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Breast cancer is currently one of the most prevalent cancers worldwide. The mechanisms by which pesticides can increase breast cancer risk are multiple and complex. We have previously observed that two aryl hydrocarbon receptor (AhR) agonists ‒pesticides hexachlorobenzene (HCB) and chlorpyrifos (CPF)‒ act on tumor progression, stimulating cell migration and invasion in vitro and tumor growth in animal models. Elevated levels of hypoxia inducible factor-1α (HIF-1α) are found in malignant breast tumors, and HIF-1α is known to induce proangiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2), which are fundamental in breast cancer progression. In this work, we studied HCB (0.005, 0.05, 0.5 and 5 μM) and CPF (0.05, 0.5, 5 and 50 μM) action on the expression of these proangiogenic factors in triple negative breast cancer cells MDA-MB-231, as well as the effect of their conditioned medium (CM) on endothelial cells. Exposure to pesticides increased HIF-1α and VEGF protein expression in an AhR-dependent manner. In addition, HCB and CPF boosted NOS-2 and COX-2 content and VEGF secretion in MDA-MB-231 cells. The treatment of endothelial cells with CM from tumor cells exposed to pesticides increased cell proliferation, migration, and tubule formation, enhancing both tubule length and branching points. Of note, these effects were VEGF-dependent, as they were blocked in the presence of a VEGF receptor-2 (VEGFR-2) inhibitor. In sum, our results highlight the harmful impact of HCB and CPF in modulating the interaction between breast cancer and endothelial cells and promoting angiogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometriosis is the presence and growth of endometrial tissue outside of the uterus. Previous studies have suggested that endocrine disrupting chemicals such as organochlorine pesticides could be a risk factor for endometriosis. Hexachlorobenzene (HCB) is a weak ligand of the aryl hydrocarbon receptor (AhR) and promotes metalloproteinase and cyclooxygenase-2 (COX-2) expression, as well as, c-Src activation in human endometrial stromal cells (T-HESC) and in rat endometriosis model. Our aim was to evaluate the effect of HCB exposure on oestrogen receptor (ER) ɑ and β, progesterone receptor (PR) and aromatase expression, as well as, on cell migration and invasion in T-HESC and primary cultures of endometrial stromal cells from eutopic endometria of control subjects (ESC). Results show that HCB increases ERɑ and aromatase protein levels and reduces PR content in both T-HESC and ESC. However, the pesticide only increases ERβ expression in ESC, without changes in T-HESC. Moreover, cell migration and invasion are promoted by pesticide exposure involving the AhR, c-Src, COX-2 and ER pathways in T-HESC. HCB also triggers ERɑ activation via phosphorylation in Y537 through AhR/c-Src pathway. Our results provide experimental evidence that HCB induces alterations associated with endometriosis, suggesting that these mechanisms could contribute to pesticide exposure-induced endometriosis development., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common primary liver tumor. Hexachlorobenzene (HCB) is an endocrine disruptor and a liver tumor promoter. Deregulation of thyroid hormone (TH) homeostasis may play a significant role in early neoplastic transformation. The aim of this study was to evaluate the relation between TH metabolism and the regulation of cell growth in an in vivo and in vitro model. We examined the role of transforming growth factor-β1 (TGF-β1) on TH deiodinase expression and hepatocyte proliferation. An initiation (DEN)/promotion (HCB) tumor model from rat liver and HepG2 cells were used. We evaluated PCNA, p21, p27, SMAD2/3, TGF-β1, deiodinase 1 (D1), D3, protein expression levels; D1 and D3 mRNA expression; TH and TGF-β1, D1, D3, and GST-P protein levels in focal/non-focal areas. In vivo, HCB decreased triiodothyronine (T3) and D1 mRNA levels and increased thyroxine (T4) and D3 mRNA levels in liver from DEN+HCB vs. DEN group. HCB increased protein levels from D3, TGF-β1, and PCNA and decreased D1 in focal-areas. In vitro, HCB increased PCNA, pSMAD 2/3, and TGF-β1 protein levels and mRNA expression and decreased p21 and p27 protein levels. Exogenous T3 treatment prevent HCB induced molecular alterations related to hepatocyte proliferation whereas T4 did not have any effect. These effects were prevented by using a TGF-β1 receptor II inhibitor. Results suggest that alteration of TH homeostasis, through D1 function, play a key role in hepatocyte proliferation and that TGF-β1-SMAD pathway is involved in this process confirming their role in early neoplastic transformation in HCC.

Breast cancer is the most common cancer type in females worldwide. Environmental exposure to pesticides affecting hormonal homeostasis does not necessarily induce DNA mutations but may influence gene expression by disturbances in epigenetic regulation. Expression of long interspersed nuclear element-1 (LINE-1) has been associated with tumorigenesis in several cancers. In nearly all somatic cells, LINE-1 is silenced by DNA methylation in the 5́'UTR and reactivated during disease initiation and/or progression. Strong ligands of aryl hydrocarbon receptor (AhR) activate LINE-1 through the transforming growth factor-β1 (TGF-β1)/Smad pathway. Hexachlorobenzene (HCB) and chlorpyrifos (CPF), both weak AhR ligands, promote cell proliferation and migration in breast cancer cells, as well as tumor growth in rat models. In this context, our aim was to examine the effect of these pesticides on LINE-1 expression and ORF1p localization in the triple-negative breast cancer cell line MDA-MB-231 and the non-tumorigenic epithelial breast cell line NMuMG, and to evaluate the role of TGF-β1 and AhR pathways. Results show that 0.5 μM CPF and 0.005 μM HCB increased LINE-1 mRNA expression through Smad and AhR signaling in MDA-MB-231. In addition, the methylation of the first sites in 5́'UTR of LINE-1 was reduced by pesticide exposure, although the farther sites remained unaffected. Pesticides modulated ORF1p localization in MDA-MB-231: 0.005 μM HCB and 50 μM CPF increased nuclear translocation, while both induced cytoplasmic retention at 0.5 and 5 μM. Moreover, both stimulated double-strand breaks, enhancing H2AX phosphorylation, coincidentally with ORF1p nuclear localization. In NMuMG similar results were observed, since they heighten LINE-1 mRNA levels. CPF effect was through AhR and TGF-β1 signaling, whereas HCB action depends only of AhR. In addition, both pesticides increase ORF1p expression and nuclear localization. Our results provide experimental evidence that HCB and CPF exposure modify LINE-1 methylation levels and induce LINE-1 reactivation, suggesting that epigenetic mechanisms could contribute to pesticide-induced breast cancer progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hexachlorobenzene (HCB) is a dioxin-like compound widely distributed and is a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is a disease characterized by growth of endometrial tissue in ectopic sites. Our aim was to investigate the impact of HCB on the endocrine, invasion and inflammatory parameters in a rat endometriosis model surgically induced. Female rats were exposed to HCB (1, 10 and 100 mg/kg b.w.) during 30 days. Results showed that HCB increases endometriotic like-lesions (L) volume in a dose-dependent manner. In L, HCB10 increases microvessel density (immunohistochemistry) and the vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and AhR levels (Western Blot), while HCB1 enhances aromatase expression (Western Blot). In addition, in eutopic endometrium (EU), HCB10/HCB100 augments microvessel density, VEGF and MMP-9 expression, while HCB1/HCB10 increases tumor necrosis factor-α (TNF-α) content in peritoneal fluid (ELISA). Interestingly, both L and EU from HCB-treated rats exhibited higher estrogen receptor α (ERα) (immunohistochemistry) and metalloproteases (MMP)-2 and -9 levels (Western Blot), as well as lower progesterone receptor (PR) expression (immunohistochemistry) than in control rats. Environmentally relevant concentrations of HCB could contribute to abnormal changes associated with endometriosis progression and development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR-/- models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05μM HCB induced cell migration and TGF-β1 signaling, whereas 5μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5μM). Interestingly, AhR-/- mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds., (Copyright © 2017. Published by Elsevier Inc.)

Given the number of women affected by breast cancer, considerable interest has been raised in understanding the relationships between environmental chemicals and disease onset. Hexachlorobenzene (HCB) is a dioxin-like compound that is widely distributed in the environment and is a weak ligand of the aryl hydrocarbon receptor (AhR). We previously demonstrated that HCB acts as an endocrine disruptor capable of stimulating cell proliferation, migration, invasion, and metastasis in different breast cancer models. In addition, increasing evidence indicates that transforming growth factor-β1 (TGF-β1) can contribute to tumor maintenance and progression. In this context, this work investigated the effect of HCB (0.005, 0.05, 0.5, and 5μM) on TGF-β1 signaling and AhR/TGF-β1 crosstalk in the human breast cancer cell line MDA-MB-231 and analyzed whether TGF-β1 pathways are involved in HCB-induced cell migration and invasion. RT-qPCR results indicated that HCB reduces AhR mRNA expression through TGF-β1 signaling but enhances TGF-β1 mRNA levels involving AhR signaling. Western blot analysis demonstrated that HCB could increase TGF-β1 protein levels and activation, as well as Smad3, JNK, and p38 phosphorylation. In addition, low and high doses of HCB were determined to exert differential effects on AhR protein levels, localization, and activation, with a high dose (5μM) inducing AhR nuclear translocation and AhR-dependent CYP1A1 expression. These findings also revealed that c-Src and AhR are involved in HCB-mediated activation of Smad3. HCB enhances cell migration (scratch motility assay) and invasion (Transwell assay) through the Smad, JNK, and p38 pathways, while ERK1/2 is only involved in HCB-induced cell migration. These results demonstrate that HCB modulates the crosstalk between AhR and TGF-β1 and consequently exacerbates a pro-migratory phenotype in MDA-MB-231 cells, which contributes to a high degree of malignancy. Taken together, our findings help to characterize the molecular mechanism underlying the effects of HCB on breast cancer progression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hexachlorobenzene (HCB) is an organochlorine pesticide that induces toxic reproductive effects in laboratory animals. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is characterized by the presence of functional endometrial tissues outside the uterine cavity. Experimental studies indicate that exposure to organochlorines can interfere with both hormonal regulation and immune function to promote endometriosis. Altered expression of metalloproteinases (MMPs) in patients with endometriosis, suggests that MMPs may play a critical role. In the endometriotic lesions, prostaglandin E2 (PGE2) produced by cyclooxygenase-2 (COX-2), binds to its EP4 receptor (EP4), and via c-Src kinase induces MMPs activation, promoting endometriosis. We examined the HCB action on MMP-2 and MMP-9 activities and expression, COX-2 levels, PGE2 signaling, and the AhR involvement in HCB-induced effects. We have used different in vitro models: (1) human endometrial stromal cell line T-HESC, (2) primary cultures of Human Uterine Fibroblast (HUF), and (3) primary cultures of endometrial stromal cells from eutopic endometrium of control (CESC) and subjects with endometriosis (EESC). Our results show that HCB enhances MMP-2 and MMP-9 activities in T-HESC, HUF and ESC cells. The MMP-9 levels were elevated in all models, while the MMP-2 expression only increased in ESC cells. HCB enhanced COX-2 and EP4 expression, PGE2 secretion and the c-Src kinase activation in T-HESC. Besides, we observed that AhR is implicated in these HCB-induced effects. In conclusion, our results show that HCB exposure could contribute to endometriosis development, affecting inflammation and invasion parameters of human endometrial cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6 weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1 month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Exposure to environmental pollutants may alter proangiogenic ability and promotes tumor growth. Hexachlorobenzene (HCB) is an organochlorine pesticide found in maternal milk and in lipid foods, and a weak ligand of the aryl hydrocarbon receptor (AhR). HCB induces migration and invasion in human breast cancer cells, as well as tumor growth and metastasis in vivo. In this study, we examined HCB action on angiogenesis in mammary carcinogenesis. HCB stimulates angiogenesis and increases vascular endothelial growth factor (VEGF) expression in a xenograft model with the human breast cancer cell line MDA-MB-231. Human microvascular endothelial cells HMEC-1 exposed to HCB (0.005, 0.05, 0.5 and 5μM) showed an increase in cyclooxygenase-2 (COX-2) and VEGF protein expression involving AhR. In addition, we found that HCB enhances VEGF-Receptor 2 (VEGFR2) expression, and activates its downstream pathways p38 and ERK1/2. HCB induces cell migration and neovasculogenesis in a dose-dependent manner. Cells pretreatment with AhR, COX-2 and VEGFR2 selective inhibitors, suppressed these effects. In conclusion, our results show that HCB promotes angiogenesis in vivo and in vitro. HCB-induced cell migration and tubulogenesis are mediated by AhR, COX-2 and VEGFR2 in HMEC-1. These findings may help to understand the association among HCB exposure, angiogenesis and mammary carcinogenesis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

It is well known the participation of oxidative stress in the induction and development of different pathologies including cancer, diabetes, neurodegeneration and respiratory disorders among others. It has been reported that oxidative stress may be induced by pesticides and it could be the cause of health alteration mediated by pollutants exposure. Large number of registered products containing chlorpyrifos (CPF) is used to control pest worldwide. We have previously reported that 50 μM CPF induces ROS generation and produces cell cycle arrest followed by cell death. The present investigation was designed to identify the pathway involved in CPF-inhibited cell proliferation in MCF-7 and MDA-MB-231 breast cancer cell lines. In addition, we determined if CPF-induced oxidative stress is related to alterations in antioxidant defense system. Finally we studied the molecular mechanisms underlying in the cell proliferation inhibition produced by the pesticide. In this study we demonstrate that CPF (50 μM) induces redox imbalance altering the antioxidant defense system in breast cancer cells. Furthermore, we found that the main mechanism involved in the inhibition of cell proliferation induced by CPF is an increment of p-ERK1/2 levels mediated by H2O2 in breast cancer cells. As PD98059 could not abolish the increment of ROS induced by CPF, we concluded that ERK1/2 phosphorylation is subsequent to ROS production induced by CPF but not the inverse., (Published by Elsevier Ltd.)

It has reported that many environmental compounds may display estrogenic actions and these findings led to researchers to associate breast cancer risk with the use of some pesticides. The aim of this work was to investigate the effect of chlorpyrifos (CPF) on cell proliferation and the ERα-dependence of this action employing MCF-7 and MDA-MB-231 breast cancer cell lines. We have also analyzed CPF action on the cell cycle distribution and the cyclins that are implicated in G1-S and intra-S checkpoints. Finally, the action on cell death and ROS production were studied. We demonstrated the ability of CPF 0.05μM to induce cell proliferation through ERα in hormone-dependent breast cancer cells. In contrast, CPF 50μM induces intra-S arrest modifying checkpoints proteins, through a mechanism that may involve changes in redox balance in MCF-7. In MDA-MB-231, we have found that CPF 50μM produces an arrest in G2/M phase which could be related to the capacity of the pesticide for binding to tubulin sites altering microtubules polymerization. Altogether, our results provide new evidences on the action of the pesticide CPF as an environmental breast cancer risk factor due to the effects that causes on the mechanisms that modulate breast cell proliferation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Anti-Hu and anti-Yo are the most well-known anti-neuronal antibodies. The anti-Ri antibodies, which are less common, are generally found in subjects with opsoclonus-myoclonus, often associated with breast cancer., Case Report: A 54-year-old woman presented anti-Ri antibodies associated with a paraneoplastic syndrome and unusual symptoms of ophthalmoplegia, blepharospasm, palilalia and ataxia. Adenocarcinoma of the breast was also found. After chemotherapy, radiotherapy, and several immunoglobulin infusions, the patient did not improve ten months after tumor surgery., Conclusion: Anti-Ri antibodies associated with paraneoplastic syndrome can be observed in patients who develop a rapidly progressive brainstem tumor. Breast or lung cancer and conduct to search a breast or pulmonary cancer.

Fifteen patients experiencing a flare-up of multiple sclerosis were given 1 g methylprednosolone per day for 5 days. The EDSS score and gait analysis using spatio-temporal variables were recorded for these patients on days 0, 5 and 45. Both methods evidenced significant improvement but the significance was observed between day 0 and day 5 for the EDSS and between day 5 and 45 for gait speed and between day 0 and 45 for step rate. Gait speed was correlated with the pyramidal scale but not with the other functional scales of the EDSS. These results suggest that EDSS and spatio-temporal gait analysis are different tools for the assessment of therapeutic effect. Gait analysis can provide a precise quantitative assessment of the locomotor handicap as a function of the proposed treatment.

We report the naming performances of a 25 year-old woman with a left internal and inferior temporal lesion caused by herpes encephalitis who showed a preferential impairment for naming man-made objects. Evidence for category-specific effect was provided by a stepwise logistic regression using 171 pictures characterized by several parameters (words frequency, diversity of responses, length, name agreement, majoritary response, familiarity, visual complexity and canonicity). Analyses were realized over a 5 month period. Methodological considerations, anatomic correlations and arguments suggesting lexical access or semantic storage disturbance are discussed.

Palinopsia and motor partial seizures were associated in a 51-year-old man. The manifestation appeared six months after a right parietal hemorrhage. The relationship between the hallucinatory phenomena and epilepsy is discussed.

We report one case of acute cervical spinal cord infarction characterized by motor impairment of the upper limbs with respect of the lower limbs. It occurs infrequently. The purpose of this paper is to discuss the clinical, neurophysiological and magnetic resonance imaging findings, and to review the presumed mechanisms of spinal cord infarction.