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

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.

Arsenic activates the expression of 3ß-HSD in mouse Leydig cells through repression of histone H3K9 methylation.

Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3ß-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3ß-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3ß-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3ß-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells.

Human Arsenic exposure via dust across the different ecological zones of Pakistan.

The present study aims to assess the arsenic (As) levels into dust samples and its implications for human health, of four ecological zones of Pakistan, which included northern frozen mountains (FMZ), lower Himalyian wet mountains (WMZ), alluvial riverine plains (ARZ), and low lying agricultural areas (LLZ). Human nail samples (N=180) of general population were also collected from the similar areas and all the samples were analysed by using ICP-MS. In general the higher levels (p<0.05) in paired dust and human nail samples were observed from ARZ and LLZ than those of other mountainous areas (i.e., WMZ and FMZ), respectively. Current results suggested that elevated As concentrations were associated to both natural, (e.g. geogenic influences) and anthropogenic sources. Linear regression model values indicated that As levels into dust samples were associated with altitude (r(2)=0.23), soil carbonate carbon density (SCC; r(2)=0.33), and population density (PD; r(2)=0.25). The relationship of paired dust and nail samples was also investigated and associations were found for As-nail and soil organic carbon density (SOC; r(2)=0.49) and SCC (r(2)=0.19) in each studied zone, evidencing the dust exposure as an important source of arsenic contamination in Pakistan. Risk estimation reflected higher hazard index (HI) values of non-carcinogenic risk (HI>1) for children populations in all areas (except FMZ), and for adults in LLZ (0.74) and ARZ (0.55), suggesting that caution should be paid about the dust exposure. Similarly, carcinogenic risk assessment also highlighted potential threats to the residents of LLZ and ARZ, as in few cases (5-10%) the values exceeded the range of US-EPA threshold limits (10(-6)-10(-4)).

Newborn meconium and urinary metabolome response to maternal gestational diabetes mellitus: a preliminary case-control study.

Recently, the number of women suffering from gestational diabetes mellitus (GDM) has risen dramatically. GDM attracts increasing attention due to its potential harm to the heath of both the fetus and the mother. We designed this case-control study to investigate the metabolome response of newborn meconium and urine to maternal GDM. GDM mothers (n = 142) and healthy controls (n = 197) were recruited during June-July 2012 in Xiamen, China. The newborns' metabolic profiles were acquired using liquid chromatography coupled to mass spectrometry. The data showed that meconium and urine metabolome patterns clearly discriminated GDM cases from controls. Fourteen meconium metabolic biomarkers and three urinary metabolic biomarkers were tentatively identified for GDM. Altered levels of various endogenous biomarkers revealed that GDM may induce disruptions in lipid metabolism, amino acid metabolism, and purine metabolism. An unbalanced lipid pattern is suspected to be a GDM-specific feature. Furthermore, the relationships between the potential biomarkers and GDM risk were evaluated by binary logistic regression and receiver operating characteristic analysis. A combined model of nine meconium biomarkers showed a great potential in diagnosing GDM-induced disorders.

Arsenic levels from different land-use settings in Pakistan: Bio-accumulation and estimation of potential human health risk via dust exposure.

The present study aims at assessing arsenic (As) levels in outdoor dust and human exposure risks at different land use setting (i.e., rural, industrial, urban) from Punjab, Pakistan. The results showed higher As concentrations (mg/kg) in all the sample types ( i.e., dust, hair and nail) collected from industrial sites (9.78, 2.36, 2.5) followed by urban (7.59, 0.38, 0.88) and rural sites (6.95, 0.52, 1.12), respectively. In the current study, we also carried out human risk assessment via contaminated dust exposure, which suggested that dust ingestion is the major route of As contamination for the associated population, followed by the inhalation and dermal contact, at all studied land use settings. Hazard Index (HI) calculated for non-carcinogenic health risks for adults showed higher values at industrial (0.65) and urban (0.53) sites, which reflected that dust exposure is the major contributing source of human arsenic burden and may pose several adverse health effects. Carcinogenic risk values showed that at industrial areas the risk of carcinogenesis to the associated population is mainly due to As contaminated dust exposure. Hair (60%) and nail samples (70%) collected from industrial land use were found above the WHO threshold limit of 1mg/kg, suggested high risks for human health in the studied area. The results of the present study would be useful for assessing the human health risks due to arsenic contamination via dust exposure in different parts of country.

Toxic metals signature in the human seminal plasma of Pakistani population and their potential role in male infertility.

Aims of this study were to provide firsthand data on the incidence of trace metals in human seminal plasma and find possible correlations between levels of toxic metals and semen quality of Pakistani population. Human semen samples were collected from male partners of couples undergoing infertility assessment at the National Institute of Health Islamabad (Pakistan). We investigated seventy-five seminal plasma samples, which were further categorized into three groups (normozoospermia, oligozoospermia and azoospermia) according to WHO guidelines. The concentration of 17 different toxic metals in human seminal plasma was determined simultaneously by using Inductively coupled plasma mass spectrometry (ICP-MS). Out of 17 trace metals, Cd and Ni showed significant difference (p < 0.05) among three monitored groups. Ni and Cd concentrations in the seminal plasma were negatively correlated with sperm concentration (r = -0.26, -0.29) and motility (r = -0.33, -0.37), respectively. This study suggested that exposure of Ni and Cd is mainly related with the consumption of contaminated dietary items, including ghee (cooking oil), flour and other agri-products. In some semen samples, the concentrations of Sn, V, Cu, Pb, Cr and Hg exhibited high levels suggesting a recent human exposure to surrounding sources. In Pakistani human semen samples, the levels of trace metals were lower and/or comparable to that found in populations of other countries. The results show the first evidence of the effect of toxic metals on semen quality and male infertility in Pakistan.

Biomonitoring of infant exposure to phenolic endocrine disruptors using urine expressed from disposable gel diapers.

Infant exposure to endocrine disruptors (EDs) may cause adverse health effects because of their fast growth and development during this life stage. However, collecting urine from infants for exposure assessment using biological monitoring is not an easy task. For this purpose, we evaluated the feasibility of using urine expressed from disposable gel absorbent diapers (GADs) as a matrix for biomonitoring selected phenolic EDs. GADs urine was expressed with the assistance of CaCl(2) and was collected using a device fabricated in our laboratory. The analytes were extracted and concentrated using a liquid-liquid method and their hydroxyl groups were modified by dansyl chloride to enhance their chromatography and detection. Finally, the analytes were measured by high-performance liquid chromatography (HPLC) coupled with electrospray ionization (ESI) tandem mass spectrometry (MS/MS). The target chemicals were bisphenol A, triclosan, 17 α-ethynylestradiol, the natural hormone estrone, and 17 ß-estradiol. The ratio of the CaCl(2) to the urine-wetted gel absorbent, variation of the inter-urination volume, and analyte deposition bias in the diaper were assessed. Analyte blank values in the diapers, the sample storage stabilities, and recoveries of the analytes were also evaluated. The results showed that 70-80 % of the urine could be expressed from the diaper with the assistance of CaCl(2) and 70.5-124 % of the spiked analytes can be recovered in the expressed urine. The limits of detections (LODs) were 0.02-0.27 ng/mL, well within the range for detection in human populations. Our pilot data suggest that infants are widely exposed to the selected EDs.

Pooling samples for "top-down" molecular exposomics research: the methodology.

BACKGROUND: Exposomics is the cutting-edge concept of screening the environmental risk factors for disease. In the novel "top-down" approach, we estimate the molecular exposome by measuring all body fluid analytes in a case-controlled study. However, to detect diverse pollutants, a sufficient sample size and multiple analytical methods are required. This may lead to dramatically increased costs and research workload. METHODS: To help reduce complexity, we suggest a sample pooling strategy along with a scheme for combining both general unknown or multi-targeted screening with targeted analysis. The sample pooling method was tested using computer simulations. RESULTS: By comprehensively analysis of pooled samples, it is possible to identify environmental risk factors. Factors are initially screened in the pooled case and control population samples, then in the randomized grouped and pooled case and control subpopulation samples. In the sample grouping, five or more pools were suggested for groups having 30 individuals per pool. CONCLUSIONS: This study suggests that sample pooling is a useful strategy for exposomics research, which provides a hypothesis-free method for pollutant risk screening.

Human biomonitoring of trace metals from different altitudinal settings of Pakistan.

Human biomonitoring of toxic trace elements is of critical importance for public health protection. The current study aims to assess the levels of selected trace metals (Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) into paired human nail and hair samples (n = 180 each) from different altitudinal setting along the Indus River, and which were measured by using inductively coupled plasma mass spectrometry (ICP-MS). The human samples (hair and nail) were collected from four different ecological zones of Pakistan which include frozen mountain zone (FMZ), wet mountain zone (WMZ), riverine delta zone (RDZ), and low-lying southern areas (LLZ). Our results showed the following occurrence trends into studied hair samples: higher values (ppm) of Zn (281), Co (0.136), and Mn (5.65) at FMZ; Cr (1.37), Mn (7.83), and Ni (1.22) at WMZ; Co (0.15), Mn (11.89), and Ni (0.99) at RDZ; and Mn (8.99) and Ni (0.90) at LLZ. While in the case of nails, the levels (ppm) of Mn (9.91) at FMZ and Mn (9.38, 24.1, and 12.5), Cr (1.84, 3.87, and 2.33), and Ni (10.69, 8.89, and 12.6) at WMZ, RDZ and LLZ, respectively, showed higher concentration. In general, among the studied trace elements, Mn and Ni in hair/nail samples were consistently higher and exceeded the WHO threshold/published reference values in most of the studied samples (> 50-60%) throughout the Indus basin. Similarly, hair/nail Pb values were also higher in few cases (2-10%) at all studied zones and exceeded the WHO threshold/published reference values. Our area-wise comparisons of studied metals exhibited altitudinal trends for Cd, Cr, Zn, and Mn (p < 0.05), and surprisingly, the values were increasing from south to north (at higher altitudes) and indicative of geogenic sources of the studied toxic elements, except Mn, which was higher at lower floodplain areas. Estimated daily intake (EDI) values showed that food and drinking water had the highest contribution towards Zn, Cu, Mn, and Ni and accumulation at all studied zones. Whereas, dust also acts as the main exposure route for Mn, Co, Cr, and Cd followed by the food, and water.

Status of organochlorine contaminants in the different environmental compartments of Pakistan: a review on occurrence and levels.

This review evaluates and summarizes the results of the studies of organochlorines-contaminated water, sediment/soil and biota in Pakistan. Pattern of occurrence of each contaminant class from different study sites is followed as DDTs > Cyclodiens > HCHs > PCBs. The studies conducted in the surrounding areas of the demolished DDT manufacturing units and obsolete pesticides stores of country showed extremely highest values of ∑DDTs, which differ significantly (p < 0.05) than those reported from the agricultural areas and fresh water bodies of the country. HCHs, heptachlor, dieldrin, and HCB were also reported in many studies, but the concentrations are comparable among all the locations in the country. The authors suggested surface run-off, dumping of waste from industries and contamination from obsolete pesticides and demolished OCPs manufacturing units as the major sources in Pakistan. Information on PCBs is scares and studies on assessment of PCBs occurrence, and spatial trends in various environmental matrices needs special attention to produce the scientific publication. The results draw attention that POPs contamination must be considered as a priority environmental concern due to their use in agricultural and industrial sector.

Freely dissolved organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) along the Indus River Pakistan: spatial pattern and risk assessment.

Freely dissolved OCPs and PCBs were measured by using polyethylene passive samplers at 15 sites during 2014 throughout the stretch of the Indus River to investigate the spatial pattern and risk assess. Levels (pg/L) of dissolved ∑OCPs and ∑PCBs ranged from 34 to 1600 and from 3 to 230. Among the detected OCPs, dissolved DDTs (p,p'-DDE, followed by p,p'-DDT) predominated with levels of 0.48 to 220 pg/L. The order of occurrence for other studied OCPs was as follows: HCB, endosulfans, chlordanes, and HCHs. Spatially, dissolved (pg/L) ∑OCPs varied (p < 0.05) as the following: surface water of the alluvial riverine zone (ARZ) showed the highest levels (114) followed by the frozen mountain zone (FMZ) (52.9), low-lying zone (LLZ) (28.73), and wet mountain zone (WMZ) (14.43), respectively. However, our zone-wise PCB data did not exhibit significant differences (p > 0.05). Principal component analysis/multilinear regression results showed pesticide usage in the crop/orchard fields and health sector, electric and electronic materials, and widespread industrial activities as the main source of OCPs and PCBs along the Indus River. Our results showed that OCPs and PCBs contaminated water intake, playing an important role towards the considerable cancer/non-cancer risk (HI and CR values) along the Indus River Flood-Plain.

Assessment of polychlorinated biphenyls (PCBs) in the Himalayan Riverine Network of Azad Jammu and Kashmir.

The emission of polychlorinated biphenyls (PCBs) in South Asian countries is one of the great environmental concerns and has resulted in the contamination of surrounding high altitude regions such as Azad Jammu and Kashmir (AJK), Pakistan. This first investigation of Polychlorinated Biphenyl (PCBs) concentrations in the ambient air, water and surface soil was conducted along the extensive stream network in the AJK valley of the Himalayan Region. In 2014, surface soil samples were taken and passive air and water samplers were deployed along the four main rivers, namely Jhelum, Neelum, Poonch and Kunhar, and analysed for PCBs (33 congeners) using GC-MS/MS. The ∑33PCBs concentrations ranged from 31.17 to 175.2 (mean ±â€¯SD: 81 ±â€¯46.4 pg/L), ND to 1908 (1054 ±â€¯588.5 pg/g), and 29.8 to 94.4 (52.9 ±â€¯22.7 pg/m3) in surface water, soil and air matrices, respectively. The levels of dioxin-like PCBs (∑8DL-PCBs) contributed considerably towards the total PCBs concentrations: 60.63% (water), 43.87% (air) and 13.76% (soil). The log transformed air-water fugacity (log fa/fw) ratios ranged from -9.37 to 2.58; with 86.3% of the sampling sites showing net volatilization of selected PCB congeners. Similarly, the fugacity fractions for air-soil exchange exhibited narrow variation (0.8 to < 1) indicating net volatilization of PCBs. The ecological risk assessment showed low potential ecological risks (Eri  = 1.58-7.63) associated with PCB contamination. The present findings provide baseline data that suggest cold trapping of POPs in the remote mountainous areas of Pakistan and can support environmental management of POPs at the regional level. This pioneer investigation campaign to assess the PCBs concentrations in Himalayan Riverine Network of Azad Jammu and Kashmir, Pakistan helps to develop baseline data of PCBs from the strategically important riverine environment that would help in future regional as well as global ecological studies. However, the effects of temperature variations on the sampling rates of chemicals across a wide spectrum of volatility along the elevation gradient were not taken under consideration for PCBs atmospheric concentrations.

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

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.

Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats.

Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33 proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb cardiac contraction and relaxation, impair heart morphogenesis and development, and induce thrombosis in rats, which is mediated by the Akt/p38 MAPK signaling pathway. Overall, these findings will augment our knowledge of the involved mechanisms and develop useful biomarkers for cardiotoxicity induced by environmental arsenic exposure.

Human exposure to trace metals and arsenic via consumption of fish from river Chenab, Pakistan and associated health risks.

This study provided the first hand data of trace elements into fish muscles (N = 65) collected from river Chenab in Pakistan during 2013, using inductively coupled plasma mass spectrometry (ICP-MS). We monitored the health risk associated with consumption of contaminated fish of river Chenab, by the local population. The mean concentrations (µg/g, wet weight), in descending order were: Zn (35.5-54.4), Cu (1.38-4.57), Mn (2.43-4.5), As (0.23-1.21), Cr (0.21-0.67), Ni (0.14-0.34), Pb (0.14-0.31), Co (0.09-0.12), Cd (0.07-0.12) with higher concentration to be observed in the herbivore fish species (i.e., Cirrhinus reba and Catla catla). The levels of trace elements in different fish species found in this study were compared with similar data worldwide, and with the international standards for consumption. The concentration (µg/g) of arsenic in many cases (>65%) exceeded the FAO/WHO expert committee on food additives permissible limits. From the human health point of view, this study highlights that the local inhabitants, (i.e., fisher folk communities and population frequently consuming fish at about 100 g/day) along the river Chenab are exposed chronically to arsenic pollution with carcinogenic (10-4 to 10-6) and non-carcinogenic (THQ>1) risks, especially from the intake of Cirrhinus reba.

Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

Spatial distribution of dust-bound trace elements in Pakistan and their implications for human exposure.

This study aims to assess the spatial patterns of selected dust-borne trace elements alongside the river Indus Pakistan, their relation with anthropogenic and natural sources, and the potential risk posed to human health. The studied elements were found in descending concentrations: Mn, Zn, Pb, Cu, Ni, Cr, Co, and Cd. The Index of Geo-accumulation indicated that pollution of trace metals were higher in lower Indus plains than on mountain areas. In general, the toxic elements Cr, Mn, Co and Ni exhibited altitudinal trends (P < 0.05). The few exceptions to this trend were the higher values for all studied elements from the northern wet mountainous zone (low lying Himalaya). Spatial PCA/FA highlighted that the sources of different trace elements were zone specific, thus pointing to both geological influences and anthropogenic activities. The Hazard Index for Co and for Mn in children exceeded the value of 1 only in the riverine delta zone and in the southern low lying zone, whereas the Hazard Index for Pb was above the bench mark for both children and adults (with few exceptions) in all regions, thus indicating potential non-carcinogenic health risks. These results will contribute towards the environmental management of trace metal(s) with potential risk for human health throughout Pakistan.

Serum metabolomics analysis reveals impaired lipid metabolism in rats after oral exposure to benzo(a)pyrene.

Benzo(a)pyrene [B(a)P] is ubiquitous in the environment. Although multiple toxicities have been reported for B(a)P, the impact of exposure to this chemical on metabolic networks remains obscure. In this study, a metabolomics approach based on ultra-high-performance liquid chromatography/mass spectrometry was used to investigate the disruption of global serum metabolic profiles in rats caused by exposure to B(a)P. Sprague-Dawley rats were treated with oral doses of 10, 100 and 1000 µg kg(-1) B(a)P for 32 consecutive days. Distinct serum metabolomic profiles were associated with these doses. Twelve metabolites were identified as potential biomarkers and indicated that exposure to B(a)P disrupted both global amino acid metabolism and lipid metabolism, especially phospholipid and sphingolipid metabolism. Serum levels of lysophosphatidylcholines showed dose-dependent decreases, whereas serum levels of sphingomyelins showed dose-dependent increases. The expressions of some key genes involved in these pathways were also investigated. Expressions of enpp2, sms and smpd were significantly altered by exposure to high doses of B(a)P. Metabolic biomarkers were more sensitive than the corresponding gene expression for exposure to B(a)P. The findings of this study suggest potential novel mechanisms for the identified metabolic pathways.

Serum metabolomics reveals that arsenic exposure disrupted lipid and amino acid metabolism in rats: a step forward in understanding chronic arsenic toxicity.

Chronic arsenic exposure through drinking water threatens public health worldwide. Although its multiorgan toxicity has been reported, the impact of chronic arsenic exposure on the metabolic network remains obscure. In this study, male Sprague Dawley rats were exposed to 0.5, 2 or 10 ppm sodium arsenite for three months. An ultra-high performance liquid chromatography/mass spectrometry based metabolomics approach was utilized to unveil the global metabolic response to chronic arsenic exposure in rats. Distinct serum metabolome profiles were found to be associated with the doses. Eighteen differential metabolites were identified, and most of them showed dose-dependent responses to arsenic exposure. Metabolic abnormalities mainly involved lipid metabolism and amino acid metabolism. The metabolic alterations were further confirmed by hepatic gene expression. Expressions of cpt2, lcat, cact, crot and mtr were significantly elevated in high dose groups. This study provides novel evidence to support the association between arsenic exposure and metabolic disruption, and it contributes to understanding the mechanism of chronic arsenic toxicity.

Mapping human health risks from exposure to trace metal contamination of drinking water sources in Pakistan.

The consumption of contaminated drinking water is one of the major causes of mortality and many severe diseases in developing countries. The principal drinking water sources in Pakistan, i.e. ground and surface water, are subject to geogenic and anthropogenic trace metal contamination. However, water quality monitoring activities have been limited to a few administrative areas and a nationwide human health risk assessment from trace metal exposure is lacking. Using geographically weighted regression (GWR) and eight relevant spatial predictors, we calculated nationwide human health risk maps by predicting the concentration of 10 trace metals in the drinking water sources of Pakistan and comparing them to guideline values. GWR incorporated local variations of trace metal concentrations into prediction models and hence mitigated effects of large distances between sampled districts due to data scarcity. Predicted concentrations mostly exhibited high accuracy and low uncertainty, and were in good agreement with observed concentrations. Concentrations for Central Pakistan were predicted with higher accuracy than for the North and South. A maximum 150-200 fold exceedance of guideline values was observed for predicted cadmium concentrations in ground water and arsenic concentrations in surface water. In more than 53% (4 and 100% for the lower and upper boundaries of 95% confidence interval (CI)) of the total area of Pakistan, the drinking water was predicted to be at risk of contamination from arsenic, chromium, iron, nickel and lead. The area with elevated risks is inhabited by more than 74 million (8 and 172 million for the lower and upper boundaries of 95% CI) people. Although these predictions require further validation by field monitoring, the results can inform disease mitigation and water resources management regarding potential hot spots.