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The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) and heavy metal cadmium (Cd) are widespread environmental pollutants. They are persistent in the environment and can accumulate in organisms. Although the individual toxicity of DDT and Cd has been well documented, their combined toxicity is still not clear. Since liver is their common target, in this study, the individual and combined toxicity of DDT and Cd in human liver carcinoma HepG2 and human normal liver THLE-3 cell lines were investigated. The results showed that DDT and Cd inhibited the viability of HepG2 and THLE-3 cells dose-dependently and altered lysosomal morphology and function. Intracellular reactive oxygen species and lipid peroxidation levels were induced by DDT and Cd treatment. The combined cytotoxicity of DDT and Cd was greater than their individual cytotoxicity, and the interaction between Cd and DDT was additive on the inhibition of cell viability and lysosomal function of HepG2 cells. The interaction was antagonistic on the inhibition of cell viability of THLE-3 cells. These results may facilitate the evaluation of the cumulative risk of pesticides and heavy metal residues in the environment.

Chlorpyrifos (CPF) and cadmium (Cd) are widespread environmental pollutants, which are often present in drinking water and foods. However, the combined effects of CPF and Cd were not entirely clear at present. There was also no biomarker available to diagnose the poisoning of the two chemicals at low dose for long-term exposures. In this study, we investigated the change of serum metabolites of rats with subchronic exposure to CPF, Cd, and CPF plus Cd using gas chromatography-mass spectrometer-based metabolomics approach. We performed a stepwise optimization algorithm based on receiver operating characteristic to identify serum metabolite biomarkers for toxic diagnosis of the chemicals at different doses after 90-day exposure. We found that aminomalonic acid was the biomarker for the toxicity of Cd alone administration, and serine and propanoic acid were unique biomarkers for the toxicities of CPF plus Cd administrations. Our results suggest that subchronic exposure to CPF and Cd alone, or in combination at their low doses, could cause disturbance of energy and amino acid metabolism. Overall, we have shown that analysis of serum metabolomics can make exceptional contributions to the understanding of the toxic effects following long-term low-dose exposure of the organophosphorus pesticide and heavy metal.

Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.

Background This study aims to establish an in vitro monitoring approach to evaluate the pesticide exposures. We studied the in vitro cytotoxicity of three different body fluids of rats to the respective corresponding tissue-derived cells. Methods Wistar rats were orally administrated daily with three different doses of chlorpyrifos (1.30, 3.26, and 8.15 mg/kg body weight/day, which is equal to the doses of 1/125, 1/50, and 1/20 LD50, respectively) for consecutive 90 days. Blood samples as well as 24-hour urine and fecal samples were collected and processed. Then, urine, serum, and feces samples were used to treat the correspondent cell lines, i.e., T24 bladder cancer cells, Jurkat lymphocytes, and HT-29 colon cancer cells respectively, which derived from the correspondent tissues that could interact with the respective corresponding body fluids in organism. Cell viability was determined by using MTT or trypan blue staining. Results The results showed that urine, serum, and feces extract of the rats exposed to chlorpyrifos displayed concentration- and time-dependent cytotoxicity to the cell lines. Furthermore, we found that the cytotoxicity of body fluids from the exposed animals was mainly due to the presence of 3, 4, 5-trichloropyrindinol, the major toxic metabolite of chlorpyrifos. Conclusions These findings indicated that urine, serum, and feces extraction, especially urine, combining with the corresponding tissue-derived cell lines as the in vitro cell models could be used to evaluate the animal exposure to pesticides even at the low dose with no apparent toxicological signs in the animals. Thus, this in vitro approach could be served as complementary methodology to the existing toolbox of biological monitoring of long-term and low-dose exposure to environmental pesticide residues in practice.

Carbamates and pyrethroids are widely used pesticides. However, their joint toxicity at low doses with long-term exposure remains unknown. Therefore, we investigated the subchronic joint hepatotoxicity of the two representative pesticides within these two classes, i.e., propoxur (PR) and permethrin (PE) in rats. The male Wistar rats were orally treated with three different doses of PR, PE and their mixtures for 90 consecutive days. Liver weight, serum clinical chemistry parameters and histopathological changes were measured to access the hepatotoxicity. In addition, oxidative stress markers in liver were measured using biochemical assays. The results showed that PR reduced liver weight and lead to prominent liver histological changes. Moreover, PR dose-dependently induced lipid peroxidation and reduced superoxide dismutase activity. In contrast, PE induced a relatively mild hepatotoxicity. Intriguingly, the mixture of PR and PE did not reduce liver weight or increase serum aspartate transaminase activity. In addition, the mixture did not reduce the antioxidant enzyme activity as PR did. Thus, these results showed that PR induced prominent hepatotoxicity with subchronic exposure, and there is a potential antagonistic interaction between PR and PE on the oxidative damage in liver of rats.

Pesticides and heavy metals can be easily biomagnified in food chains and bioaccumulated in individuals, thus pose significant threat to human health. However, their joint toxicity for long-term exposure at low dose has not been thoroughly investigated. In the present study, we investigated the oxidative damages in brain of rats exposed subchronically to organophosphorus pesticide chlorpyrifos (CPF) and heavy metal cadmium (Cd), and their mixtures at the environmentally relevant doses. Rats were given different doses of CPF and Cd by oral gavage for three months. After treatment, brain tissues were subjected for biochemical analysis. Mitochondrial damage and reactive oxidative species were also measured in neuroblastoma SH-SY5Y cells treated with CPF, Cd and their mixtures. The results showed that CPF and Cd generated protein and lipid peroxidation, disturbed the total antioxidant capability, and altered mitochondria ultrastructure in the brain. Lipids and proteins were sensitive to the oxidative damage induced by CPF and Cd. CPF and Cd decreased mitochondrial potential and induced reactive oxygen species in SH-SY5Y cells. However, the mixture did not display higher toxicity than the sum of that of the individual treatments. Thus, CPF and Cd could have a potential antagonistic interaction on the induction of oxidative stress.

Heavy metals and pesticides can be easily enriched in food chains and accumulated in organisms, thus pose significant threat to human health. However, their combined effects for long-term exposure at low dose has not been thoroughly investigated; especially there was no biofluid biomarker available to noninvasively diagnose the toxicosis of the combined exposure of the two chemicals at their low levels. In this study, we investigated the change of urine metabolites of rats with 90-day exposure to heavy metal cadmium (Cd) and/or organophosphorus pesticide chlorpyrifos (CPF) using gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach. Our results showed that the interaction of Cd and CPF mainly displayed an antagonistic effect. We identified the panels of metabolite biomarkers in urine: benzoic acid and mannose were unique biomarkers for Cd exposure; creatinine and N-phenylacetyl glycine were unique biomarkers for CPF exposure; anthranilic acid, ribitol, and glucose were unique biomarkers for Cd plus CPF exposure. Our results suggest that 90-day exposure to Cd and/or CPF could cause a disturbance in energy and amino acid metabolism. And urine metabolomics analysis can help understand the toxicity of low dose exposure to mixed environmental chemicals.

Cadmium (Cd) and chlorpyrifos (CPF) often coexist in the environment and induce combined toxicity to organisms. Here we studied the combined nephrotoxicity of environmentally relevant low doses of Cd and CPF. We treated the mice for 90 days with different doses of Cd and CPF and their mixtures via oral gavage. Then histopathological evaluation and biochemical analysis for kidney tissues were carried out. The change of metabolites in kidney was detected by using a metabolomics approach using GC-MS. We found that Cd, CPF, and their mixtures caused oxidative damage as well as disturbance of renal amino acid metabolism. We identified potential metabolite biomarkers in kidney, which included acetic acid for CPF treatment, glycerol and carboxylic acid for Cd treatment, and l-ornithine for the mixture of CPF and Cd treatment, respectively. In addition, we found that Cd promoted the metabolism of CPF in kidney. This may contribute to the result that the toxicity of the mixtures was lower than the sum of the toxicities of Cd and CPF alone. In conclusion, our results indicated that CPF and Cd could disrupt the kidney metabolism in rats even when they were exposed to a very low dose of CPF and Cd.

Organophosphates and pyrethroids are widely used pesticides with prominent toxicity to humans. However, their joint toxicity has not been thoroughly investigated. In this study, we investigated the oxidative damages induced by low dose dichlorvos (DDVP) and deltamethrin (DM), the representative organophosphate and pyrethroid, respectively, and their mixtures in the liver of rats for 90 consecutive days. Two oxidative stress markers, malondialdehyde (MDA) and protein carbonyl (PCO) levels, were measured to reflect the extent of lipid peroxidation and protein oxidation, respectively. DDVP, DM, and their mixtures induced levels of MDA and PCO dose-dependently, although no toxic signs and pathological changes of liver were found in the rats following 90-day exposure. DDVP and DM induced greater increase of MDA than PCO, which indicated that lipids were particularly sensitive to the oxidative damage. We found that DDVP, DM and their mixtures could inhibit the activity of two antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). The effects of DM on SOD activity, lipid peroxidation and protein oxidation were greater than those of DDVP. The combined effect of DDVP and DM was lower than the sum of their individual effects. Thus the interaction between dichlorvos and deltamethrin may be antagonistic on the induction of oxidative stress in rat liver.

Organophosphorus (OP) and carbamate (CM) pesticides are widely used in agriculture. These pesticides are highly toxic to humans and their residues in food pose potential threat to human health. In this study, we investigated the effect of subchronic low-level exposure of OPs (dichlorvos, DDVP; malathion, MAL), CM pirimicarb (PI), or their mixtures (DDVP+MAL, DDVP+PI) on mice liver. Metabonomic analysis based on (1)H nuclear magnetic resonance spectroscopy was carried out in combination with biochemical assays. Serum metabonomic analysis showed that levels of trimethylamine-N-oxide, lactate, acetone, very low- and low-density lipoprotein and 3-hydroxybutyrate changed after exposure to the pesticides. In the liver extracts, lactate, glucose, choline, glutathione, alanine, glutamine and isoleucine levels changed after the treatment by pesticides. Our results indicated that exposure to low dose DDVP, MAL and PI, either alone or in combination lead to alteration of liver glucose, fat and protein metabolism, energy metabolism and oxidative balance. This study also showed that metabonomics is of potential use in food toxicity study.

The potential synergy between metal centers makes multinuclear metal complexes promising candidates for artificial nucleases. However, few multinuclear mimics have shown higher DNA cleavage efficiencies than their mononuclear analogues. By using 1,8-naphthalene dicarboxylic acid (1,8-H2ndc) and 1,10-phenanthroline (phen) ligands, one mononuclear complex [Mn(1,8-ndc)(phen)2(H2O)]·CH3OH·2H2O (1), two dinuclear complexes [Mn(1,8-Hndc)(phen)2]2·2ClO4·4H2O (2) and [Mn(1,8-ndc)(phen)(H2O)2]2·CH3OH·H2O (3), and one hexanuclear complex [Mn(1,8-ndc)(phen)(H2O)2]6·11H2O (4) were synthesized and structurally characterized by single-crystal X-ray analysis. Complexes 2–4 have closed-ring structures bridged by 1,8-ndc ligands that adopt a peculiar μ2-η1:η1 bridging mode, which has never been reported before. Circular dichroism and fluorescence studies show that the four complexes interacted with calf thymus DNA through the intercalative binding mode, and the binding ability order is 2 > 1 > 3 > 4. All of the complexes can efficiently promote the oxidative cleavage of plasmid pBR 322 DNA in the presence of H2O2 with an efficiency order 3 > 4 > 2 > 1. The higher DNA cleavage abilities of the multinuclear complexes than the mononuclear one, combined with the fact that 3 with the shortest intramolecular Mn···Mn distance and the strongest magnetic coupling between MnII ions shows the highest DNA cleavage efficiency, confirm the great effect of the synergy between metal centers on the DNA cleavage efficiency of complexes. The four complexes also show strong concentration-dependent cytotoxicity to human breast cancer cells.

Anticholinesterase pesticides have been widely used in agricultural and domestic settings and can be detected in the environment after long-term use. Although the acute toxic effects of chlorpyrifos and carbaryl have been well described, little is known about the chronic toxicity of the pesticides mixture. To investigate their chronic neurotoxicity, Wistar rats were exposed to chlorpyrifos, carbaryl, and their mixture (MIX) for 90 consecutive days. The activities of serum cholinesterase (ChE) as well as acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in nerve tissues were determined. Furthermore, the histopathological examination was carried out. The results showed that ChE activity significantly decreased in all treated rats except the rats treated with low dose carbaryl. Treatment with middle- and high-dose chlorpyrifos and MIX in rats significantly inhibited AChE activity in the central nervous tissues, whereas treatment with carbaryl alone did not. In sciatic nerve, AChE activity was significantly inhibited by high-dose carbaryl and MIX, but not by chlorpyrifos alone. No significant NTE inhibition was observed in all treatment groups. Histopathological examination revealed that both chlorpyrifos and MIX treatment induced hippocampal damage. However, no obvious hippocampal damage was found in carbaryl-treated rats. Carbaryl and MIX, but not chlorpyrifos alone, induced pathological damage of sciatic nerve. Taken together, all of the results indicated that chlorpyrifos and carbaryl have different toxicological target tissues in nervous system and showed corresponding effects in the nervous tissues, which may reflect the different sensitivity of central and peripheral nervous tissues to different pesticides individually and in combination.

The widely used organophosphorus compound tri-o-cresyl phosphate (TOCP) elicits delayed neurotoxicity characterized by progressive axonal degeneration in the spinal cord and peripheral nerves. However, the precise mechanisms of TOCP-induced delayed neurotoxicity are not clear. Because autophagy has been linked to the pathogenesis of neurodegenerative diseases, we aimed to characterize autophagy in the progression of TOCP-induced delayed neurotoxicity. In vivo experiments using the adult hen animal model showed that autophagy in spinal cord axons and in sciatic nerves was markedly induced at the early preclinical stage of TOCP-induced delayed neurotoxicity; it was decreased as the delayed neurotoxicity progressed to the overt neuropathy stage. In cultured human neuroblastoma SH-SY5Y cells, TOCP reduced cell growth, and induced prominent autophagy. The autophagy inhibitor 3-methyladenine could attenuate TOCP-induced cytotoxicity, indicating that the autophagy is accountable for TOCP-induced neurotoxicity. In addition, we found that TOCP-induced Parkin translocation to mitochondria in SH-SY5Y cells, suggesting that autophagy may function to degrade mitochondria after TOCP exposure. These results suggest that autophagy may play an important role in the initiation and progression of axonal damage during TOCP-induced neurotoxicity.

Tri-o-cresyl phosphate (TOCP) is a widely used organophosphorus compound, which can cause a neurodegenerative disorder, i.e., organophosphate-induced delayed neurotoxicity (OPIDN). The biochemical events in the initiation of OPIDN were not fully understood except for the essential inhibition of neuropathy target esterase (NTE). NTE, located in endoplasmic reticulum (ER), catalyzes the deacylation of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to glycerophosphocholine (GPC). The present study aims to study the changes of ER phospholipids profile as well as levels of important intermediates of phospholipid synthesis such as diacylglycerol (DAG) and phosphatidic acid (PA) at the initiation stage of OPIDN. Hens are the most commonly used animal models of OPIDN. The spinal cord phospholipidomic profiles of hens treated by TOCP were studied by using HPLC-MS-MS. The results revealed that TOCP induced an increase of PC, LPC, and sphingomyelin (SM) levels and a decrease of GPC, phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylserine (LPS), phosphatidylglycerol (PG), and phosphatidylinositol (PI) levels., Levels of DAG and PA were also decreased. Pretreatment with phenylmethylsulfonyl fluoride (PMSF) 24 h before TOCP administration prevented OPIDN and restored the TOCP-induced changes of phospholipids except GPC. Thus, the disruption of ER phospholipid homeostasis may contribute to the initiation of organophosphate-induced delayed neurotoxicity.

A new family of coordination polymers, {[Cu(btm)2(H2O)2](NO3)2(H2O)4} n (1, btm = bis(1,2,4-triazol-1-yl)methane), {[Cu(bte)2(H2O)2](NO3)2} n (2, bte = 1,2-bis(1,2,4-triazol-1-yl)ethane), [Cu(btp)2(NO3)2] n (3, btp = 1,3-bis(1,2,4-triazol-1-yl)propane), and {[Cu(btb)2(H2O)2](NO3)2} n (4, btb = 1,4-bis(1,2,4-triazol-1-yl)butane), have been prepared under hydrothermal conditions and characterized by X-ray structural analyses. The bis(triazole) ligands with different spacer lengths exhibit conformational flexibility and lead to diverse architectures. Compound 1 shows 2-D rectangular networks with (4,4) topology, with 2-D planar nanogrid networks stacked in a step stacking fashion. Compounds 2 and 3 show 1-D double-strained chains; 4 is a 3-D dia diamond network with one point, {66}. Elemental analysis, IR, and thermal stability also characterize the compounds.

A highly active electrorheological (ER) material, nano-sized boehmite, AlO(OH), has been obtained. The relative shear stress (τr = τE/τ0, τ0 and τE are the shear stresses at the electric field strength of 0 kV/mm and 4.2 kV/mm, respectively) of the suspension (25 wt.%) in silicone oil reached 212 at a shear rate of 14.5 s−1 and a DC electric field. The dielectric property, conductivity, surface energy, microstructure, and composition of boehmite [AlO(OH)] and alkaline alumina containing both AlO(OH) and Al2O3 have been studied. The results showed that the hydroxyl group plays a critical role in influencing the ER activity of the material by changing the dielectric property and conductivity of the material.

Chitosan nitrate (CTS-HNO 3 ) as an electrorheological (ER) material was synthesized by a simple method. The nontoxic and facile chitosan (CTS) as a substrate of the materials, as well as nitric acid were chosen as starting materials. The ER properties of the suspensions of the CTS and CTS-HNO 3 materials were researched. The CTS-HNO 3 suspension has much better ER performance than the CTS suspension. The ER effect (relative shear stress, τ r = τ E / τ 0 ) of the CTS-HNO 3 suspension (25 wt%) in silicon oil under a dc electric field reached 94 at a shear rate of 14.5 s −1 , which is eight times higher than that of the CTS suspension, where τ E and τ 0 are the shear stresses at the electric field strengths of 4.2 and 0.0 kV/mm, respectively. The formation of chitosan nitrate helped to decrease effectively the shear stress at zero electric field, and to enhance the ER effect of chitosan material markedly. The influence of the surface energy, conductivity, dielectric constant and dielectric loss tangent on the ER property of the particle materials was investigated, and the results indicate that surface energy played a predominant role. Moreover, the magnitude of the ER effect of the CTS-HNO 3 suspension was closely related to the shear rate. In addition, the chitosan nitrate had better thermal stability. The properties of CTS-HNO 3 are advantageous in its application as an ER material.

A new class of electrorheological (ER) material using rare earth (RE = Y) oxide as the substrate, NaNO3doped Y2O3 materials, were synthesized using Na2CO3 and Y(NO3)3 as starting materials. Their ER performance, dielectric property, and crystal structure were studied. The results show that doping NaNO3 can markedly enhance the ER activity of the Y2O3 material. For the suspensions of these materials in dimethyl silicone oil, a clear dependence of the shear stress on the doping degree of NaNO3 was observed, and the optimal value of Na/Y molar ratio of 0.6 in doping degree was discovered, the relative viscosity ηr(ηE/ηO, E = 4.2 kV·mm−1) of the suspensions is nine times higher than that of pure Y2O3 material. The new results of the relationship between ER effect and the microstructure were obtained, which are helpful for further understanding the mechanism of ER effect and synthesizing a good ER material.

The new electrorheological (ER) material, a particle material composed of Y 4 O(OH) 9 (NO 3 ) and NH 4 NO 3 , was obtained. They display better ER performance. The shear stress of the suspension of Y 4 O(OH) 9 (NO 3 ) (NH 4 NO 3 ) 2.8 material in dimethyl silicone oil reaches 1469 Pa at an electric field strength ( E ) of 4.2 kV. mm −1 and the shear rate (γ) of 150s −1 . The relative shear stress, τ E /τ 0 (τ E and τ 0 are the shear stresses at E = 4.2 and O kV-mm −1 , respectively), is up to 29, which is 19 times that of pure Y 2 O 3 material. The dielectric and conductive property of the materials play important roles in the modification of the ER effect of the particle materials. The researches on these new ER materials are very useful for obtaining a better understanding on the mechanism of the ER effect and finding an ideal ER material.

A novel 3D Er–Cu heteronuclear coordination polymer, f½Er2Cu3L6 �� 7H2Ogn (H2L ¼ iminodiacetic acid), containing large amount of spacious channels was synthesized. Its crystal structure was determined by X-ray diffraction. The highly stable skeleton and the adsorption performance of this polymer were demonstrated by thermogravimetric analysis (TGA) and X-ray diffraction (XRD) analysis. 2003 Elsevier Science B.V. All rights reserved.