Adam Daragó

Disturbed homeostasis of zinc and other essential elements in the prostate gland dependent on the character of pathological lesions

Pathophysiological changes in the prostate take the form of benign prostate hyperplasia (BPH) and prostate adenocarcinoma (PCa). In prostate, zinc is particularly important to its normal functioning, especially in terms of the consequences of hormone disturbance. The aim of this study was to assess the levels of Zn, Cu, Ca, Mg, and Se in the prostate dependent on the character of patological changes. Zinc, copper, magnesium and calcium were determined by AAS and selenium with spectrofluorometric method. Zn levels in BPH patients were over twofold higher than in controls. On the other hand, in the patients with PCa, the levels of Zn were found almost three times lower than in BPH patients and by almost 50% lower than in controls. In this study, significant changes in the levels of other essential elements were observed. The results apparently confirm the disturbed homeostasis of zinc and other essential elements in the etiology of BPH and PCa.

Subacute toxicity of polychlorinated naphthalenes and their effect on cytochrome P-450.

The aim of the study was to investigate the subacute toxicity of a polychlorinated naphthalene (PCN) mixture and its effect on cytochrome P-450 levels in rats. The animals were administered PCNs intragastrically in repeated daily doses of 1, 10, and 100 mg/kg. The animals were dissected after 7, 14, or 21 doses. Doses of 10 and 100 mg/kg induced a significant decrease in the body weight at all time points of the experiment compared with the control group. The exposure to PCNs increased both the level of total cytochrome P-450 and the activity of CYP 1A at the same time points. In the groups of rats given PCNs in doses of 10 and 100 mg/kg, an evident dose- and time-dependent increase in malondialdehyde (MDA) level was observed throughout the experiment. The correlation between the increased MDA and decreased glutathione (GSH) levels in the liver was also observed.

The correlation between zinc and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and prostate-specific antigen (PSA) in prostate cancer

Abstract Background: The objective of the present study is to explore the association between zinc concentrations and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and total prostate-specific antigen (tPSA) levels in the serum of patients with prostate cancer (PCa) and prostate intraepithelial neoplasia (PIN), a pre-cancer state matched for age. Methods: The study was carried out in a group of 229 patients who had transurethral prostate biopsy performed. The patients were divided into three groups: control group (BPH), PIN group or PCa group. The patients had plasma zinc concentration determined by atomic absorption spectrometry; IGF-1, IGFBP-3 analyzed using the chemiluminescence method and tPSA detected in serum with DELFIA assay. Results: The studies revealed that, in PCa and PIN patients aged under 65 years, mean zinc concentrations were significantly lower compared with the control group. IGF-1 level significantly increased with decreasing level of zinc in plasma, hence a significantly decreased Zn/IGF-1 ratio. The mean tPSA concentration was significantly increased only in PCa patients of both age groups, whereas the Zn/tPSA ratio significantly decreased with increasing severity of neoplastic lesions, particularly in patients aged under 65 years. Statistical significance was noted for IGF-1:tPSA and IGFBP-3:tPSA ratios, being almost two-fold lower in the PCa patients than in the control group. Conclusions: A significantly lowered Zn/tPSA ratio appears to be a sensitive marker of neoplastic lesions, PCa and PIN, regardless of age. In men under 65 years, the Zn/IGF-1 ratio was reduced, depending on the stage of neoplastic lesions (PIN>PCa). These finding can be useful in early diagnosis of prostate cancer.

Involvement of oxidative stress in the mechanism of cadmium-induced toxicity on rat uterus

The study was undertaken to explore whether cadmium bioaccumulation can induce oxidative stress in the uterus of rats. Cadmium (0.09, 0.9, 1.8 or 4.5mgCd/kg b.w.) was administered by gavage for 28 days. The animals were dissected on the first day and then after 90 days post exposure (second group of animals). The results show that cadmium accumulates in the uterus in a dose-dependent manner. The uterine Cd concentrations were almost the same in both groups, which is indicative of its long half-life in this organ. The accumulated cadmium caused significant changes in catalase (CAT) activity and lipid peroxidation (MDA) levels at concentrations from 0.09 to 0.35μgCd/g wet uterine tissue. In summary our results show that the induction of oxidative stress and lipid peroxidation in the uterus may play important roles in the mechanism of toxicity in this organ and may have a negative impact on reproductive processes.

The effect of cadmium on the coagulation and fibrinolytic system in women with uterine endometrial cancer and myoma

ObjectivesCadmium (Cd) is a persistent and widespread environmental pollutant, which may constitute a potential risk factor for hormone-dependent tumors such as endometrial cancer. The vascular endothelium is an important target of cadmium toxicity, which may interfere with the coagulation cascade and fibrinolytic system. The aim of this research was to investigate whether in female patients with uterine endometrial cancer or myoma in comparison to healthy women, the concentration of cadmium in blood affects the process of coagulation and fibrinolysis.Materials and MethodsThe study group comprised 91 women: 35 healthy (A-control), 39 with uterine myoma (B) and 17 with endometrial cancer (C), in which blood cadmium concentrations (BCd), coagulation and selected fibrinolysis parameters in plasma were assayed.ResultsIn the women with myoma and especially in those with endometrial cancer disturbances in coagulation and fibrinolysis were detected when compared to the healthy women. In the group of women with endometrial cancer significant changes in prothrombin index, levels of fibrinogen, fibrin D-dimer and t-PA were observed. Whereas, in the patients with myoma significant changes in prothrombin time, index of vWillebrand Factor and fibrin D-dimer level were noted. Mean BCd concentrations in subsequent groups were as follows: B — 0.91±0.81; C — 0.78±0.45 μg Cd/l and did not differ significantly in comparison with the control group (0.86±0.35 μg Cd/l). However, in each study group smokers had approximately twice as high BCd as non-smokers. Studies also showed significant associations between BCd and fibrinogen level and thrombin time among the women with myoma and endometrial cancer, as well as in healthy women. Moreover, thrombin time significantly correlated with fibrinogen level in the women studied.ConclusionsIn the patients with myoma and especially in these with endometrial cancer disturbances in coagulation and fibrinolysis parameters leading to hypercoagulability were detected. Exposure to cadmium can be one of the factors inducing these changes.

The effect of exposure route on the distribution and excretion of hexachloronaphthalene in rats

ObjectivesPolychlorinated naphthalenes (PCNs), like other persistent organic pollutants (POPs), are widespread, global environmental contaminants. These compounds still represent a great environmental problem, mostly because of the risk of secondary air pollution. They are characterized by long durability and tendency to bioaccumulate, which means that they are practically ubiquitous in all environmental media and ecosystems. The aim of this study was to investigate the distribution and excretion of hexachloronaphthalene (HxCN) in rats following a single intraperitoneal or intragastrical administration.Materials and MethodsExperiments were performed on male outbred Wistar rats with body weight of 220–240 g. They were given [14C]-HxCN intraperitoneally (i.p.) or intragastrically (p.o.) in a single dose of 0.3 mg (150 kBq) per rat. The distribution of radioactivity in blood and selected organs or tissues, as well as urine and faeces excretion were traced following the administration.ResultsThe decline of [14C]-HxCN in plasma was biphasic and the calculated half-lives for phases I and II were ∼6 and 350 h, respectively. Following 120 h after administration, ∼51% (intragastrical) and ∼34% (intraperitoneal) of the dose were excreted with faeces. Regardless of the administration route, the highest HxCN concentrations were found in liver and adipose tissue, where the compound showed high retention: the highest retention in liver was found 24 h after intragastrical (32%) and intraperitoneal (38%) administration while in adipose tissue ∼30% retention was observed 120 h after HxCN administration regardless of its route.ConclusionsFollowing the calculation of the balance of total [14C]-HxCN excreted and stored, it was found that hexachloronaphthalene belongs to the compounds of a slow turnover rate, and in the case of repeated exposure it may accumulate in the rat body.

Optimization of ultra-performance liquid chromatography (UPLC) with fluorescence detector (FLD) method for the quantitative determination of selected neurotransmitters in rat brain

BACKGROUND Glutamate (Glu) and γ-aminobutyric acid (GABA) are the main neurotransmitters in the central nervous system for excitatory and inhibitory processes, respectively. Monitoring these neurotransmitters is an essential tool in establishing pathological functions, among others in terms of occupational exposure to toxic substances. MATERIAL AND METHODS We present modification of the HPLC (high-performance liquid chromatography) to the UPLC (ultra-performance liquid chromatography) method for the simultaneous determination of glutamate and γ-aminobutyric acid in a single injection. The isocratic separation of these neurotransmitter derivatives was performed on Waters Acquity BEH (ethylene bridged hybrid) C18 column with particle size of 1.7 μm at 35°C using a mobile phase consisting of 0.1 M acetate buffer (pH 6.0) and methanol (60:40, v/v) at a flow rate of 0.3 ml/min. The analytes were detected with the fluorescence detector (FLD) using derivatization with o-phthaldialdehyde (OPA), resulting in excitation at 340 nm and emission at 455 nm. RESULTS Several validation parameters including linearity (0.999), accuracy (101.1%), intra-day precision (1.52-1.84%), inter-day precision (2.47-3.12%), limit of detection (5-30 ng/ml) and quantification (100 ng/ml) were examined. The developed method was also used for the determination of these neurotransmitters in homogenates of selected rat brain structures. CONCLUSIONS The presented UPLC-FLD is characterized by shorter separation time (3.5 min), which is an adaptation of the similar HPLC methods and is an alternative for more expensive references techniques such as liquid chromatography coupled with tandem mass-spectrometry (LC-MS/MS) methods. Med Pr 2017;68(5):583-591.

Developmental toxicity of hexachloronaphthalene in Wistar rats. A role of CYP1A1 expression.

Hexachloronaphthalene (HxCN) is one of the most toxic congeners of polychlorinated naphthalenes (PCNs). This study assesses the prenatal toxicity of HxCN after daily administration at doses of 0.1-1.0mg/kg b.w. to pregnant Wistar rats during organogenesis. We evaluated also the expression of CYP1A1 mRNA and protein in the livers of dams and fetuses, as well as the placenta. The results indicate that 0.3mg/kg b.w. was the lowest HxCN toxic dose for dams (LOAEL) while a dose of 0.1mg/kg b.w. was sufficient to impair the intrauterine development of embryos/fetuses without maternal toxicity. Regardless of the applied dose, HxCN generated embryotoxic effects. Dose-dependent fetotoxic effects were associated with HxCN exposure. HxCN was found to be a strong inducer of maternal and fetal CYP1A1. Expression of CYP1A1 mRNA in the placenta appears to be the most sensitive marker of HxCN exposure.

Concentrations of cadmium and selected essential elements in malignant large intestine tissue

Introduction Colorectal cancer is one of the most common cancers worldwide. Incidence rates of large intestine cancer indicate a role of environmental and occupational factors. The role of essential elements and their interaction with toxic metals can contribute to the explanation of a complex mechanism by which large intestine cancer develops. Bearing this in mind, determining the levels of essential and toxic elements in tissues (organs), as well as in body fluids, seems to shed light on their role in the mode of action in malignant disease. Aim Determination of the levels of cadmium, zinc, copper, selenium, calcium, magnesium, and iron in large intestine malignant tissue. Material and methods Two intraoperative intestine sections were investigated: one from the malignant tissue and the other one from the normal tissue, collected from each person with diagnosed large intestine cancer. Cadmium, zinc, copper, calcium, magnesium, and iron levels were determined with atomic absorption spectrometry, and selenium levels by spectrofluorimetric method. Results The levels of copper, selenium, and magnesium were higher in the malignant than in normal tissues. In addition, the zinc/copper and calcium/magnesium relationship was altered in malignant tissue, where correlations were lower compared to non-malignant tissue. Conclusions The results seems to demonstrate disturbed homeostasis of some essential elements. However, it is hard to confirm their involvement in the aetiology of colorectal cancer.

The effects of hexachloronaphthalene on selected parameters of heme biosynthesis and systemic toxicity in female wistar rats after 90-day oral exposure

Hexachloronaphthalenes (HxCNs) are the most toxic congeners of polychlorinated naphthalenes, a group of compounds lately included into the list of persistent organic pollutants (POPs). This study presents the effects of 90‐day intragastric administration of HxCN to female Wistar rats at doses of 0.03, 0.1, and 0.3 mg/kg body weight. The study examined selected parameters of the heme synthesis pathway, oxidative stress, hepatic cytochromes level, and basic hematology indicators. A micronucleus test was also performed. The subchronic exposure of rats to HxCN resulted in disruption of heme biosynthesis, hematological disturbances, and hepatotoxicity. The highest dose of HxCN inhibited aminolevulinic acid dehydratase (ALA‐D) and uroporphyrinogen decarboxylase (URO‐D). Accumulation of higher carboxylated porphyrins in the liver and increased excretion of 5‐aminolevulinic acid in the urine was observed after a dose of 0.1 mg/kg body weight. The most sensitive effect of HxCN in rats was very strong induction of hepatic CYP1A1 activity, which was observed after the lowest dose. The highest dose of HxCN induced significant thrombocytopenia, thymic atrophy and hepatotoxicity, expressed as hepatomegaly and hepatic steatosis.