quality. Epigenetic modifications such as DNA methylation might be linked chemical exposure and spermatogenesis epigenetic reprogramming. In the present study, we investigated associations between phthalate exposures, DNA methylation and sperm quality in undergoing fertility assessment male population. Urine was used for phthalate exposures monitoring, six selected metabolites (i.e., monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP) and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP)) were measured by using HPLC-MS/MS. Sperm quality parameters were determined by computer-assisted semen analysis (CASA). Sperm DNA methylation patterns (long interspersed nuclear element-1(LINE-1), H19 and LIT1) were analysed employing high-melting resolution (HRM) PCR. Urinary MMP, MEHP, MEOHP, sum of DEHP metabolites (∑DEHP) and sum of selected phthalates metabolites (∑PAEs) were significantly positively associated with sperm motility. Sperm LINE-1 DNA methylation were found to be negatively associated with ∑DEHP exposure and sperm quality (ejaculate volume, total sperm number and motility). Epigenetic modification LINE-1 DNA methylation demonstrated mediating effects in association between DEHP exposure and sperm motility, and 20.7% of the association was mediated by serum LIEN-1 DNA methylation. These results extend the previous studies in association between phthalate exposures and classical semen parameters, mainly of inverse association, and sperm DNA methylation may be linked phthalate exposures and male reproductive health outcome.
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http://dx.doi.org/10.1016/j.chemosphere.2018.12.155DOI Listing
April 2019

Enhanced histone H3K9 tri-methylation suppresses steroidogenesis in rat testis chronically exposed to arsenic.

Ecotoxicol Environ Saf 2019 Apr 14;170:513-520. Epub 2018 Dec 14.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, PR China. Electronic address:

Arsenic poses a profound health risk including male reproductive dysfunction upon prolonged exposure. Histone methylation is an important epigenetic driver; however, its role in arsenic- induced steroidogenic pathogenesis remains obscure. In current study, we investigated the effect of histone H3K9 tri-methylation (H3K9me3) on expression pattern of steroidogenic genes in rat testis after long-term arsenic exposure. Our results revealed that arsenic exposure down-regulated the mRNA expressions of all studied steroidogenic genes (Lhr, Star, P450scc, Hsd3b, Cyp17a1, Hsd17b and Arom). Moreover, arsenic significantly increased the H3K9me3 level in rat testis. The plausible explanation of increased H3K9me3 was attributable to the up-regulation of histone H3K9me3 methyltransferase, Suv39h1 and down-regulation of demethylase, Jmjd2a. Since H3K9me3 activation leads to gene repression, we further investigated whether the down-regulation of steroidogenic genes was ascribed to the increased H3K9me3 level. To elucidate this, we determined the H3K9me3 levels in steroidogenic gene promoters, which also showed significant increase of H3K9me3 in the investigated regions after arsenic exposure. In conclusion, arsenic exposure suppressed the steroidogenic gene expression by activating H3K9me3 status, which contributed to steroidogenic inhibition in rat testis.
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http://dx.doi.org/10.1016/j.ecoenv.2018.12.035DOI Listing
April 2019

Biphasic effects of perfluorooctanoic acid on steroidogenesis in mouse Leydig tumour cells.

Reprod Toxicol 2019 01 30;83:54-62. Epub 2018 Nov 30.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which may possess endocrine disrupting properties. Herein, we investigated the possible mechanism(s) of toxicity and steroidogenesis in mouse Leydig cells. MLTC-1 (mouse Leydig tumour cells) cells were exposed to 0, 50, 100 or 200 μM PFOA for 48 h to ascertain their effects on the nuclear (membrane) receptor responses, steroidogenesis pathway and related regulated gene expression and steroid hormone secretion profiles. Our results reveal that nuclear receptors PXR, SR-B1 and LHR are sensitive to PFOA exposure. PFOA can accumulate in mitochondria and alter cholesterol precursor (fatty acid) mitochondrial transport process-related gene expression and thus inhibit steroid hormone precursor (cholesterol) production. In particular, PFOA exhibits biphasic effects on testosterone and progesterone production at differing levels of exposure. These findings indicate the potential endocrine-related effects of PFOA on steroid hormone secretion in Leydig cells and point to a novel disruption model.
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http://dx.doi.org/10.1016/j.reprotox.2018.11.006DOI Listing
January 2019

The modification of indoor PM exposure to chronic obstructive pulmonary disease in Chinese elderly people: A meet-in-metabolite analysis.

Environ Int 2018 12 30;121(Pt 2):1243-1252. Epub 2018 Oct 30.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

Background: Exposure to airborne fine particulate matter (PM) has been associated with a variety of adverse health outcomes including chronic obstructive pulmonary disease (COPD). However, the linkages between PM exposure, PM-related biomarkers, COPD-related biomarkers and COPD remain poorly elucidated.

Objectives: To investigate the linkages between PM exposure and COPD outcome by using the meet-in-middle strategy based on urinary metabolic biomarkers.

Methods: A cross-sectional study was designed to illustrate the mentioned quadripartite linkages. Indoor PM and its element components were assessed in 41 Chinese elderly participants including COPD patients and their healthy spouses. Metabolic biomarkers involved in PM exposure and COPD were identified by using urinary metabolomics. The associations between PM- and COPD-related biomarkers were investigated by statistics and metabolic pathway analysis.

Results: Seven metabolites were screened and identified with significant correlations to PM exposure, which were majorly involved in purine and amino acid metabolism as well as glycolysis. Ten COPD-related metabolic biomarkers were identified, which suggested that amino acid metabolism, lipid and fatty acid metabolism, and glucose metabolism were disturbed in the patients. Also, PM and its many elemental components were significantly associated with COPD-related biomarkers. We observed that the two kinds of biomarkers (PM- and COPD-related) integrated in a locally connected network and the alterations of these metabolic biomarkers can biologically link PM exposure to COPD outcome.

Conclusions: Our study indicated the modification of PM to COPD via both modes of action of lowering participants' antioxidation capacity and decreasing their lung energy generation; this information would be valuable for the prevention strategy of COPD.
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http://dx.doi.org/10.1016/j.envint.2018.10.046DOI Listing
December 2018

Multiple elements related to metabolic markers in the context of gestational diabetes mellitus in meconium.

Environ Int 2018 12 29;121(Pt 2):1227-1234. Epub 2018 Oct 29.

Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, China. Electronic address:

Background: Gestational diabetes mellitus (GDM) is a typical fetus development niches dysfunction and many toxic/nutrient elements have been associated with its onset and progression. However, the classic epidemiologic approach is regarded as "black-box epidemiology" and fails to elucidate these elements' biological roles on the damaged fetus developmental microenvironment.

Objective: We aimed to characterize the associations between meconium of multiple elements with GDM for illustrating their interruption effects on in-uterus microenvironment.

Methods: In this case-control study (n = 137 cases; n = 197 controls), the participants were nested from a cross-sectional retrospection of 1359 recruitments in Xiamen, China. Twenty-one meconium elements were characterized using inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma optical emission spectrometry (ICP-OES). For shifting the present paradigm from a black-box approach to a molecular approach, GDM-related metabolic markers were identified in our previous metabolome report. Based on the meet-in-middle strategy, the associations among the elements, metabolic markers and GDM incidence were assessed by using redundancy analysis and correlation-adjusted correlation; mediation analysis was further used to test the hypothesis that metabolic markers mediate the associations of the elements with GDM incidence.

Results: Eight elements were related with the GDM occurrence in dose-dependent manners, which positively (Al, As, Ba, Cd, Hg, and Sn) or negatively (Ca and V) associated with GDM. Among them, As, Cd, Ba, and Ca significantly contributed to the variation of GDM-related metabolic markers. Additionally, the associations of Cd, Ba, Ca and As with GDM were mediated by the metabolic markers which majorly involved in the lipid metabolism and the Adenosine/l-Arginine/Nitric Oxide (ALANO) pathways.

Conclusions: The two-side mediations of meconium metabolic markers between the multiple elements and GDM occurrence indicated that maternal exposure to As, Ba, Cd, and Ca may be associated with the dysfunction of fetus development niche through disrupting lipid metabolism and ALANO pathways.
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http://dx.doi.org/10.1016/j.envint.2018.10.044DOI Listing
December 2018

Association of In Utero Persistent Organic Pollutant Exposure With Placental Thyroid Hormones.

Endocrinology 2018 10;159(10):3473-3481

Helmholtz Zentrum München-German Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany.

In utero exposure to persistent organic pollutants (POPs) can result in thyroid function disorder, leading to concerns about their impact on fetal and neonatal development. The associations between placental levels of various POPs and thyroid hormones (THs) were investigated. In a prospective Danish study initially established for assessing congenital cryptorchidism, 58 placenta samples were collected from mothers of boys born with (n = 28) and without (n = 30) cryptorchidism. The concentrations of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), organotin chemicals (OTCs), organochlorine pesticides (OCPs), T4, T3, and rT3 were measured. The associations between placental THs and various POPs were analyzed using multiple linear regression. Five PBDEs, 35 PCBs, 14 PCDD/Fs, 3 OTCs, 25 OCPs, T4, T3, and rT3 were measured. No correlation between THs and the odds of cryptorchidism was found. Several POPs were significantly associated with THs: (1) T4 was inversely associated with BDEs 99, 100, ΣPBDE, and 2378-TeCDD, and positively associated with 1234678-HpCDF; (2) T3 was positively associated with 2378-TeCDF and 12378-PeCDF; and (3) rT3 was positively associated with PCB 81, 12378-PeCDF, and 234678-HxCDF, and inversely associated with tributyltin, ΣOTC, and methoxychlor. These results revealed that POP exposures were associated with TH levels in placenta, which may be a possible mechanism for the impacts of POP exposures on children's growth and development. This study provides new insight into the complexity of thyroid-disrupting properties of POPs. More research is needed to elucidate the biological consequences of POP exposures.
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http://dx.doi.org/10.1210/en.2018-00542DOI Listing
October 2018

[Modification of HLB-HPLC-MS/MS method for the determination of phthalate metabolites in infant urine].

Wei Sheng Yan Jiu 2017 Jul;46(4):650-657

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China.

Objective: Monitoring infants' exposure to 10 phthalates by measuring their urinary metabolites using a modified high performance liquid chromatography tandemelectrospray ionization mass spectrometry( HPLC-ESI-MS/MS) method.

Methods: A total of 50 infants at 0-6 month-old were recruited and their urine samples were collected by commercial available gel diapers. After the urine expression, phthalates were hydrolyzed by β-glucuronidase, cleaned up by HLB cartridge, then these metabolites were measured by HPLC-ESI-MS/MS equipped with a Hypersil Gold Phenyl column. The target compounds were quantified by the stable isotope dilution technique.

Results: The limit of detection( LOD) was 0. 06-0. 16 μg/L with linear ranged 0. 2-500 μg/L. 8 of 10 phthalate metabolites could be detected with > 98% frequencies, from the high to low levels( geometric mean, μg/L) they were Mi BP( 10. 35), MECPP( 5. 13), MBP( 4. 53), MEP( 1. 98), MMP( 1. 69), MEHP( 1. 22), MEHHP( 1. 18) and MEOHP( 0. 99). MBz P and MCHP could be detected in very low frequencies of 28% and 2%, respectively. Formula feeding might be one of the major routes of infant exposure to DEHP( parent compound of MEHP, MEOHP, MEHHP and MECPP) and BBz P( parent compound of MBz P).

Conclusion: The modified HLB-HPLC-MS/MS method can be used for determination of PAEs metabolites in infant urine effectively, and it is valuable for monitoring the infant'exposure risk to PAEs.
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July 2017

Determination of thyroid hormones in placenta using isotope-dilution liquid chromatography quadrupole time-of-flight mass spectrometry.

J Chromatogr A 2018 Jan 24;1534:85-92. Epub 2017 Dec 24.

Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Molecular EXposomics, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

The transplacental passage of thyroid hormones (THs) is of great significance since the maternal THs are vitally important in ensuring the normal fetal development. In this paper, we determined the concentrations of seven THs, viz. L-thyroxine (T), 3,3',5-triiodo-l-thyronine (T), 3,3',5'-triiodo-l-thyronine (rT), 3,3'-diiodo-l-thyronine (T), 3,5-diiodo-l-thyronine (rT), 3-iodo-l-thyronine (T) and 3-iodothyronamine (TAM), in placenta using isotope dilution liquid chromatography quadrupole time-of-flight mass spectrometry. We optimized the method using isotopically labeled quantification standards (C-T, C-T, C-rT and C-T) and recovery standard (C-T) in combination with solid-liquid extraction, liquid-liquid extraction and solid phase extraction. The linearity was obtained in the range of 0.5-150 pg uL with R values >0.99. The method detection limits (MDLs) ranged from 0.01 ng g to 0.2 ng g, while the method quantification limits (MQLs) were between 0.04 ng g and 0.7 ng g. The spike-recoveries for THs (except for T and TAM) were in the range of 81.0%-112%, with a coefficient of variation (CV) of 0.5-6.2%. The intra-day CVs and inter-day CVs were 0.5%-10.3% and 1.19%-8.88%, respectively. Concentrations of the THs were 22.9-35.0 ng g T, 0.32-0.46 ng g T, 2.86-3.69 ng g rT, 0.16-0.26 ng g T, and < MDL for other THs in five human placentas, and 2.05-3.51 ng g T, 0.37-0.62 ng g T, 0.96-1.3 ng g rT, 0.07-0.13 ng g T and < MDL for other THs in five mouse placentas. The presence of T was tracked in placenta for the first time. This method with improved selectivity and sensitivity allows comprehensive evaluation of TH homeostasis in research of metabolism and effects of environmental contaminant exposures.
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http://dx.doi.org/10.1016/j.chroma.2017.12.048DOI Listing
January 2018