Weidong Qu

Systematic review of pentachlorophenol occurrence in the environment and in humans in China: Not a negligible health risk due to the re-emergence of schistosomiasis

Pentachlorophenol (PCP) has been widely used for killing snails in areas of China where schistosomiasis is epidemic. With the re-emergence of schistosomiasis, the warranted production and consumption of PCP has inevitably resulted in persistent environmental contamination by it and its impurities, polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). This study aimed to evaluate the contamination status and human burden of PCP and its impurities (PCDD/Fs) in China, considering the previous epidemic and re-emergence of schistosomiasis. We searched studies relevant to PCP occurrence in the environment and in humans in China. Data on snail elimination areas were included to estimate PCP consumption. Relevant publications were analyzed to distinguish PCDD/Fs contamination from PCP usage. PCP contamination was detected ubiquitously in various environmental media and in human samples; environmental levels were generally low, with the exception of some hot spots. In schistosomiasis-epidemic areas, there were significantly higher PCP levels in the environment and in humans than in control areas. Spatial disparities indicated the consistency between serious schistosomiasis epidemic areas and hot spots of PCP contamination. The data suggest an increased trend in PCP contamination of the environment. Specific PCDD/Fs contamination from PCP usage existed even at low environmental levels. The occurrence of PCP in the environment and in humans positively correlated with the epidemic of schistosomiasis. Thyroid-disrupting effects and cancer risk caused by PCP and PCDD/Fs even at low environmental levels in Chinas schistosomiasis-epidemic areas are of concern.

Global trends and diversity in pentachlorophenol levels in the environment and in humans: a meta-analysis.

Pentachlorophenol (PCP) was banned or restricted in many countries worldwide because of its adverse effects on the ecological environment and humans. However, the endocrine disrupting effects caused by low environmental PCP exposure levels has warranted more analysis. We reviewed 80 studies conducted in 21 countries and published between 1967 and 2010, using meta-regression analysis to examine the time trends and regional differences in PCP levels. The results suggested that in indoor air, bodies of water, freshwater sediments in western countries, invertebrates and freshwater vertebrates, PCP levels had declined over time, with half-lives ranging from 2.0 years to 11.1 years. However, in marine sediments/vertebrates and Chinese surface water/sediments, PCP levels increased over time. PCP levels in human blood and urine had decreased since the 1970s, with population half-lives of 3.6 years and 5.7 years, respectively. The intervals for global population blood and urine reference values decreased to 1.1-6.3 μg/L (2002-2008) and 2.5-7 μg/L (1995-2003), respectively. The possible thyroid disrupting effects and other health risks correlated with low environmental PCP exposure should be concerning. This study can help to ascertain the effects of the banning/restriction policy, providing data for cost-benefit analysis in policy-making and further control of health risks caused by low environmental exposure to PCP.

Regulatory Role of KEAP1 and NRF2 in PPARγ Expression and Chemoresistance in Human Non-small Cell Lung Carcinoma Cells

The nuclear factor-E2-related factor 2 (NRF2) serves as a master regulator in cellular defense against oxidative stress and chemical detoxification. However, persistent activation of NRF2 resulting from mutations in NRF2 and/or downregulation of or mutations in its suppressor, Kelch-like ECH-associated protein 1 (KEAP1), is associated with tumorigenicity and chemoresistance of non-small-cell lung carcinomas (NSCLCs). Thus, inhibiting the NRF2-mediated adaptive antioxidant response is widely considered a promising strategy to prevent tumor growth and reverse chemoresistance in NSCLCs. Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin, despite moderately increased NRF2 levels. In lung adenocarcinoma epithelial A549 cells, silencing of KEAP1 augmented the expression of peroxisome proliferator-activated receptor γ (PPARγ) and genes associated with cell differentiation, including E-cadherin and gelsolin. In addition, KEAP1-knockdown A549 cells displayed attenuated expression of the proto-oncogene cyclin D1 and markers for cancer stem cells (CSCs) and reduced nonadherent sphere formation. Moreover, deficiency of KEAP1 led to elevated induction of PPARγ in response to As(2)O(3). Pretreatment of A549 cells with PPARγ agonists activated PPARγ and augmented the cytotoxicity of As(2)O(3). A mathematical model was formulated to advance a hypothesis that differential regulation of PPARγ and detoxification enzymes by KEAP1 and NRF2 may underpin the observed landscape changes in chemosensitivity. Collectively, suppression of KEAP1 expression in human NSCLC cells resulted in sensitization to chemotherapeutic agents, which may be attributed to activation of PPARγ and subsequent alterations in cell differentiation and CSC abundance.

Association between Arsenic Suppression of Adipogenesis and Induction of CHOP10 via the Endoplasmic Reticulum Stress Response

Background: There is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis. Objective: We sought to determine the mechanisms of arsenic suppression of adipogenesis. Methods: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue–derived stem cells (ADSCs). Results: Exposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ≤ 5 μM), inorganic arsenate (≤ 20 μM), trivalent monomethylated arsenic (MMA3+, ≤ 1 μM), and trivalent dimethylated arsenic (DMA3+, ≤ 2 μM) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein β (C/EBPβ), which regulates the transcription of peroxisome proliferator-activated receptor γ and C/EBPα. Conclusions: Low-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBPβ transcriptional activity, thus suppressing adipogenesis. Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

Drinking Water Disinfection Byproduct Iodoacetic Acid Induces Tumorigenic Transformation of NIH3T3 Cells

Iodoacetic acid (IAA) and iodoform (IF) are unregulated iodinated disinfection byproducts (DBPs) found in drinking water. Their presence in the drinking water of China has not been documented. Recently, the carcinogenic potential of IAA and IF has been a concern because of their mutagenicity in bacteria and genotoxicity in mammalian cells. Therefore, we measured their concentrations in Shanghai drinking water and assessed their cytotoxicity, genotoxicity, and ability to transform NIH3T3 cells to tumorigenic lines. The concentrations of IAA and IF in Shanghai drinking water varied between summer and winter with maximum winter levels of 2.18 μg/L IAA and 0.86 μg/L IF. IAA with a lethal concentration 50 (LC50) of 2.77 μM exhibited more potent cytotoxicity in NIH3T3 cells than IF (LC50 = 83.37 μM). IAA, but not IF, induced a concentration-dependent DNA damage measured by γ-H2AX staining and increased tail moment in single-cell gel electrophoresis. Neither IAA nor IF increased micronucleus frequency. Prolonged exposure of NIH3T3 cells to IAA increased the frequencies of transformed cells with anchorage-independent growth and agglutination with concanavalin A. IAA-transformed cells formed aggressive fibrosarcomas after inoculation into Balb/c nude mice. This study demonstrated that IAA has a biological activity that is consistent with a carcinogen and human exposure should be of concern.

Human urinary/seminal phthalates or their metabolite levels and semen quality: A meta-analysis

Health concerns surrounding human exposure to phthalates include diminished semen quality. Epidemiological findings remain inconsistent. We have performed a quality appraisal and meta-analysis to quantitatively summarize evidence for associations between phthalate exposures and human semen quality. Pubmed and Web of Science were searched for pertinent studies through October 2014. Cited references were reviewed to identify secondary studies. Studies that reported quantitative estimates of the association between phthalates or their metabolite levels in humans and semen quality were eligible. Random effects models were used to calculate pooled effects estimates. Overall, 20 studies met our inclusion criteria. Subsequently, 14 studies were included in the meta-analysis. Urinary monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP) were associated with reduced sperm concentration (MBP [7.4-25.3 µg/L], pooled odds ratio [OR]=2.60, 95% confidence interval [CI]=1.32-5.15; MBzP [14.0-540.2 µg/L], pooled OR=2.23, 95% CI=1.16-4.30). Both MBP (24.6-14,459.0 µg/L) and MEHP (3.1-208.1 µg/L) were inversely associated with straight line velocity (VSL; MBP, pooled β=-2.51, 95% CI=-4.44, -0.59; MEHP, pooled β=-1.06, 95% CI=-1.99, -0.12). An IQR increase in MBzP and MEP levels (MBzP, IQR=11.35 µg/L; MEP, IQR=449.4 µg/L) was associated with an increase in comet extent (CE; MBzP, pooled β=3.57, 95% CI=0.89-6.25; MEP, pooled β=4.22, 95% CI=1.66-6.77). No associations were observed between monomethyl phthalate and any semen parameters. Our meta-analysis strengthens the evidence that specific phthalates or their metabolite levels may affect semen quality.

Protective Role of Nuclear Factor E2-Related Factor 2 against Acute Oxidative Stress-Induced Pancreatic β-Cell Damage

Oxidative stress is implicated in the pathogenesis of pancreatic β-cell dysfunction that occurs in both type 1 and type 2 diabetes. Nuclear factor E2-related factor 2 (NRF2) is a master regulator in the cellular adaptive response to oxidative stress. The present study found that MIN6 β-cells with stable knockdown of Nrf2 (Nrf2-KD) and islets isolated from Nrf2-knockout mice expressed substantially reduced levels of antioxidant enzymes in response to a variety of stressors. In scramble MIN6 cells or wild-type islets, acute exposure to oxidative stressors, including hydrogen peroxide (H2O2) and S-nitroso-N-acetylpenicillamine, resulted in cell damage as determined by decrease in cell viability, reduced ATP content, morphology changes of islets, and/or alterations of apoptotic biomarkers in a concentration- and/or time-dependent manner. In contrast, silencing of Nrf2 sensitized MIN6 cells or islets to the damage. In addition, pretreatment of MIN6 β-cells with NRF2 activators, including CDDO-Im, dimethyl fumarate (DMF), and tert-butylhydroquinone (tBHQ), protected the cells from high levels of H2O2-induced cell damage. Given that reactive oxygen species (ROS) are involved in regulating glucose-stimulated insulin secretion (GSIS) and persistent activation of NRF2 blunts glucose-triggered ROS signaling and GSIS, the present study highlights the distinct roles that NRF2 may play in pancreatic β-cell dysfunction that occurs in different stages of diabetes.

Occurrence of regulated and emerging iodinated DBPs in the Shanghai drinking water.

Drinking water chlorination plays a pivotal role in preventing pathogen contamination against water-borne disease. However, chemical disinfection leads to the formation of halogenated disinfection by products (DBPs). Many DBPs are highly toxic and are of health concern. In this study, we conducted a comprehensive measurements of DBPs, including iodoacetic acid (IAA), iodoform (IF), nine haloacetic acids and four trihalomethanes in drinking waters from 13 water plants in Shanghai, China. The results suggested that IAA and IF were found in all the water treatment plants, with maximum levels of 1.66 µg/L and 1.25 µg/L for IAA and IF, respectively. Owing to deterioration of water quality, the Huangpu River has higher IAA and IF than the Yangtze River. Our results also demonstrated that low pH, high natural organic matter, ammonia nitrogen, and iodide in source waters increased IAA and IF formation. Compared to chlorine, chloramines resulted in higher concentration of iodinated DBP, but reduced the levels of trihalomethanes. This is the first study to reveal the widespread occurrence of IAA and IF in drinking water in China. The data provide a better understanding on the formation of iodinated disinfection byproducts and the findings should be useful for treatment process improvement and disinfection byproducts controls.

CNC-bZIP Protein Nrf1-Dependent Regulation of Glucose-Stimulated Insulin Secretion

AIMS The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. RESULTS Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. INNOVATION Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. CONCLUSION Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.Abstract Aims: The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Results: Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and ae...

Dissolved microcystins in surface and ground waters in regions with high cancer incidence in the Huai River Basin of China.

Microcystins (MCs) are potent hepatotoxins and have also implicated in liver tumor promotion. The present study investigates the temporal and spatial variations of MCs in different water bodies in the Huai River Basin in China. Water samples including rivers, ponds and wells were collected every quarter during December 2008 and December 2009. MCs were determined by high pressure liquid chromatography after solid phase extraction. MCs concentrations in river samples were 0.741±0.623μgL(-1) with maximum of 1.846μgL(-1). MCs in pond were 0.597±0.960μgL(-1) with maximum of 2.298μgL(-1). MCs were also detected in 51.7% of the groundwater samples, MCs in groundwater were 0.060±0.085μgL(-1) with maximum of 0.446μgL(-1). MCs concentrations in groundwater did not differ significantly among different depths or towns (Wilcoxon test, p>0.05). The average MCs in groundwater in each sampling period were 0.068μgL(-1), 0.118μgL(-1), 0.052μgL(-1), 0.059μgL(-1) and 0.020μgL(-1). Through multi linear regression, the best fit model was built on MCs in groundwater with River B (R(2)=0.13, p<0.05), rather than with pond water. The results suggested that MCs contamination in groundwater originated from rivers, causing potential health risk on population who drink groundwater directly.