Vitamin D3 protects against lead-induced testicular toxicity by modulating Nrf2 and NF-κB genes expression in rat.

Lead (Pb) is an environmental toxin that has the ability to alter biological processes by inducing oxidative stress (OS) and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) are two transcriptional factors that participate in the regulation of cellular responses against OS and inflammation. This study was conducted to evaluate the effects of vitamin D3 (VD) on the prevention of testicular damages of Pb and its association with Nrf2 and NF-κB gene expression levels and their downstream molecules. Forty male Wistar rats were divided into four groups and treatments were performed as following for four weeks: control group received no treatment, VD group were injected intramuscularly with 1000 IU of VD/Kg every other day, Pb group received 1000 mg of Pb/L of drinking water, and Pb + VD group were exposed to Pb and VD simultaneously. The results demonstrated significant decrease in the levels of tissue antioxidants, and increase in inflammatory cytokines in the Pb-intoxicated group, with increased Nrf2 and NF-κB mRNA levels. A remarkable reduction in sperm criteria and a significant disruption in serum hormones were also observed. Anyhow, VD supplementation during exposure to Pb showed a significant protective effect against all pathophysiologic alterations caused by Pb. Furthermore, VD affected the expression of Nrf2 and NF-κB and mitigated the harsh effects of Pb. In conclusion, our findings indicate that VD attenuated the toxic impacts of Pb on testis through modulation of Nrf2 and NF-κB gene expression levels which further regulated the OS and inflammatory responses.

Cognitive decline prevention in offspring of Pb+2 exposed mice by maternal aerobic training and Cur/CaCO3@Cur supplementations: In vitro and in vivo studies.

Heavy metals are considered contaminants that hazardously influence the healthy life of humans and animals as they are widely used in industry. Contact of youngsters and women at ages of parturition with lead (Pb+2) is a main related concern, which passes through the placental barricade and its better absorption in the intestine leads to flaws in the fetal developfment. However, the metals threaten animal and human life, in particular throughout developmental stages. Products existing in the nature have a major contribution to innovating chemo-preventives. As a naturally available polyphenol and necessary curcuminoid, curcumin (Cur) is a derivative of the herb Curcuma longa (L.) rhizome, which globally recognized as "wonder drug of life"; however, Cur has a limited clinical use as it is poorly dissolved in water. Therefore, to enhance its clinically relevant parameters, curcumin-loaded calcium carbonate (CaCO3@Cur) was synthesized by one step coprecipitation method as a newly introduced in this research. Initially, its structure was physio chemically characterized using FT-IR, FESEM and DLS equipment and then the cytotoxicity of lead when it was pretreated with Cur/CaCO3@Cur were assessed by MTT assay. Both Cur and CaCO3@Cur diminished the toxic effects of Pb+2 while the most protective effect on the Pb+2 cytotoxicity was achieved by pre-incubation of cells with CaCO3@Cur. Besides, the morphological changes of Pb+2-treated cells that were pre-incubated with or without Cur/CaCO3@Cur were observed by normal and florescent microscopes. A non-pharmacologic method that lowers the hazard of brain damage is exercise training that is capable of both improving and alleviating memory. In the current study, the role of regular aerobic training and CaCO3@Cur was assessed in reducing the risk of brain damage induced by lead nitrate contact. To achieve the mentioned goal, pregnant Balb/C mice were assigned to five groups (six mice/group) at random: negative and positive controls, aerobic training group and Cur and CaCO3@Cur treated (50 mg/kg/b.wt) trained groups that exposed to Pb+2 (2 mg/kg) by drinking water during breeding and pregnancy. With the completion of study, offspring were subjected to the behavioral tasks that was tested by step-through ORT, DLB, MWM and YM tests. As a result, having regular aerobic training and CaCO3@Cur co-administration with lead nitrate could reverse the most defected behavioral indicators; yet, this was not visible for both sexes and it seems that gender can also be a source of different effects in the animal's body. In fact, having regular aerobic training along with CaCO3@Cur supplementation during pregnancy may be encouraging protecting potential agents towards the toxicity of Pb+2 that could be recommended in the areas with high pollution of heavy metals.

Selenium modulates inorganic mercury induced cytotoxicity and intrinsic apoptosis in PC12 cells.

Mercury (Hg) in its all forms, including inorganic Hg (iHg) is an environmental contaminant due to toxicity and diseases in human. However, a little is known about the underlying mechanisms responsible for iHg toxicity. Selenium (Se) is an essential trace element, recognized as an antioxidant and protective agent against metal toxicities. The purpose of this research was to investigate ameliorations of Se counter to iHg-mediated toxicity in PC12 cells. Cytotoxic assays have been shown that iHg (5 µM) caused oxidative stress and intrinsic apoptosis via ROS generation, oxidizing glutathione, damaging DNA, degrading cell membrane integrity, down-regulating mTOR, p-mTOR, akt and ERK1, and up-regulating cleaved caspase 3 and cytochrome c release in PC12 cells 48 h after incubation. Co-treatment of Se (5 µM) inhibited intrinsic apoptosis and oxidative stress induced by iHg (5 µM) via inhibiting ROS formation, boosting GPx contents, increasing reduced glutathione, limiting DNA degradation, improving cell membrane integrity, up-regulating mTOR, p-mTOR, akt, ERK1 and caspase 3, and down-regulating cleaved caspase 3 and cytochrome c leakage in PC12 cells. In conclusion, these results recommended that excessive ROS generation acts a critical role in iHg-influenced oxidative stress and co-treatment of Se attenuates iHg-cytotoxicity through its antioxidant properties.

Revealing the toxicity of dimethyl phthalate (DMP) to the oxygen-carrying function of red blood cells (RBCs): The iron release mechanism.

Phthalic acid esters (PAEs), as typical hormone pollutants, do harms to human health after enrichment over a long term exposure, causing the loss of oxygen-carrying function of red blood cells (RBCs). This study has investigated the mechanism for the toxicity of dimethyl phthalate (DMP) on the oxygen-carrying function of RBCs by measuring the iron release content of hemoglobin (Hb) in vivo and in vitro. The hematologic examination showed that the high dose of DMP at 1000 mg/kg significantly reduced the Hb content and increased the granulocyte content, whereas such toxicity was not relatively observed at a low (50 mg/kg) or a medium (250 mg/kg) dose of DMP. The in vitro experiments showed that DMP, incubated with RBCs, increased the iron release content as a function of DMP concentration. Interestingly, such a phenomenon was not observed when DMP was incubated with Hb alone, indicating that the release of hemoglobin iron could not directly caused by the combination of DMP and hemoglobin. The in vivo experiments indicated that DMP induced iron release and oxidative stress for rat RBCs. Moreover, vitamin C and E was found to reduce the level of iron release by recovering erythrocytes from the oxidative stress induced by DMP. This work has revealed that the oxidative stress induced by DMP, causing the release of Hb iron from RBCs, is the reason for the toxicity of DMP to the oxygen-carrying function.

Grouping of UVCB substances with new approach methodologies (NAMs) data.

One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of repre­sentative substances in each group for testing when needed, and to fill data gaps by read-across.

Protective effects of selenium yeast against cadmium-induced necroptosis via inhibition of oxidative stress and MAPK pathway in chicken liver.

The aim of the study was to investigate the protective effects of selenium yeast (SeY) against necroptosis triggered by Cd via inhibition of oxidative stress and MAPK pathway in the liver of chicken. Two hundred 120-day-old layers were randomly divided into four groups and raised for 120 days. The histopathological examination showed that necrosis characteristics were observed in Cd-exposed chicken livers. The exposure of Cd significantly reduced the activities of SOD, GSH-Px and CAT while improving MDA level in both serum and liver of chickens (P < 0.05), and induced oxidative stress. The MLKL, Rip1, RIP3, ERK, JNK and P38 mRNA expression of Cd group were significantly higher than other three groups (P ＜ 0.01), and those in the Se + Cd group were significantly higher than control group and Se group (P ＜ 0.01). However, the mRNA expression level of caspase8 of Cd was significantly lower than other three groups (P ＜ 0.01), and that in the Se + Cd group was significantly higher than control group and Se group (P ＜ 0.01), so the supplement of SeY could improve these situations. Similar results were also detected at the protein level. The results of the present study indicated that Cd could induce oxidative stress, activate MAPK pathway and evoke necroptosis damage in chicken livers, whereas SeY had protective effects in preventing this kind of Cd-induced injury by inhibition of oxidative stress and down-regulation MAPK pathway.

The Hazardous Level of Heavy Metals in Different Medicinal Plants and Their Decoctions in Water: A Public Health Problem in Brazil.

The determination of Cd, Co, Cr, Cu, Fe, Na, Zn, and Pb by inductively coupled plasma-optical emission spectrometry (ICP OES) was performed on dry matter and decoctions of the medicinal plants Cordia salicifolia, Chiococca alba (L.) Hitchc., and Echites peltata used as an appetite suppressant and diuretic in Brazil. The accuracy of the measurements was analyzed by the spike recovery test. Results showed that the concentration of these seven metals (Cd, Co, Cr, Cu, Fe, Na, and Zn) in dry plant samples is below the oral concentration of elemental impurities established by the United States Pharmacopoeia Convention (USP). However, there are no concentration limits for Fe, Na, and Zn established by the USP in drug substances and excipients. Levels higher than the recommended value by the USP were observed for Pb and the lowest for Cd, Co, Cr, and Cu, both in dried plant samples and their decoctions. In the decoctions prepared from these plants were found elements such as Cd, Co, Cr, Cu, Fe, Na, Zn, and Pb. In the decoction prepared from 40 g C. salicifolia leaves and 40 g C. alba wood, the content of Cd is above the oral daily exposure value set by the USP. Hazard index (HI) for decoctions prepared from these plants exceeded the threshold (1). Given the uncertainties associated with the estimates of toxicity values and exposure factors, futures researches should address the possible toxicity in humans. Uncontrolled selling and long-term ingestion of medicinal plants can cause toxicity and interfere with the effect of drugs. Limited knowledge on the interaction potential of medicinal plants poses a challenge and public health problem in Brazil and other countries.

Ziziphus spina-christi leaf extract attenuates mercury chloride-induced testicular dysfunction in rats.

Mercury (Hg) is a heavy metal toxicant, causing several adverse reactions to animals and humans including reproductive dysfunction. The potential protective role of Ziziphus spina-christi leaf extract (ZSCLE) against testicular impairments associated with mercury chloride (HgCl2) exposure in rats was investigated in the current study. Four experimental groups were employed as follows (n = 7): group I served as control, group II was gavaged with ZSCLE (300 mg/kg), group III was administered with HgCl2 (0.4 mg/kg), and group IV was preadministered with ZSCLE 1 h before HgCl2. All groups were treated daily for 28 days. The exposure to HgCl2 caused a marked increase in Hg concentration in the testicular tissue, which was accompanied with a decrease in testis index. A reproductive impairment was recorded following HgCl2 exposure as verified through the decrease in levels of testosterone, luteinizing, and follicle-stimulating hormones. HgCl2 was found to enhance the development of oxidative damage in the testicular tissue as presented by the imbalance between pro-oxidants and antioxidant molecules. In addition, excessive release of tumor necrosis factor-α and interleukin-1ß was recorded in response to HgCl2 intoxication. Furthermore, a disturbance in the apoptotic proteins in favor of the pro-apoptotic proteins was also observed following HgCl2 intoxication. However, ZSCLE administration along with HgCl2 abolished significantly the molecular, biochemical, and histopathological alterations induced by HgCl2 intoxication. Our findings suggest that ZSCLE could be used to mitigate reproductive dysfunction associated with HgCl2 exposure.

PFOA evokes extracellular Ca2+ influx and compromises progesterone-induced response in human sperm.

Perfluorooctane acid (PFOA), a persistent organic pollutant, is ubiquitously present in the environment and may detrimentally affect male reproductive health. In this study, mature human sperm were in vitro exposed to different concentrations of PFOA (0.25, 2.5 or 25 µg/ml) alone or in combination with progesterone (P4) to evaluate the toxicity and the potential mechanism of action. Exposure to high-dose PFOA (25 µg/ml) alone for 4 h caused a decline in capacity of human spermatozoa to penetrate synthetic mucus, with an increased production of reactive oxygen species (ROS). Furthermore, PFOA treatment (2.5 and 25 µg/ml) evoked a transient rise in intracellular calcium concentration [Ca2+]i by activating the sperm-specific CatSper channel. However, preincubation with PFOA (2.5-25 µg/ml) for 4 h significantly suppressed P4-stimulated extracellular Ca2+ influx in human spermatozoa. Moreover, PFOA pretreatment at all concentrations evaluated markedly compromised P4-induced acrosome reaction and sperm penetration into viscous medium. Taken together, these results suggest that PFOA exposure may impair human sperm function through inducing oxidative stress and disturbing P4-induced Ca2+ signaling.

Senna alexandrina extract supplementation reverses hepatic oxidative, inflammatory, and apoptotic effects of cadmium chloride administration in rats.

Senna alexandrina is traditionally used for its antioxidant and anti-inflammatory properties, but little information is available concerning its potential protective effects against cadmium, which is a widespread environmental toxicant that causes hepatotoxicity. Here, we explored the effects of S. alexandrina extract (SAE) on cadmium chloride (CdCl2)-induced liver toxicity over 4 weeks in rats. Rats were allocated into four groups: control, SAE (100 mg/kg), CdCl2 (0.6 mg/kg), and SAE + CdCl2, respectively. Cadmium level in hepatic tissue, blood transaminases, and total bilirubin as indicators of liver function were assessed. Oxidative stress indices [malondialdehyde (MDA), nitrate/nitrite (NO), and glutathione (GSH)], antioxidant molecules [superoxide dismutase (SOD, catalase (CAT), glutathione-derived enzymes, and nuclear factor erythroid 2-related factor 2 (Nrf2)], pro-inflammatory mediators [interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α)], apoptosis proteins (Bcl-2, Bax, and caspase-3), and histological alterations to the liver were examined. SAE administration before CdCl2 exposure decreased cadmium deposition in liver tissue and the blood liver function indicators. SAE pre-treatment prevented oxidative, inflammatory, and apoptotic reactions and decreased histological alterations to the liver caused by CdCl2 exposure. SAE can be used as a promising protective agent against CdCl2-induced hepatotoxicity by increasing Nrf2 expression. Graphical abstract.

Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats.

Acrylamide (AA) is a heat-induced toxin formed during thermal processing of many commonly consumed foods, including meat products, French fries, potato crisps, bread, cereals, cookies, and coffee. There is thus potentially high dietary exposure of humans to AA, which can induce significant oxidative stress. Hesperidin (HS) and diosmin (DS) are flavone glycosides that have antioxidant properties. The aim of this study was to investigate the protective effects of HS and DS against AA toxicity. Fifty-six adult male Wistar albino rats were divided into seven groups. The first group was orally administered 0.5% (w/v) dimethyl sulfoxide (DMSO) and considered as the control group. The second and third groups were orally administered 10 mg/kg/day of HS or DS, respectively. The fourth group received 20 mg/kg/day of AA orally for 14 days. The fifth and sixth groups were given 10 mg/kg/day of HS or DS, respectively, followed by AA. The seventh group was given both HS and DS after AA administration. AA intoxication significantly (p ≤ 0.05) increased serum levels of liver function enzymes (ALT, AST, and ALP), kidney function products (urea and creatinine), oxidative DNA damage marker (OHdG), proinflammatory markers (TNF-α, IL-1ß, and IL-6), lipid peroxidation marker (malondialdehyde), and nitric oxide (NO). On the other hand, it significantly (p ≤ 0.05) decreased levels of reduced glutathione (GSH) in the liver, kidney, and brain. The activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in the liver, kidney, and brain tissues were also reduced. HS and DS supplementation prevented lipid peroxidation, normalized the serum parameters altered by AA, and enhanced the tissue concentrations and activities of antioxidant biomarkers. It could be concluded that HS and DS have potent protective effects against oxidative stress, lipid peroxidation, and DNA damage induced by AA toxicity in rats.

Geochemical Characteristics and Toxic Elements in Alumina Refining Wastes and Leachates from Management Facilities.

A nationwide investigation was carried out to evaluate the geochemical characteristics and environmental impacts of red mud and leachates from the major alumina plants in China. The chemical and mineralogical compositions of red mud were investigated, and major, minor, and trace elements in the leachates were analyzed. The mineral and chemical compositions of red mud vary over refining processes (i.e., Bayer, sintering, and combined methods) and parental bauxites. The main minerals in the red mud are quartz, calcite, dolomite, hematite, hibschite, sodalite, anhydrite, cancrinite, and gibbsite. The major chemical compositions of red mud are Al, Fe, Si, Ca, Ti, and hydroxides. The associated red mud leachate is hyperalkaline (pH > 12), which can be toxic to aquatic life. The concentrations of Al, Cl-, F-, Na, NO32-, and SO42- in the leachate exceed the recommended groundwater quality standard of China by up to 6637 times. These ions are likely to increase the salinization of the soil and groundwater. The minor elements in red mud leachate include As, B, Ba, Cr, Cu, Fe, Ni, Mn, Mo, Ti, V, and Zn, and the trace elements in red mud leachate include Ag, Be, Cd, Co, Hg, Li, Pb, Sb, Se, Sr, and Tl. Some of these elements have the concentration up to 272 times higher than those of the groundwater quality standard and are toxic to the environment and human health. Therefore, scientific guidance is needed for red mud management, especially for the design of the containment system of the facilities.

Assessment of acute toxicity and cytotoxicity of fluorescent markers produced by cardanol and glycerol, which are industrial waste, to different biological models.

The amphyphylic triazoanilines recently synthesized 1-(4-(3-aminophenyl)-1H-1,2,3- triazole-1-yl)-3-(3-pentadecylphenoxy)propan-2-ol (1) and 1-(4-(4-aminophenyl)-1H- 1,2,3-triazole-1-yl)-3-(3-pentadecylphenoxy)propan-2-ol (2), synthesized from cardanol and glycerol, have photophysical properties which allow their use in the development of fluorescent biomarkers with applicability in the biodiesel quality control. Based on this, the present research evaluated the toxic effects of both compounds in different biological models through the investigation of survival and mortality percentages as a measure of acute toxicity on Daphnia similis and Oreochromis niloticus, larvicidal assay against Aedes aegypti, and cytotoxic activity on mammary cells. Results demonstrate that these triazoanilines 1 and 2 have shown low acute toxicity to the biological models investigated in this study up to the following concentrations: 4.0 mg L-1 (D. similis), 4.0 mg L-1 (A. aegypti larvae), 1.0 mg L-1 (O. niloticus), and 1.0 mg mL-1 (mammary cells). This fact suggests the potential for safe use of compounds 1 and 2 as fluorescent markers for the monitoring of biodiesel quality, even in the case of environmental exposure. Besides all of that, the reuse of cardanol and glycerol, both industrial wastes, favors the maintenance of environmental health and is in agreement with the assumptions of green chemistry. Graphical abstract ᅟ.

Shielding the Negative Impact of Cadmium in Avian Embryos by Supplementing with Beetroot Juice.

The increased correlation between maternal cadmium (Cd) exposure and restricted fetal growth has become a matter of global concern. Because dietary nitrate has been demonstrated to offer a range of beneficial vascular effects, we attempt to unveil the effect of one such nitrate-rich food, beetroot, on recovering Cd-induced fetal growth retardation. Using chick embryos as a model, our results confirm that retarded growth is a result of exposure to Cd at an early stage of development and that Cd hinders vasculogenesis and angiogenesis. We find that beetroot juice (BRJ) recovers fetal growth retardation effects of Cd via its vasodilatory effect and promotes embryonic angiogenesis. In conclusion, this study confirms that BRJ reduces the rate of congenital malformations with Cd exposure in utero and suggests the importance of dietary supplements for pregnant women.

Preclinical hazard evaluation strategy for nanomedicines.

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics.

The environmental contaminant tributyltin leads to abnormalities in different levels of the hypothalamus-pituitary-thyroid axis in female rats.

Tributyltin is a biocide used in nautical paints, aiming to reduce fouling of barnacles in ships. Despite the fact that many effects of TBT on marine species are known, studies in mammals have been limited, especially those evaluating its effect on the function of the hypothalamus-pituitary-thyroid (HPT) axis. The aim of this study was to investigate the effects of subchronic exposure to TBT on the HPT axis in female rats. Female Wistar rats received vehicle, TBT 200 ng kg-1 BW d-1 or 1000 ng kg-1 BW d-1 orally by gavage for 40 d. Hypothalamus, pituitary, thyroid, liver and blood samples were collected. TBT200 and TBT1000 thyroids showed vacuolated follicular cells, with follicular hypertrophy and hyperplasia. An increase in epithelial height and a decrease in the thyroid follicle and colloid area were observed in TBT1000 rats. Moreover, an increase in the epithelium/colloid area ratio was observed in both TBT groups. Lower TRH mRNA expression was observed in the hypothalami of TBT200 and TBT1000 rats. An increase in Dio1 mRNA levels was observed in the hypothalamus and thyroid in TBT1000 rats only. TSH serum levels were increased in TBT200 rats. In TBT1000 rats, there was a decrease in total T4 serum levels compared to control rats, whereas T3 serum levels did not show significant alterations. We conclude that TBT exposure can promote critical abnormalities in the HPT axis, including changes in TRH mRNA expression and serum TSH and T4 levels, in addition to affecting thyroid morphology. These findings demonstrate that TBT disrupts the HPT axis. Additionally, the changes found in thyroid hormones suggest that TBT may interfere with the peripheral metabolism of these hormones, an idea corroborated by the observed changes in Dio1 mRNA levels. Therefore, TBT exposition might interfere not only with the thyroid axis but also with thyroid hormone metabolism.

QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

Assessment of arsenic trioxide toxicity on cock muscular tissue: alterations of oxidative damage parameters, inflammatory cytokines and heat shock proteins.

To evaluate the toxicity of arsenic trioxide (As2O3) in the muscular tissues (wing, thigh and pectoral) of birds, 72 one-day-old Hy-line cocks were selected and randomly divided into four groups. They were fed either a commercial diet or an arsenic-supplemented diet containing 7.5, 15 or 30 mg/kg As2O3. The experiment lasted for 90 days and the samples of muscular tissues were collected at 30, 60 and 90 days. The results showed that As2O3 exposure significantly lowered the activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GSH-Px)) and inhibition ability of hydroxyl radicals (OH) and increased the malondialdehyde (MDA) contents. Furthermore, the mRNA levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), prostaglandin E synthase (PTGEs)) and heat shock proteins (HSPs) in muscular tissue were significantly upregulated in the As2O3 exposure groups. The results indicated that As2O3 exposure resulted in oxidative damage, induced the inflammatory response, and influenced the mRNA levels of HSPs in muscular tissue of cocks. Additionally, the results suggested that HSPs possibly resisted due to the As2O3 exposure-induced oxidative stress and inflammatory response, which provided a favorable environment and played protective roles in the muscular tissues of cocks. The information presented in this study is helpful to understand the mechanism of As2O3 toxicity in bird muscular tissues.

The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission.

It has been reported that fluoride exposure may cause serious public health problems, particularly neurotoxicity. However, the underlying mechanisms remain unclear. This study used Neuro-2A cells to investigate the effects of fluoride on the cytoskeleton. The Neuro-2A cells were exposed to 0, 1, 2, 4 and 6 mM sodium fluoride (NaF) for 24 h. Cell viability and lactate dehydrogenase (LDH) release were examined. It was observed that exposure to NaF reduced cell viability, disrupted cellular membrane integrity, and high levels of LDH were released. The observed changes occurred in a dose response manner. Morphologic observations showed that cell became rounded and were loosely adherent following exposure to NaF. Axon spines and normal features disappeared with high dose NaF treatment. The expression of MAP2 and synaptophysin decreased, particularly at 4 mM and 6 mM (P < 0.05) for MAP2. These results corroborate the morphologic observations. The content of glutamate and NMDAR (glutamate receptor) protein were assessed to help understand the relationship between synapses and neurotransmitter release using ELISA and Western-blot. Compared with the control, glutamate and NMDAR expression declined significantly at 4 mM and 6 mM (P < 0.05) group. Finally, the ultrastructural changes observed with increasing doses of NaF were: disappearance of synapses, mitochondrial agglutination, vacuole formation, and cellular edema. Taken together, NaF exposure disrupted cellular integrity and suppressed the release of neurotransmitters, thus effecting neuronal function. These findings provide deeper insights into roles of NaF in neuron damage, which could contribute to a better understanding of fluoride-induced neurotoxicity.

Short-term social memory deficits in adult female mice exposed to tannery effluent and possible mechanism of action.

The accumulated organic residues in tannery-plant courtyards are an eating attraction to small rodents; however, the contact of these animals with these residues may change their social behavior. Thus, the aim of the present study is to investigate whether the exposure to tannery effluent (TE) can damage the social recognition memory of female Swiss mice, as well as to assess whether vitamin C supplementation could provide information about how TE constituents can damage these animals' memory. We have observed that resident females exposed to TE (without vitamin supplementation) did not explore the anogenital region, their body or chased intruding females for shorter time or with lower frequency during the retest session of the social recognition test, fact that indicates social recognition memory deficit in these animals. Such finding is reinforced by the confirmation that there was no change in the animals' olfactory function during the buried food test, or locomotor changes in females exposed to the pollutant. Since no behavioral change was observed in the females exposed to TE and treated with vitamin C (before or after the exposure), it is possible saying that these social cognitive impairments seem to be directly related to the imbalance between the cellular production of reactive oxygen species and the counteracting antioxidant mechanisms (oxidative stress) in female mice exposed to the pollutant (without vitamin supplementation). Therefore, the present study evidences that the direct contact with tannery effluent, even for a short period-of-time, may cause short-term social memory deficits in adult female Swiss mice.