Toxic Effects Of Chronic Exposure Research Articles

Reproductive toxic effects of chronic exposure to bisphenol A and its analogues in marine medaka (Oryzias melastigma)

As awareness of BPA's health risks has increased, many countries and regions have implemented strict controls on its use. Consequently, bisphenol analogues like BPF and BPAF are being increasingly used as substitutes. However, these compounds are also becoming increasingly prevalent in the environment due to production, use and disposal processes. The oceans act as a repository for various pollutants, and recent studies have revealed the extensive presence of bisphenols (BPs, including BPA, BPF, BPAF, etc.) in the marine environment, posing numerous health hazards to marine wildlife. Nevertheless, the reproductive toxicity of these chemicals on marine fish is not comprehensively comprehended yet. Thus, the histological features of the gonads and the gene expression profiles of HPG (Hypothalamic-Pituitary-Gonadal) axis-related genes in marine medaka (Oryzias melastigma) were studied after exposure to single and combined BPs for 70 days. The effects of each exposure group on spawning, embryo fertilization, and hatching in marine medaka were also assessed. Furthermore, the impacts of each exposure group on the genes related to methylation in the F2 and F3 generations were consistently investigated. BPs exposure was found to cause follicular atresia, irregular oocytes, and empty follicles in the ovary; but no significant lesions in the testis were observed. The expression of several HPG axis genes, including cyp19b, 17βhsd, 3βhsd, and fshr, resulted in significant changes compared to the control group. The quantity of eggs laid and fertilization rate decreased in all groups treated with BPs, with the BPAF-treated group showing a notable reduction in the number of eggs laid. Additionally, the hatching rate showed a more significant decline in the BPF-treated group. The analysis of methylated genes in the offspring of bisphenol-treated groups revealed significant changes in the expression of genes including amh, dnmt1, dnmt3ab, mbd2, and mecp2, indicating a potential transgenerational impact of bisphenols on phenotype through epigenetic modifications. Overall, the potential detrimental impact of bisphenol on the reproduction of marine medaka emphasizes the need for caution in considering the use of BPAF and BPF as substitutes.

Microcystin-leucine arginine exposure induced intestinal lipid accumulation and MC-LR efflux disorder in Lithobates catesbeianus tadpoles

Few studies exist on the toxic effects of chronic exposure to microcystins (MCs) on amphibian intestines, and the toxicity mechanisms are unclear. Here, we evaluated the impact of subchronic exposure (30 days) to environmentally realistic microcystin-leucine arginine (MC-LR) concentrations (0 μg/L, 0.5 μg/L and 2 μg/L) on tadpole (Lithobates catesbeianus) intestines by analyzing the histopathological and subcellular microstructural damage, the antioxidative and oxidative enzyme activities, and the transcriptome levels. Histopathological results showed severe damage accompanied by inflammation to the intestinal tissues as the MC-LR exposure concentration increased from 0.5 μg/L to 2 μg/L. RNA-sequencing analysis identified 634 and 1,147 differentially expressed genes (DEGs) after exposure to 0.5 μg/L and 2 μg/L MC-LR, respectively, compared with those of the control group (0 μg/L). Biosynthesis of unsaturated fatty acids and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were upregulated in the intestinal tissues of the exposed groups, with many lipid droplets being observed on transmission electron microscopy, implying that MC-LR may induce lipid accumulation in frog intestines. Moreover, 2 μg/L of MC-LR exposure inhibited the xenobiotic and toxicant biodegradation related to detoxification, implying that the tadpoles’ intestinal detoxification ability was weakened after exposure to 2 μg/L MC-LR, which may aggravate intestinal toxicity. Lipid accumulation and toxin efflux disorder may be caused by MC-LR-induced endoplasmic reticular stress. This study presents new evidence that MC-LR harms amphibians by impairing intestinal lipid metabolism and toxin efflux, providing a theoretical basis for evaluating the health risks of MC-LR to amphibians.

Hepatic, renal, and pancreatic damage associated with chronic exposure to oral and inhaled 2,4-dichlorophenoxy acetic acid (2,4-d): an environmental exposure model in rats

2,4-Diclophenoxyacetic acid (2,4-D) is one of the most widely used herbicides in the world. The aim of this study was to evaluate the possible toxic effect of chronic exposure to oral and inhaled 2,4-D herbicide on the liver, kidney, and pancreas by simulating environmental exposure. Eighty male albino adult Wistar rats divided into eight groups were exposed for 6 months to inhaled and oral (contaminated feed) three different doses of 2,4-D [3.71 × 10−3 g of active ingredient per hectare (g a.i./ha), 6.19 × 10−3 g a.i./ha and 9.28 × 10−3 g a.i./ha]. Blood, liver, kidney, spleen, and pancreas samples were collected for analysis. There was a difference in ALT (alanine aminotransferase) levels between groups exposed to 2,4-D. The groups exposed to oral 2,4-D had a higher incidence of steatosis, and exposed to high doses had increased liver inflammation. All animals in the groups exposed to high 2,4-D concentrations showed renal tubular hydropic degeneration. Atrophy of Langerhans islets was observed in animals exposed to 2,4-D. The simulation of chronic environmental exposure to the 2,4-D herbicide resulted in hepatic changes that were both dose-dependent and exposure-dependent and renal and pancreatic changes that were dose-dependent.

Toxic Effects of Chronic Exposure to High-Fat Diet and Arsenic on the Reproductive System of the Male Mouse

Objective: Obesity is associated with reproductive disorders. Arsenic disrupts male reproduction by direct effects on the male gonads or androgens secretion. So, the present study was conducted to evaluate the toxic effects of chronic concomitant administration of high-fat diet (HF) and arsenic on the reproductive system of the male mouse. Materials and methods: In this experimental study, 72 adult male mice were randomly divided into 6 groups: low-fat diet (LF0), LF+arsenic 25 ppm, LF+arsenic 50ppm, HF0, HF+arsenic 25 ppm and, HF+arsenic 50 ppm. 24 hours after the last experimental day, plasma samples, the cauda of epididymis and testis were prepared and removed for hormonal, sperm count and histopathological assessments. Results: Testis weight and volume increased in HF0 than other groups except for LF0. Plasma LH and testosterone levels decreased in LF50, HF0, HF25, and HF50 compared to LF0. A similar effect was observed in plasma FSH levels of HF0, HF25 and HF50 groups compared with LF0. Plasma level of estradiol increased in LF50 versus to other groups. Testosterone to estradiol ratio and sperm count decreased in all groups compared to LF0. Reduced interstitial cells and large numbers of vacuoles were observed in germinal epithelium of HF0 group, that these changes were more intense in both concentrations of arsenic-treated mice. Conclusion: Present study indicated that chronic exposure to HF and arsenic-induced hypogonadotropic hypogonadism concomitant with sperm count reduction and testicular damage.

MP06-07 CHRONIC EXPOSURE TO MICROCYSTIN-LEUCINE-ARGININE PROMOTED PROLIFERATION OF PROSTATE EPITHELIAL CELLS RESULTING IN BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (MP06)1 Apr 2020MP06-07 CHRONIC EXPOSURE TO MICROCYSTIN-LEUCINE-ARGININE PROMOTED PROLIFERATION OF PROSTATE EPITHELIAL CELLS RESULTING IN BENIGN PROSTATIC HYPERPLASIA Haixiang Qin*, Chun Pan, Xiaodong Han, and Hongqian Guo Haixiang Qin*Haixiang Qin* More articles by this author , Chun PanChun Pan More articles by this author , Xiaodong HanXiaodong Han More articles by this author , and Hongqian GuoHongqian Guo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000820.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With a combination of factors including global warming and lake eutrophication, mass proliferation of cyanobacteria and release of cyanotoxins including Microcystins (MCs), have drawn a growing public concern. MC-leucine-arginine (MC-LR), as the most common and deleterious variant among all structural analogues of MCs, has been reported to cause male reproductive dysfunction. However, its toxic effects on prostate, which is the largest accessory organs in adult male and plays a pivotal role in reproductive systems, have not been investigated in detail, as well as the underlying molecular mechanisms. METHODS: Herein, we investigated the toxic effects of chronic exposure to low-dose of MC-LR on the structure and function of prostate in vivo. Male BALB/c mice aged 6-weeks were divided into 10 groups with 10 mice in each group. The experiment groups were given drinking water containing 1 μg/L, 10 μg/L, 20 μg/L, or 30 μg/L MC-LR for 90 or 180 consecutive days. In addition, an immortalized prostate epithelial cell line, RWPE-1, was also applied to investigate the toxic effects and the molecular mechanisms of MC-LR exposure to the prostate epithelial in vitro. RESULTS: We observed that MC-LR dissolved in drinking water could be transported into the stromal and epithelial cells of mouse prostate. Following exposure to low-dose of MC-LR for 90 days or 180 days, focal hyperplasia as well as prostate inflammation were observed in the mouse prostate. Moreover, increased levels of prostate specific antigen (PSA) and prostate acid phosphatase (PAP) in the serum of mice following chronic exposure to MC-LR were detected. Mechanistically, treatment with MC-LR at low levels induced upregulation of forkhead box protein M1 (FOXM1) in RWPE-1 cells, which then resulted in PSA elevation. Furthermore, MC-LR also increased the expression of CyclinD1 via FOXM1/Wnt/β-catenin signaling in the epithelial cells, promoting cell proliferation and resulting in prostate hyperplasia. As a foreign substance, MC-LR was also found to induce immune reaction by promoting production of pro-inflammatory cytokines and chemokines mediated via NF-κB pathway. CONCLUSIONS: To the best of our knowledge, this is the first study to illustrate that chronic exposure to low dose of MC-LR could induce prostatic hyperplasia and prostatitis in mice. Our work involving the regulatory mechanisms may provide a new perspective in developing new diagnosis and treatment strategies for MC-LR-induced prostatic toxicity. Source of Funding: This work was supported by National Natural Science Foundation of China (31370524, 21377052, and 31670519) and Fundamental Research Funds for the Central Universities (021414380332). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e53-e53 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Haixiang Qin* More articles by this author Chun Pan More articles by this author Xiaodong Han More articles by this author Hongqian Guo More articles by this author Expand All Advertisement PDF downloadLoading ...

The disturbance of autophagy and apoptosis in the gizzard caused by copper and/or arsenic are related to mitochondrial kinetics

As toxic elements when excessive, arsenic (As) and copper (Cu) are two naturally occurring elements that may be ingested by the organism at the same time. However, the precise damaged mechanism and the pathways that are activated by As and/or Cu is rarely researched in gizzard, a unique organ of birds. In this study, ultrastructural observations, TdT-mediated dUTP Nick-End Labeling, real-time quantitative PCR and Western blotting were performed to evaluate the toxic effects of chronic exposure to Cu2+ and/or arsenite on chicken gizzard. The results revealed that increased apoptosis and autophagy levels induced by Cu2+ and arsenite appeared to be independent of oxidative stress, which didn't have significant changes in different treatment groups at the same time point. Nevertheless, the redox balance gradually deviated with the extension of time. And increased mitochondrial division and decreased fusion were also caused by Cu2+ and arsenite. In conclusion, apoptosis and autophagy in gizzard induced by Cu2+ and/or arsenite, at least, strongly linked with the disruption of mitochondrial homeostasis. Our study showed that the combination of Cu2+ and arsenite produces stronger toxicity. The results of this study can serve as a reference for agicultural feeding and environmental protection, that is, to avoid the combined exposure of Cu2+ and arsenite to prevent greater economic losses and health risks.

Toxic effects of chronic exposure to dyes among workers of synthetic textile industries

Background: textile industry is one of the major industries in Egypt. However, the working environment is associated with potential health hazards. Aim of the work: to study the toxic effects of different types of dyes among workers in textile industries and its effect on their respiratory, renal, and immunological systems. Subjects and methods: this study was conducted on 50 male workers exposed to textile dyeing of different ages, selected from all textile plants with dyeing industry at Borg Al-Arab City compared with 50 males, who were not exposed to textile dye as a control group. Results: both groups were comparable as patient age, while smoking was significantly increased in exposed group (38.0% vs 14.0%). Reported symptoms such as itching, abdominal pain, etc. and respiratory symptoms were significantly increased in exposed group. There was significant increase of AST, ALT, total bilirubin and alkaline phosphatase, urea and serum creatinine in study when compared to control group. Furthermore, there was statistically significant decrease of respiratory function percentage of predicted in study group, and there was statistically significant increase of serum lead concentration in study when compared to the control group (17.18±2.35 vs 6.74±2.29 respectively). In addition, there was significant increase of IgM and IgG in study group. Conclusion: workers in textile industry were significantly exposed to health hazards especially on respiratory system. However, multi-organ affection is the role with increased oxidative stress.

Toxic effects of chronic exposure to dyes among workers of synthetic textile industries

Toxic effects of chronic exposure to dyes among workers of synthetic textile industries

Metabolomic analysis of the toxic effect of chronic exposure of cadmium on rat urine

This study aimed to assess the toxic effect of chronic exposure to cadmium through a metabolomic approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). Forty male Sprague-Dawley rats were randomly assigned to the following groups: control, low-dose cadmium chloride (CdCl2) (0.13mg/kg body weight (bw)), middle-dose CdCl2 (0.8/kgbw), and high-dose CdCl2 (4.9mg/kgbw). The rats continuously received CdCl2 via drinking water for 24weeks. Rat urine samples were then collected at different time points to establish the metabolomic profiles. Multiple statistical analyses with principal component analysis and partial least squares-discriminant analysis were used to investigate the metabolomic profile changes in the urine samples and screen for potential biomarkers. Thirteen metabolites were identified from the metabolomic profiles of rat urine after treatment. Compared with the control group, the treated groups showed significantly increased intensities of phenylacetylglycine, guanidinosuccinic acid, 4-pyridoxic acid, 4-aminohippuric acid, 4-guanidinobutanoic acid, allantoic acid, dopamine, LysoPC(18:2(9Z,12Z)), and L-urobilinogen. By contrast, the intensities of creatinine, L-carnitine, taurine, and pantothenic acid in the treated groups were significantly decreased. These results indicated that Cd disrupts energy and lipid metabolism. Meanwhile, Cd causes liver and kidney damage via induction of oxidative stress; serum biochemical indices (e.g., creatinine and urea nitrogen) also support the aforementioned results.

EFFECT OF SUB-CHRONIC EXPOSURE TO CHROMIUM ON HAEMATOLOGICAL AND BIOCHEMICAL PARAMETERS OF MALE ALBINO RAT

Objectives : Exposure to chromium, the transition element found in many compounds of earth’s crust, leads to various health hazards including cancer, dermatitis, damage of liver and kidneys and reproductive toxicity in both male and female. Toxic effect of chronic exposure to chromium at low environmentally relevant dose is recently recognized and less studied. In the present study, we evaluated the effect of sub-chronic exposure to low doses of chromium VI (K2Cr2O7) on various haematological and biochemical parameters in male albino rats.Methods : Male albino rats (160±10 gm) received 1/25, 1/50 and 1/100 of reported oral LD50 dose of chromium VI (K2Cr2O7) for 90 consecutive days. After treatment, the blood was collected for analysis of various haematological and biochemical parameters.Results : Exposure to chromium VI at 1/25 LD50 dose caused decrease in body weight gain and reduction in the weight of the reproductive organs along with increase in the weight of liver and kidney. Numbers of red blood cells, white blood cells, platelets and haemoglobin concentration reduced with increase in clotting time. The total sperm count and motility was also reduced in exposed rats. There was decrease in plasma protein and albumin concentration, with increase in plasma glucose and cholesterol level. The activity of enzyme alanine aminotransferase and enzyme aspertate aminotransferase was stimulated in treated rats.Conclusion : The results of the present study revealed that chronic low dose exposure to chromium VI resulted in a toxic effect in experimental male albino rats. Keywords: Chromium VI (K2Cr2O7), Haematological parameters, Biochemical parameters.

Metabolomics analysis of urine from rats administered with long-term, low-dose acrylamide by ultra-performance liquid chromatography-mass spectrometry

1. To study the toxic effect of chronic exposure to acrylamide (AA) at low-dose levels, we applied metabolomics approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC–MS). A total of 40 male Wistar rats were randomly assigned to different groups: control, low-dose AA (0.2 mg/kg.bw), middle-dose AA (1 mg/kg.bw) and high-dose AA (5 mg/kg.bw). The rats continuously received AA via drinking water for 16 weeks. Rat urine samples were collected at different time points for measurement of metabolomic profiles.2. Thirteen metabolites, including the biomarkers of AA exposure (AAMA, GAMA and iso-GAMA), were identified from the metabolomic profiles of rat urine. Compared with the control group, the treated groups showed significantly increased intensities of GAMA, AAMA, iso-GAMA, vinylacetylglycine, 1-salicylate glucuronide, PE (20:1(11Z)/14:0), cysteic acid, L-cysteine, p-cresol sulfate and 7-ketodeoxycholic acid, as well as decreased intensities of 3-acetamidobutanal, 2-indolecarboxylic acid and kynurenic acid in rat urine. Notably, three new candidate biomarkers (p-cresol sulfate, 7-ketodeoxycholic acid and 1-salicylate glucuronide) in rat urine exposed to AA have been found in this study.3. The results indicate exposure to AA disrupts the metabolism of lipids and amino acids, induces oxidative stress.

ALTERATION IN PROTEIN AND GLUCOSE LEVEL IN THE OVARY OF A FRESH WATER CAT FISH HETEROPNEUSTES FOSSILIS (BLOCH) EXPOSED TO TEXTILE DYES

Problems of water quality with particular refer to Natural and Synthetic Chemicals have greatly intensified during recent past. The most dangerous fact of these chemicals is that, they do not decay and/or for break down readily in natural environment. Once incorporated in a food web, they pass along and accumulate in the highest member of web. Fish being at high trophic level, also gets affected through food chain. Among aquatic pollutants, dyes, pigments and effluents from textile industry are of utmost importance, which affect the life processes of aquatic organisms. The present study is undertaken to assess the toxic effects of chronic exposure to textile dyes, on protein and glucose level in female gonads of fresh water teleost Heteropneustesfossilis. A decline in ovarian protein and glucose indicates adverse effects of textile dyes on the reproductive physiology of fish.

Toxic effects of chronic mercury exposure on the retinal nerve fiber layer and macular and choroidal thickness in industrial mercury battery workers.

BackgroundThe aim of this study was to evaluate the toxic effects of mercury on retinal nerve fiber layer thickness (RNFLT), macular thickness (MT), and choroidal thickness (CT) by using spectral-domain optical coherence tomography (SD-OCT) in battery industry workers who had been chronically exposed to mercury.Material/MethodsBattery factory workers (n=31) and healthy non-factory employee controls (n=15) participated in the study. Participants were divided into 3 groups: Group 1 (n=15) was factory workers who had worked for more than 5 years in a mercury battery factory; Group 2 (n=16) was factory worker who had worked for less than 5 years in a mercury battery factory; and Group 3 (n=15) was healthy non-employees. Systemic symptoms were recorded. Ophthalmic examination included best-corrected visual acuity test, color vision test, full ophthalmologic examination, and SD-OCT of the RNLF, macula, and choroid. To determine mercury exposure, venous blood samples were collected and mercury levels were assessed.ResultsIn our study group the most common systemic symptoms were insomnia (67.7%) and fatigue (67.7%). There were no significant differences between Group 1 and Group 2, but there were significant differences between Group 3 and both Group 1 and Group 2 in best-corrected visual acuity values (1=2<3), color vision scores, blood mercury levels, and duration (mean ±SD, range) of mercury exposure(1>2>3). OCT values of RNFLTs, MTs, and CTs of all 3 groups were statistically different from each another (1<2<3).ConclusionsSD-OCT can be useful for evaluating the toxic effects of chronic exposure to mercury.

Metabonomic analysis of urine from rats after low-dose exposure to 3-chloro-1,2-propanediol using UPLC–MS

To study the toxic effect of chronic exposure to 3-chloro-1,2-propanediol (3-MCPD) at low doses, a metabonomics approach based on ultrahigh-performance liquid chromatography and quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was performed. Two different doses of 3-MCPD (1.1 and 5.5mg/kg bw/d) were administered to Wistar rats for 120 days (1.1mg/kg bw/d: lowest observed adverse effect level [LOAEL]). The metabolite profiles and biochemical parameters were obtained at five time points after treatment. For the 3-MCPD-treated groups, a significant change in urinary N-acetyl-β-d-glucosaminidase and β-d-galactosidase was detected on day 90, while some biomarkers based on the metabonomics, such as N-acetylneuraminic acid, N-acetyl-l-tyrosine, and gulonic acid, were detected on day 30. These results suggest that these biomarkers changed more sensitively and earlier than conventional biochemical parameters and were thus considered early and sensitive biomarkers of exposure to 3-MCPD; these biomarkers provide more information on toxicity than conventional biochemical parameters. These results might be helpful to investigate the toxic mechanisms of 3-MCPD and provide a scientific basis for assessing the effect of chronic exposure to low-dose 3-MCPD on human health.

Metabolomic analysis of the toxic effect of chronic low-dose exposure to acephate on rats using ultra-performance liquid chromatography/mass spectrometry

To study the toxic effect of chronic exposure to acephate at low-dose levels, a metabolomics approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS) was applied. Three different doses of 0.5mg/kg/day, 1.5mg/kg/day, and 4.5mg/kg/day acephate were administered to Wistar rats for 24 weeks. Endogenous metabolite profiles were obtained with UPLC-MS for all rats at six time points after treatment. Some metabolites like dimethylthiophosphate and uric acid in urine were detected at week 4. Dimethylthiophosphate, which had the most significant elevations compared with other biomarkers, was considered as an early, sensitive biomarker of exposure to acephate. Moreover, there were some endogenous metabolite changes, which demonstrated that the doses of 1.5mg/kg/day and 4.5mg/kg/day of acephate led to renal injury and perturbed the normal metabolic processes of rats, including glucose, nucleic acid, and protein metabolism. A connection between exposure to acephate and the metabolic disturbance has been found and interpreted. Our study indicates that the metabolomics approach based on UPLC-MS of urine provides more information on toxicity than the conventional toxicological evaluation methods in measuring changes and can be considered as a promising technique for the study of the toxic effect of acephate.

Metabolomic analysis of the toxic effects of chronic exposure to low-level dichlorvos on rats using ultra-performance liquid chromatography–mass spectrometry

The purpose of the current study was to assess the effects of long-term exposure to low levels of DDVP on the biochemical parameters and metabolic profiles of rats. Three different doses (2.4, 7.2, and 21.6mg/kgbody weight/day) of DDVP were administered to rats through their drinking water over 24 weeks. Significant changes in blood cholinesterase, creatinine, urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and albumin concentrations were observed in the middle and high dose groups. Changes in the concentration of some urine metabolites were detected via ultra performance liquid chromatography–mass spectrometry (UPLC–MS). Dimethyl phosphate (DMP), which was exclusively detected in the treated groups, can be an early, sensitive biomarker for DDVP exposure. Moreover, DDVP treatment resulted in an increase in the lactobionic acid, estrone sulfate, and indoxyl sulfic concentrations, and a decrease in citric acid, suberic acid, gulonic acid, urea, creatinine, and uric acid. These results suggest that chronic exposure to low-level DDVP can cause a disturbance in carbohydrate and fatty acid metabolism, the antioxidant system, etc. Therefore, an analysis of the metabolic profiles can contribute to the understanding of the adverse effects of long-term exposure to low doses of DDVP.

Chronic Treatment with Fluphenazine Alters Parameters of Oxidative Stress in Liver and Kidney of Rats

The aim of this study was to assess the toxic effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the possible protective effect of diphenyl diselenide on the fluphenazine-induced damage. Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates. Diphenyl diselenide treatment did not affect delta-aminolevulinate dehydratase (delta-ALA-D) activity, but fluphenazine alone or in combination with diphenyl diselenide showed an inhibitory effect on delta-ALA-D activity in liver. Diphenyl diselenide plus fluphenazine treatment increased the reactivation index of hepatic delta-ALA-D by approximately 80%. Superoxide dismutase activity decreased in liver of rats treated with fluphenazine alone. The combined treatment with fluphenazine and diphenyl diselenide was able to ameliorate superoxide dismutase activity in liver of rats. Catalase activity was augmented in liver from rats treated with fluphenazine, and this increase was prevented when diphenyl diselenide was co-administered. Taken together, these results indicate that the association of diphenyl diselenide with fluphenazine could protect the liver from lipid peroxidation and ameliorate superoxide dismutase and catalase activities. Moreover, our data point to the relationship between the oxidative stress and fluphenazine treatment in liver and kidney of rats.

Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment

In this review, we discuss genetic disorders involving altered copper metabolism, particularly in relation to Menkes disease (MD), occipital horn syndrome (OHS), and Wilson’s disease (WD). The responsible genes for MD and WD are ATP7A and ATP7B, respectively. Both proteins encoded by these genes are responsible for transporting copper from the cytosol to the Golgi apparatus. However, the pathology of MD is completely different from that of WD, that is, MD is characterized by a copper deficiency while WD is caused by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cell types except hepatocytes, whereas ATP7B is mainly expressed in hepatocytes. MD and OHS are X-linked recessive disorders characterized by copper deficiency. Typical features of MD, such as neurological disturbances, connective tissue disorders, and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care treatment for MD is parenteral administrations of copper–histidine. When the treatment is initiated in newborn babies prior to two months of age, the neurological degeneration may be prevented, but delayed treatment is considerably less effective. Moreover, copper–histidine treatment does not improve symptoms of the connective tissue disorders. As such, systems for mass screening of neonates for MD should be implemented. At the same time, novel treatments targeting connective tissue disorders need to be developed. OHS is a milder form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to those with MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. The hepatic and nervous systems are typically most severely affected. Numerous other symptoms can also be observed, however, making an early diagnosis difficult. Chelating agents and zinc are effective for the treatment of WD, but they are ineffective for the patients with fulminant hepatic failure. Some patients with neurological diseases show poor response to chelating agents; here again, early diagnosis and treatment are critical. Screening of newborn babies or infants for WD can help lead to timely diagnosis and treatment. Patients with WD may have a risk of hepatocellular carcinoma despite receiving treatment. An understanding of the relation between WD and hepatocellular carcinoma will provide clues to help prevent hepatocellular carcinoma in patients with WD.

Gray Matter Changes in Late Life Depression—a Structural MRI Analysis

Multiple brain morphometric changes have been reported in late-life depression (LLD), mostly in studies comparing volumes of circumscribed brain areas. The aim of our study is to characterize the volumetric changes of multiple gray matter regions in relation to age of onset/duration of illness. We predicted that the association of gray matter volumes with total duration of illness and age of onset would differ depending on whether the region was susceptible to the toxic effects of chronic exposure to cortisol or to the vascular/neurodegenerative changes accompanying prodromal dementia. Seventy-one elderly depressed subjects were studied along with thirty-two comparison subjects. High-resolution T1-weighted brain MRIs were processed using an automated labeling pathway technique. To protect against type-I error, we combined the right and left hemisphere volume data. We sampled 24 regions of interest (ROIs). We used the primary visual cortex volume to normalize for individual variations in brain size. LLD Subjects had smaller volumes than non-depressed subjects in 17 of the 24 examined ROIs. Shorter duration of illness and later age of onset was correlated with smaller volumes of parahippocampal area and parietal inferior area. A later age of onset was also correlated with smaller volumes of several frontal and temporal areas, cingulum, and putamen. Our findings support a dementia prodrome model more strongly than a toxic stress model in this group of subjects. However, it remains likely that both processes as well as other factors contribute to the heterogeneity of volumetric brain changes in LLD.

Exposição cianídrica em suínos: uma abordagem dos parâmetros toxicocinéticos utilizando o tiocianato como biomarcador

O objetivo do presente estudo foi verificar os efeitos sobre a cinética do cianeto, em suínos, em diferentes fases da vida, usando o tiocianato como biomarcador. Vinte e dois suínos, foram divididos em quatro grupos (60 dias da idade, 95 dias da idade, 80 dias do gestação e 21 dias de lactação), e receberam por via oral, a dose única de 3.0 mg /kg de peso vivo de cianeto do potássio (KCN). As concentrações do tiocianato no sangue foram medidas dentro de 24h. O tempo máximo (Tmax) e constante de eliminação (Kel) foram mais elevados em porcas lactantes (15 hs e 0.045, respectivamente); por ouro lado, a maior concentração do tiocianato (Cmax) foi observada nas fêmeas grávidas (161.8). A meia vida de eliminação (t1/2) e o volume da distribuição (Vd) foram mais elevados nas fêmeas adultas (41, 57 e 1.23, respectivamente). Contudo a área sob a curva (AUC) do tiocianato foi mais elevado nos animais novos (354183, 28), e o clearance o mais baixo (0.007) nestes animais. Concluindo, os resultados do presente estudo, evidenciam que o metabolismo do cianeto, varia extremamente, considerando o estado fisiológico dos suínos fêmeas, e que são os animais novos, provavelmente, os mais sensíveis aos efeitos tóxicos, da exposição crônica as baixas doses do cianeto.