An assessment of the (anti)androgenic properties of hexachloronaphthalene (HxCN) in male rats.

The persistent organic pollutants (POPs) defined by the Stockholm Convention include polychlorinated naphthalenes (PCNs); of these, the most toxic, persistent, abundant, dioxin-like congeners found in human tissues are the hexachloronaphthalenes (HxCNs). Recent research also indicates that PCNs may disrupt hormonal homeostasis. The aim of this study was to evaluate the (anti)androgenic action of HxCN. Immature, castrated male Wistar rats were exposed per os to HxCN in corn oil at daily doses ranging from 0.3 to 3.0 mg kg-1 for 10 days. According to the OECD 441 protocol (Hershberger Bioassay), the anti-androgenic assay groups were co-exposed with testosterone propionate (TP), while the androgenic groups were not. TP was used as the reference androgen (subcutaneous daily doses of 0.4 mg kg-1), and flutamide (FLU) as the reference antiandrogen (per os daily doses of 3.0 mg kg-1). Five assessory sex tissues (ASTs) were weighed: ventral prostate, seminal vesicles, levator ani-bulbocavernosus muscle (LABC), Cowper's glands and glans penis. HxCN + TP significantly decreased the weight of the ventral prostate and seminal vesicle indicating an anti-androgenic action via 5α-reductase inhibition. These weight changes were also accompanied by abnormalities in cell morphology and hormonal disturbances: lowered levels of the testosterone and thyroid hormones thyroxine and triiodothyronine. Disturbances were also noted in the lipid profile, viz. total cholesterol, triglycerides and high-density lipoprotein and non-HDL fraction content. However, the direction of these changes differed depending on the size of the HxCN dose. No dose-effect relationship was noted for most of the obtained results; as such, exposure to even small HxCN doses run the risk of anti-androgenic effects in the general population, especially when encountered in combination with other POPs and endocrine-disrupting chemicals in the environment.

Changes in Endogenous Essential Metal Homeostasis in the Liver and Kidneys during a Six-Month Follow-Up Period after Subchronic Cadmium Exposure.

Cadmium (Cd) is one of the most dangerous environmental pollutants. Its mechanism of action is multidirectional; among other things, it disrupts the balance of key essential elements. The aim of this study was to assess how cumulative exposure to Cd influences its interaction with selected essential elements (Cu, Zn, Ca, and Mg) in the kidney and liver during long-term observation (90 and 180 days) after subchronic exposure of rats (90 days) to Cd at common environmental (0.09 and 0.9 mg Cd/kg b.w.) and higher (1.8 and 4.5 mg Cd/kg b.w.) doses. Cd and essential elements were analyzed using the F-AAS and GF-AAS techniques. It was shown that the highest bioaccumulation of Cd in the kidney occurred six months after the end of exposure, and importantly, the highest accumulation was found after the lowest Cd dose (i.e., environmental exposure). Organ bioaccumulation of Cd (>21 µgCd/g w.w. in the kidney and >6 µgCd/g w.w. in the liver) was accompanied by changes in the other studied essential elements, particularly Cu in both the kidney and liver and Zn in the liver; these persisted for as long as six months after the end of the exposure. The results suggest that the critical concentration in human kidneys (40 µgCd/g w.w.), currently considered safe, may be too high and should be reviewed, as the observed long-term imbalance of Cu/Zn in the kidneys may lead to renal dysfunction.

An Assessment of Metallothionein-Cadmium Binding in Rat Uterus after Subchronic Exposure Using a Long-Term Observation Model.

Cadmium (Cd) is an environmental pollutant known to pose a public health issue. The mechanism of Cd toxicity on the uterus, including the protective role of metallothionein (MT), is still not fully understood. The aim of the study was to evaluate the degree of MT-Cd binding in the uterus of rats exposed per os to Cd at daily doses of 0.09, 0.9, 1.8 and 4.5 mg Cd/kg b.w. for 90 days. To assess the permanence of the bond, the rats were observed over long observation periods: 90 and 180 days after termination of exposure. Additionally, uterine concentration of Zn, Cu, Ca, Mg was determined. Cd leads immediately after exposure to a max. 30-fold increase in the concentration of Cd in the uterus, with only small amounts being bound to MT. After 90 days following termination of exposure, and especially after 180 days, an increase in MT-Cd concentration was noted for the three highest doses; even so, the degree of Cd binding by MT was still small. Additionally, the accumulation of Cd in the uterus disturbs the homeostasis of determined essential elements, manifested by a significant increase in Cu concentration and a decrease in Zn, Mg and Ca, especially 180 days after termination of exposure. The obtained results indicate that MT has only a slight protective role in the uterus and that Cd ions may have harmful effects not related to MT: directly on the uterine tissue, and indirectly by disturbing the homeostasis of its essential elements.

An assessment of the estrogenic and androgenic properties of tetra- and hexachloronaphthalene by YES/YAS in vitro assays.

Many persistent organic pollutants (POPs) exhibit endocrine disrupting activity but studies on some POPs, e.g., polychlorinated naphthalenes (PCNs), are very scarce. The present study investigates the (anti)estrogenic and (anti)androgenic activities of 1,2,3,5,6,7-hexachloronaphthalane (PCN67) and 1,3,5,8-tetrachloronaphthalene (PCN43) using the yeast estrogen and androgen reporter bioassays. Among the tested substances, antiestrogenic response was only shown by PCN67. The strongest inhibition of estrogenic activity (up to 17.4%) was observed in the low concentration ranges (5 pM - 0.5 nM) in the presence of 1.5 nM 17ß-estradiol. Both tested compounds showed partial estrogenic activity with a hormetic-type response. However, both studied chemicals showed strong antiandrogenic effects: their potency in the presence of 100 nM 17ß-testosterone for PCN43 (IC50 = 2.59 µM) and PCN67 (IC50 = 3.14 µM) was approximately twice that of the reference antiandrogen flutamide (IC50 = 6.14 µM). It cannot be excluded that exposure to PCNs, together with other endocrine disrupting chemicals (EDCs), may contribute to the deregulation of sex steroid hormone signaling.

The Role of Zinc in Selected Female Reproductive System Disorders.

Zinc is an essential microelement that plays many important functions in the body. It is crucial for the regulation of cell growth, hormone release, immunological response and reproduction. This review focuses on its importance in the reproductive system of women of reproductive and postmenopausal ages, not including its well described role in pregnancy. Only recently, attention has been drawn to the potential role of zinc in polycystic ovary syndrome (PCOS), dysmenorrhea, or endometriosis. This review is mainly based on 36 randomized, controlled studies on reproductive, pre- and post-menopausal populations of women and on research trying to explain the potential impact of zinc and its supplementation in the etiology of selected female reproductive system disorders. In women with PCOS, zinc supplementation has a positive effect on many parameters, especially those related to insulin resistance and lipid balance. In primary dysmenorrhea, zinc supplementation before and during each menstrual cycle seems to be an important factor reducing the intensity of menstrual pain. On the other hand, little is known of the role of zinc in endometriosis and in postmenopausal women. Therefore, further studies explaining the potential impact of zinc and its supplementation on female reproductive system would be highly advisable and valuable.

Subchronic Exposure to Cadmium Causes Persistent Changes in the Reproductive System in Female Wistar Rats.

Cadmium (Cd) is an environmental toxicant and endocrine disruptor in humans and animals, and recent studies have illustrated that the uterus is exceedingly sensitive to Cd toxicity. The aim of the study was to investigate the influence of subchronic (90 days) oral Cd exposure in daily doses of 0.09-4.5 mg/kg b.w. on the balance of sex hormones by estimating estradiol (E2) and progesterone (P) concentrations in the uterus and plasma in comparison with the effects of 17ß-E2. Additionally, the uterine weight, histopathological changes in the uterus and ovaries, the regularity of the estrous cycle, Cd bioaccumulation in uterine tissue, and selected biochemical parameters of oxidative stress were determined. A long period of observation (three and six months following the administration period) was used to assess whether the existing effects are reversible. The lowest dose of Cd caused effects similar to 17ß-E2: an increase of E2 concentration in the uterus, endometrial epithelium thickness, and disturbed estrous cycle with estrus phase prolongation. The obtained results suggest that Cd causes nonlinear response. Higher doses of Cd caused a significant decrease in E2 concentration in the uterus and plasma, estrous cycle disturbances, endometrium atrophy, and structural damage in the ovaries. This dose additionally induces lipid peroxidation in the uterine tissues. It is noteworthy that a prolonged time of observation after terminating the exposure showed persistent changes in the concentration of E2 in uterine tissue, as well as alterations in estrous cycle phases, and an increase in lipid peroxidation in the uterus. Moreover, significant positive correlations between the plasma E2 concentration and endometrial epithelium thickness in all studied groups were found. In summary, subchronic oral Cd exposure of female rats may result in impaired fertility processes.

Hexachloronaphthalene (HxCN) as a potential endocrine disruptor in female rats.

Hexachloronaphthalene (HxCN) is one of the most toxic and most bioaccumulative congeners of polychlorinated naphthalenes (PCNs) known to be present in animal and human adipose tissue. Unfortunately, little data is available regarding the negative effect of PCNs on endocrine function. The aim of the study was to investigate the direct influence of subacute (two and four-week) and subchronic (13-week) daily oral exposure of female rats to 30, 100 and 300 µg kg b.w.-1 HxCN on ovarian, thyroid function and neurotransmitters level. The levels of selected sex hormones (progesterone: P and estradiol: E2) in the serum and uterus, regularity of estrous cycle, levels of thyroid hormones (fT3 and fT4), TSH, γ-aminobutyric acid and glutamate levels in selected brain areas and the activity of CYP1A1 and CYP2B in the liver were examined. Estrogenic action (elevated E2 concentration in the uterus and serum) was observed only after subacute exposure, and antiestrogenic activity (decreased E2 level and uterus weight) after 13 weeks administration of 300 µg kg b.w.-1 day-1. Subchronic administration of HxCN significantly lengthens the estrous cycle, by up to almost 50%, and increases the number of irregular cycles. In addition, increased TSH and decreased fT4 serum levels were observed after all doses and durations of exposure to HxCN. Only subacute exposure led to a significant decrease in the level of examined neurotransmitters in all analyzed structures. Additionally, exposure to low doses of HxCN appears to lead to strong induction of CYP1A1 in a liver. It can be hypothesized that HxCN produces effects which are very similar to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds (DLCs), particularly concerning endocrine and estrous cyclicity disorders. Therefore, HxCN exposure may exert unexpected effects on female fecundity among the general population.

The effect of repeated cadmium oral exposure on the level of sex hormones, estrous cyclicity, and endometrium morphometry in female rats.

Cadmium (Cd) is regarded as a potential endocrine disruptor. However, the exact mechanism by which this metal may interfere with the reproductive system has not yet been elucidated. The present study aimed to investigate the effect of subacute Cd oral administration at daily doses of 0.09, 1.8, and 4.5 mgCd/kg b.w. and the impact of Cd on sex hormones (estradiol (E2) and progesterone (P)) in the plasma and uterus, as well as on estrous cyclicity and histopathological changes in uterine and ovary in female rats after terminating the exposure and after a prolonged observation period (3 months). Moreover, Cd bioaccumulation in the uterine and brain tissue of rats was analyzed. The study revealed that oral Cd exposure induced changes in the plasma levels of steroid hormones: decrease in E2 and increase in P after the highest dose of Cd. Probably, for the first time, it was evidenced that circulation sex hormone disturbances in Cd-exposed rats caused irregular estrous cycle, persisting for 3 months after exposure termination; no alterations in these hormone levels in uterine tissue were noted. Cd did not induce estradiol-like hyperplasia of endometrium, but resulted in endometrial edema irrespective of the dose, and caused damage of the ovaries after the highest dose. In summary, subacute oral exposure of female rats to Cd may lead to long-term disturbances in reproductive system.

The Effect of Zinc and Selenium Supplementation Mode on Their Bioavailability in the Rat Prostate. Should Administration Be Joint or Separate?

It is thought that zinc and selenium deficiency may play a significant role in the etiology of prostate cancer. Although joint zinc and selenium supplementation is frequently applied in the prevention of prostate diseases, the bioavailability of these elements in the prostate after co-administration is still unknown. The study examines the effect of subchronic supplementation of zinc gluconate and selenium compounds (sodium selenite or selenomethionine), administered together or separately, on their bioavailability in the prostate, as well as the induction of metallothionein-like proteins (MTs) bound to zinc in the prostate and liver. Zinc concentration in the dorso-lateral lobe of the prostate was significantly elevated already after the first month of supplementation of zinc alone. In the supplementation period, the MTs level increased together with zinc concentration. In contrast, the ventral lobe of the prostate did not demonstrate significantly higher levels of zinc until after three months of supplementation, despite the MTs induction noted after one-month supplementation. Increased selenium levels in the dorsolateral lobe were observed throughout the administration and post-administration periods, regardless of the selenium compound used or whether zinc was co-administered. The results of our studies suggested for the first time that these elements should not be administered jointly in supplementation.

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 bioavailability of different zinc compounds used as human dietary supplements in rat prostate: a comparative study.

The normal human prostate accumulates the highest levels of zinc (Zn) of any soft tissue in the body. The pool of zinc available to the body is known to significantly decrease with age. It is suggested that dietary Zn supplementation protects against oxidative damage and reduces the risk of cancer. Zinc sulfate and zinc gluconate were the most frequently mentioned in per os administration in studies on Zn supplementation. The major aim of the study was to compare the bioavailability of different Zn compounds (sulfate, gluconate and citrate) in the prostate after their daily administration to male rats at three different doses (3.0; 15.0; and 50.0 mg Zn/kg b.w.) for 30 days. The results show that bioavailability in the prostate differs significantly between individual zinc preparations. A significantly elevated Zn concentration in the dorso-lateral lobe of the prostate, compared to controls, was found in the rats supplemented with two compounds only: zinc gluconate and zinc citrate. However, after administration of zinc gluconate, this effect occurred even at the lowest dose. The lowest zinc bioavailability in the prostate was found in the rats administered zinc sulfate: no significant Zn increase was seen in particular zones of the prostate. To sum up, the use of zinc gluconate is worth considering as a possible means of zinc supplementation in men.

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

OBJECTIVES: Cadmium (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 METHODS: The 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. RESULTS: In 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. CONCLUSIONS: In 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 correlation between zinc and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and prostate-specific antigen (PSA) in prostate cancer.

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.

The effect of cadmium on steroid hormones and their receptors in women with uterine myomas.

Cadmium (Cd) is one of the environmental metalloestrogens, and its role in uterine tissues has not yet been fully elucidated. The aim of the study was to investigate estrogenic properties of Cd in uterine tissues by analyzing the expression of estrogen receptor (ER) and progesterone receptor (PR) as well as estrogen and progesterone levels in serum and Cd concentrations in blood and tissues. The samples of tissues (leiomyoma and surrounding myometrium) collected intrasurgically and blood samples drawn from 53 women (age 39 to 52 years) with uterine myomas were thoroughly analyzed. In the study group, blood Cd concentration ranged from 0.33 to 3.5 µg/L. Cd concentration in leiomyoma tissues was twice as low [corrected] as that in surrounding myometrium (0.047 and 0.075 µg Cd/g [corrected] wet tissue, respectively), albeit the difference was not statistically significant. Cd concentrations in blood significantly correlated with Cd concentrations in tissues (leiomyoma and surrounding myometrium). The measurement of ER expression showed no difference between leiomyoma tissues and surrounding myometrium. The statistical analysis showed a significant correlation between ER expression and Cd concentration in both tissues under study. An additional statistical analysis (path analysis) demonstrated the correlation of uterine tissue levels of Cd and ER expression. However, there was no association between ER expression in both tissues and E(2) level in serum. Our results suggest a metalloestrogenic effect of Cd by way of ER stimulation in the uterus.

[Toxic effect of dust and fumes of aluminium and its compounds on workers' respiratory tract]. / Toksyczne oddzialywanie pylów i dymów glinu oraz jego zwiazków na drogi oddechowe pracowników.

Based on the literature review, the authors discuss problems concerning differentiated exposure of workers to dust and fumes of aluminum and its compounds and describe the observed toxic effect on the respiratory tract. Long- term occupational exposure to the above factors leads to changes in lungs of the pneumoconiotic nature. Other disorders presented in the literature include: pulmonary fibrosis, pulmonary alveolitis and alveolar proteinosis, asthma, chronic bronchitis, and chronic pneumonia. The respiratory effect depends to some extent on the form of aluminum or the stage of processing in which exposure occurs. Numerous studies of workers occupationally exposed to aluminum dust and fumes have demonstrated the increase in the incidence of pulmonary fibrosis, depending on the air concentration of respirable fraction of dust.

The trace elements in response to lithium intoxication in renal failure.

The polyuric syndrome that develops as a consequence of chronic administration of lithium salts is most frequent and often causes complication in the treatment of manic depressive disease with the administration of drugs. It is known that kidneys play an essential role in systematic depositing of toxic metals. The purpose of this study was not only the determination of dose-dependent lithium concentration in serum and urine but also an estimation of sensitive biochemical indicators of nephrotoxicity detectable at an early stage after the administration of lithium carbonate to rats. Animals were given orally lithium salt to female Wistar rats at the dose of 10 and 20mg Li/kg daily during 5 weeks. In the urine diuresis protein concentration, copper, zinc, lithium and N-acetyl-beta-glucoaminidase (NAG) activity were determined. In the serum also lithium, copper and zinc were analyzed. The results of the experiments indicate that the changes in urinary concentrations of essential copper, proteins, NAG activity and diuresis were observed when the concentration of lithium was ca. 9.79+/-1.68 mmol Li/L and in serum it corresponded to 0.3+/-0.06 mmol Li/L. These values corresponded to total doses of 150 mg Li/kg body weight administered to rats. In summary the increase of copper concentration, diuresis and urinary concentrations of protein and the NAG activity may be interpreted as a general metabolic response of kidneys induced by lithium detectable as an earlier indicator of nephrotoxicity. Therefore, regular determinations of lithium concentrations in serum of patients are important tools in the prevention of intoxication.

Essential elements as early indicators of hexavalent chromium nephrotoxicity.

The kidney is the appropriate critical organ for indicating chronic exposure to chromium compounds. The present work investigates the effect of dose-dependent hexavalent chromium concentration in various tissues of rats, the disturbances in metabolism of zinc and copper in liver and kidney, and histopathological changes in kidneys. White Wistar rats were used. Animals were injected intraperitoneally at a dose of 0.5 and 5 mg Cr/kg as K2CrO4. The animals were sacrificed after single and repeated doses at 24 h after the last injection. Disturbances in the metabolism of zinc and copper in the kidney of rats occur when the concentration of chromium in this organ attains about 30 microg Cr/g. An increase in urinary output of these essential metals is a more sensitive indicator of nephrotoxicity than ultrastructural damage of kidney.