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Representative photographs of mouse peritoneum. Vehicle control (A), propoxur (B), lindane (C), endosulfan (D). The formation of blood vessels in the peritoneum of lindane-treated mice was extensively increased as compared to that in untreated mice. Propoxur and endosulfan treatment induce less formation of blood vessels, as compared to lindane.
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Due to their estrogen-mimicking ability, pesticides are considered as prime etiological suspects of increasing tumor incidence, although a direct link is still undefined. The present study aimed to identify the effect of xenoestrogens (lindane, propoxur and endosulfan) at 20 mg/l each on tumorigenesis, by evaluating endothelial cell proliferation,...
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... peritoneum of EAT-bearing mice exposed to propoxur and lindane (20 mg/l each) exhibited extensive neova- scularization, analogous to the one observed in untreated EAT-bearing mice. Endosulfan treatment, on the other hand, weakly-stimulated angiogenesis as compared to untreated EAT-bearing mice ( Figure 6). ...
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Due to their estrogen-mimicking ability, pesticides are considered as prime etiological suspects of increasing tumor incidence, although a direct link is still undefined. The present study aimed to identify the effect of xenoestrogens (lindane, propoxur and endosulfan) at 20 mg/l each on tumorigenesis, by evaluating endothelial cell proliferation,...
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... Pesticides are considered one of the major factors contributing to increased tumor incidence, although the direct link is still not well established (Anwar, 1997;Dich et al., 1997;Bharathi et al., 2013). In the present study, we observed the development of tumours in ES exposed (5 mg/kg, 10 doses) mice after 3 and 16 months of completion of the dose (Figures 8, 9). ...
Increased infertility in humans is attributed to the increased use of environmental chemicals in the last several decades. Various studies have identified pesticides as one of the causes of reproductive toxicity. In a previous study, infertility was observed in male mice due to testicular atrophy and decreased sperm count when a sublethal dose of endosulfan (3 mg/kg) with a serum concentration of 23 μg/L was used. However, the serum concentration of endosulfan was much higher (up to 500 μg/L) in people living in endosulfan-exposed areas compared to the one used in the investigation. To mimic the situation in an experimental setup, mice were exposed to 5 mg/kg body weight of endosulfan, and reproductive toxicity and long-term impact on the general biology of animals were examined. HPLC analysis revealed a serum concentration of ∼50 μg/L of endosulfan after 24 h endosulfan exposure affected the normal physiology of mice. Histopathological studies suggest a persistent, severe effect on reproductive organs where vacuole degeneration of basal germinal epithelial cells and degradation of the interstitial matrix were observed in testes. Ovaries showed a reduction in the number of mature Graafian follicles. At the same time, mild vacuolation in liver hepatocytes and changes in the architecture of the lungs were observed. Endosulfan exposure induced DNA damage and mutations in germ cells at the molecular level. Interestingly, even after 8 months of endosulfan exposure, we observed increased DNA breaks in reproductive tissues. An increased DNA Ligase III expression was also observed, consistent with reported elevated levels of MMEJ-mediated repair. Further, we observed the generation of tumors in a few of the treated mice with time. Thus, the study not only explores the changes in the general biology of the mice upon exposure to endosulfan but also describes the molecular mechanism of its long-term effects.
... To our knowledge, GBH effects on uterine angiogenesis have not been previously described, and thus further studies are needed to know whether the effects of GBH on angiogenesis could be attributed to glyphosate itself and/or to the additives in the formulations. Based on the fact that other xenoestrogens such as bisphenol A (BPA), lindane, propoxur and endosulfan have shown angiogenic effects in both in vitro and in vivo models (Bharathi et al., 2013;Durando et al., 2011), the angiogenic alterations here reported in rats exposed to GBH on PND8 could lead to developmental disturbances that may have repercussions in the future uterine functionality. ...
Glyphosate-based herbicides (GBHs) are the agrochemicals most used around the globe. However, they might have adverse effects on human and animal health. Previously, we showed that female rats neonatally exposed to GBHs exhibit altered expression of morphogenetic molecules and biomarkers of uterine development. We also observed a reduction in the size of implantation sites, altered expression of decidualization-related molecules, and increased post-implantation losses. Since decidualization comprises morphogenetic, biochemical and vascular changes, here we investigated the effects of neonatal GBH exposure on uterine angiogenesis in neonatal and pregnant rats. To achieve this, Wistar female rats were exposed to saline solution or GBH (2 mg glyphosate/kg-bw/day) on post-natal days (PND) 1, 3, 5 and 7. On PND8, uterine samples were collected for developmental studies. On PND90, the remaining females were mated and in the morning of gestational day (GD) 9, the implantation sites were collected. Angiogenesis-related molecules and cells involved in this process were identified and/or measured by immunohistochemistry or RT-PCR. On PND8, GBH-treated rats showed increased vascular endothelial growth factor (VEGF) expression and decreased Notch1, inducible nitric oxide synthase (iNOS) and Angiopoietin-2 (Ang2) mRNA levels. Vascular area, vessel diameter, endothelial cell proliferation, VEGF and Nestin protein expression, and VEGF, Notch1, iNOS and cyclooxygenase-2 (Cox-2) genes were downregulated in implantation sites of exposed females, while Ang2, VEGF receptor 1 and interleukin-10 (IL-10) were increased. Mast cells and macrophages were increased on PND8 and GD9 of treated rats. The increased Transforming growth factor-beta expression in the antimesometrial zone and IL-10 mRNA expression suggest that the M2 type is the predominant population of macrophages on implantation sites. In conclusion, neonatal GBH exposure alters the expression of angiogenesis-related molecules at neonatal uterine development and decidual reaction, suggesting altered vascular support. These alterations might contribute to the increased post-implantation losses observed in GBH-treated rats.
... Other pesticides, including organochlorines, creosote, and sulfallate, have been reported to be carcinogenic in in vivo studies (12), whereas dichlorodiphenyltrichloroethane, chlordane, and lindane have been found to act as tumor promoters (13)(14)(15). However, individual pesticides have only been evaluated in a limited number of human studies. ...
Cancer development is a multistep process that may be induced by a variety of compounds. Environmental substances, such as pesticides, have been associated with different human diseases. Organophosphorus pesticides (OPs) are among the most commonly used insecticides. Despite the fact that organophosphorus has been associated with an increased risk of cancer, particularly hormone‑mediated cancer, few prospective studies have examined the use of individual insecticides. Reported results have demonstrated that OPs and estrogen induce a cascade of events indicative of the transformation of human breast epithelial cells. In vitro studies analyzing an immortalized non‑tumorigenic human breast epithelial cell line may provide us with an approach to analyzing cell transformation under the effects of OPs in the presence of estrogen. The results suggested hormone‑mediated effects of these insecticides on the risk of cancer among women. It can be concluded that, through experimental models, the initiation of cancer can be studied by analyzing the steps that transform normal breast cells to malignant ones through certain substances, such as pesticides and estrogen. Such substances cause genomic instability, and therefore tumor formation in the animal, and signs of carcinogenesis in vitro. Cancer initiation has been associated with an increase in genomic instability, indicated by the inactivation of tumor‑suppressor genes and activation of oncogenes in the presence of malathion, parathion, and estrogen. In the present study, a comprehensive summary of the impact of OPs in human and rat breast cancer, specifically their effects on the cell cycle, signaling pathways linked to epidermal growth factor, drug metabolism, and genomic instability in an MCF‑10F estrogen receptor‑negative breast cell line is provided.
... No DNA fragments were found, however, in human peripheral blood cells after incubation with lindane for 24 hours at a concentration of 20 mg/l (Bharathi et al. 2013). Likewise, the number of DNA strand breaks was not increased in a study that investigated DNA strand breaks in primary rat hepatocytes by alkaline elution with 0.08 and 0.12 mM lindane (Gealy et al. 2007). ...
... One of the mechanisms of estrogen carcinogenicity is its binding to the specific nuclear receptor ER-α, exerting a potent stimulus on cell proliferation through increased production of growth factors [30]. Some pesticides such as Acetochlor, Dicofol, Endosulfan, Propoxur, and Lindane mimic estrogen activity in terms of structure and function (xenoestrogens) as these can bind estrogen receptors and stimulate tumor production [31,32]. In silico analysis did not show structural alerts that indicate probable estrogen receptor binding in the ethyl-carbamates studied; therefore, the risk that they can induce cancer by this mechanism is low. ...
Ethyl-4-bromophenyl-carbamate (LQM 919) and Ethyl-4-chlorophenyl-carbamate (LQM 996) are compounds that inhibit egg-laying and hatching of tick larvae that are resistant to conventional ixodicides. The structure-activity relationship (SAR) to get the endpoint predictions of mutagenicity and carcinogenicity of the LQM 919 and LQM 996 was performed and the absence of mutagenicity was confirmed by Ames test. SAR analysis show no structural alerts indicating the ability of ethyl-carbamates to bind biomolecules or estrogen receptors. Endpoint of mutagenicity with and without metabolic activation showed that the ethyl-carbamates were negative (p <0.05) for mutagenicity induction in strains TA97, TA98, TA102, TA1535, TA1537 and TA1538 of Salmonella typhimurium. Pre-incubation with different ethyl-carbamate concentrations did not increase the number of spontaneously reverting colonies; moreover, the compounds did not induce a concentration-dependent increase in the number of reverting colonies in any of the strains used. This confirmed the absence of mutagenic activity in this test system. Exogenous metabolic activation did not modify these observations; suggesting that no metabolites with mutagenic activity were present. The endpoint of carcinogenicity in rats were negative for LQM 919 (p <0.05,) and LQM 996 (p <0.001). The results of the present study strongly suggest that ethyl-carbamates do not represent a risk for cancer in mammals.
... Although a direct link has yet to be defined. Therefore, it is necessary to clarify the role of propoxur in the development of estrogenrelated cancer, such as breast cancer, including cell proliferation, survival; invasion, metastasis, and angiogenesis [7].Estrogens are one class of steroid hormones that includes estrone, estradiol (E2), and estriol. 17β-Estradiol, the most potent estrogen hormone in the circulation, is involved in a wide variety of vital physiological functions that range from the development and maintenance of reproductive organs to the regulation of cardiovascular, musculoskeletal, immune, and central nervous system homeostasis.Estradiol also contributes to the initiation and development of target tissue malignancies [8]. ...
... In order to study the effect of α-endosulfan on epigenetic enzymes, the present study was initiated by evaluating the effects of environmentally relevant doses of the insecticide on cell proliferation and expression of the epigenetic markers in multiple cells. It was shown that αendosulfan at higher dose (N10 μM) induce cell death (Ledirac et al., 2005;Antherieu et al., 2007;Zhu et al., 2009), but at lower dose (≤10 μM) promote cell growth of human colonic epithelial cell lines (Greenman et al., 1997) as well as of MCF-7 cells (Soto et al., 1994;Cossette et al., 2002;Zhu et al., 2009;Bharathi et al., 2013); also increases total histone protein expression (Zhu et al., 2009). Previously similar studies were reported, where increased proliferation of MCF-7 cells was observed Ibarluzea et al., 2004;Grünfeld and Bonefeld-Jorgensen, 2004. ...
Environmental cues and chemicals can potentially modulate the phenotypic expression of genome through alterations in the epigenetic mechanisms. Endosulfan is one of the extensively used organochlorine pesticides around the world which is known for its endocrine, neuro- and reproductive toxicity. This study was aimed to investigate the potential of α-endosulfan in modulation of multiple epigenetic enzymes in MCF-7 cells. The cells were treated with DMSO (control) or α-endosulfan (1 and 10μM) and the expression of various epigenetic enzymes was assayed by real-time PCR and immunoblotting, in addition to their activity assays. The results shows α-endosulfan, at 1 and 10μM concentration, significantly promoted viability of MCF-7 cells compared to untreated cells after 24h. The expression of DNA methyltransferases (DNMTs) was upregulated while the global DNA methylation status was initially affected, but later recovered. Total intracellular histone deacetylase (HDAC) activity was found to be significantly increased which was correlated with upregulation of class I HDACs (HDAC 1 and 3) while no significant alteration in the other HDAC classes was observed. The expression and activity of arginine and lysine methylation enzymes, protein arginine methyltransferase 5 (PRMT5) and Enhancer of Zeste homolog 2 (EZH2), respectively, were also found to be modulated by α-endosulfan. We found increased expression of histones H3 and H4, trimethylated H3K27 (product of EZH2), symmetric dimethylation of H4R3 (product of PRMT5) and five different (unidentified) proteins whose arginine residues are symmetrically dimethylated (by increased level of PRMT5) were enhanced in response to 10μM α-endosulfan after 24h exposure window. Moreover, overexpression of basal level of estrogen receptor alpha (ERα), suggests estrogenicity of α-endosulfan. In summary, our results shows modulatory impact of α-endosulfan on multiple cellular epigenetic regulators, known to possess oncogenic potential which might contribute to mechanistic insight of its action in future.
... A large variety of synthetic organic chemicals of different chemical classes has been released into the environment over the last few decades [1][2][3]. Among them, carbamate insecticides, widely used in agricultural and nonagricultural fields, attract widespread concern due to their high biological activity, reduced rate of degradation, and longterm environmental persistence and high biomagnification in the food chain [4,5]. Propoxur, a N-methylcarbamate ester (2-isopropoxyphenyl N-methylcarbamate), is a carbamate insecticide with a wide spectrum of applications. ...
... More importantly, it is also classified as a Group B2 probable human carcinogen by EPA [8]. Due to its estrogenmimicking ability, propoxur is still considered a prime etiological suspect of increasing tumor incidence [5,9], although a direct link has yet to be defined. Therefore, it is necessary to clarify the role of propoxur in the development of estrogen-related cancer, such as breast cancer, including cell proliferation, survival, invasion, metastasis, and angiogenesis. ...
Propoxur is considered a prime etiological suspect of increasing tumor incidence, but the role is still undefined. In this study, two human breast cancer cells lines, MCF-7 and MDA-MB-231 cells, were used as cell models. Cells were respectively treated with 0, 0.01, 1, or 100 μM propoxur. PD98059, a MEK inhibitor, was administered to block the ERK/MAPK pathway. Migration and reactive oxygen species were measured by wound healing and Transwell assays, and flow cytometry. Protein expression and subcellular location were detected by western blotting and immunofluorescence staining, respectively. Results showed that propoxur treatment enhanced cell migration and invasion in a dose-dependent manner, while MMP-2 expression, but not MMP-9, was significantly increased in two cell lines. Meanwhile, the treatment increased intracellular reactive oxygen species, Nrf2 expression and nuclear translocation, and ERK1/2 phosphorylation. Inversely, inhibition of ERK1/2 activation with PD98059 significantly attenuated propoxur-induced Nrf2 expression and nuclear translocation. Moreover, PD98059 suppressed propoxur-induced cell migration and invasion, and MMP-2 overexpression. Collectively, these results indicate that propoxur can trigger reactive oxygen species overproduction, further promoting breast cancer cell migration and invasion by regulating the ERK/Nrf2 signaling pathways.
... Endosulfan exposure was recently associated to higher risk of prostate cancer incidence in humans probably due to its mutagenic [61], anti-androgen, estrogen agonist and aromatase inducer activites [62]; endosulfan increase activating phosphorylation of EGFR type 2 and it increases activity of several oncogens like MAPK in prostate cancer cells [63]. Endosulfan with other xenoestrogens like lindane and propoxur, act as angiogenesis stimulator both in vitro as well as in vivo models but more molecular and biochemical studies are needed [64]. Another industrial chemical with estrogenic activity is nonylphenol (Figure2); considering its high hydrophobicity, nonyphenol accumulate in several matrices like soils, rivers, as well as, food and drinking water and it was found in human plasma, breast milk [65]. ...
This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.
... 5,6 Some XEs are known to promote tumor development in many tissues by stimulating inappropriate endocrine responses via ERs, promoting angiogenesis, increasing DNA adducts, or altering the epigenome. [7][8][9][10][11][12] Actions of XEs via ERs have also been shown to cause the proliferation of established endocrine tumors or tumor cell lines of many types, including those from brain, breast, kidney, lung, pancreas, prostate, and testis. [13][14][15][16][17][18][19][20] Alternatively, some XEs, especially dietary compounds, have been credited with preventing tumors in some of these tissues, [21][22][23][24] highlighting a broad range of XE response profiles. ...
Xenoestrogens (XEs) are exogenous mimics capable of binding to estrogen receptors (ERs), competing with/disrupting the actions of physiological estrogens, and promoting tumor growth in the prostate and other endocrine tissues. Humans are exposed to numerous XEs including environmental contaminants such as plastics monomer bisphenol A (BPA), and dietary phytoestrogens such as coumestrol and genistein from soy, and resveratrol, highest in red grapes. There is growing interest in the ability of phytoestrogens to prevent or treat tumors. We previously reported that multiple cellular mechanisms influence the number of prostate cancer cells after estradiol or diethylstilbestrol treatment. We now examine the effect of these XEs on signaling mechanisms that alter the number of LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cells at environment- and diet-relevant concentrations. Coumestrol and genistein both increased the number of LAPC-4 and PC-3 cells dramatically. Rapid alterations of phospho- and total-cyclin D1 levels most closely correlated with the XE-induced changes in cell numbers. Sustained activation (phosphorylation) of the extracellular signal-regulated kinases 1 and 2 as a prelude to generation of reactive oxygen species also partially contributed to the XE's effects on cell numbers. Early-stage cells expressed higher levels of all three ERs (including those in membranes) than did late-stage cells; ER subtypes were variably involved in the signaling responses. Taken together, these results show that each XE can elicit its own signature constellation of signaling responses, highlighting the importance of managing exposures to both environmental and dietary XEs for existing prostate tumors. These mechanisms may offer new cellular targets for therapy.
