El hexaclorobenceno como factor de riesgo en el cáncer de mama / Hexachlorobenzene as a risk factor in breast cancer

Hexachlorobenzene (HCB) is a widespread environmental pollutant and an endocrine disruptor. Chronic exposure of humans to HCB elicits porphyria, neurologic symptoms, immune disorders and thyroid dysfunctions. It is a dioxin-like compound and a weak ligand of the AhR (aryl hydrocarbon receptor), a transcription factor that modulates genes related to detoxification, proliferation, migration and invasion. This study was carried out to revise the results of HCB action on mammary gland and breast cancer, summarizing the main ideas of its mechanism of action. HCB increases tumor development and active c-Src/EGFR (epidermal growth factor receptor) signaling pathways, while reducing tyrosine537-ER-alpha (estrogen receptor-alpha) phosphorylation, and promoting a phenotype with enhanced malignancy and lung metastasis in different animal models. In a rat mammary gland, HCB promotes an estrogenic microenvironment by activation of ER-alpha and Insulin/IGFs (insulin growth factors) pathways. HCB induces cell proliferation, promoting cell cycle progression and enhancing cyclin D1 expression and c-Src/p27 interaction in (ER-alpha) MCF-7 human breast cancer cell line. In (ER-alpha)(-) MDA-MB-231 breast cancer cells, the pesticide enhances cell migration and invasion as well as metalloproteases and TGF-beta1 (transformig growth factor-beta1) expression. In conclusion our current study suggests that alterations in the estrogenic microenvironment may influence the biological behavior of mammary gland or breast tumors, leading to preneoplastic lesions or enhanced malignancy, respectively. Our findings suggest that HCB may be a risk factor for human breast cancer progression.

El hexaclorobenceno (HCB) es un contaminante ambiental ampliamente distribuido y un desorganizador endocrino. Su exposición crónica en seres humanos produce porfiria, síntomas neurológicos, trastornos inmunitarios y disfunciones tiroideas. Es un agonista débil del receptor de hidrocarburos aromáticos (AhR), un factor de transcripción que modula genes relacionados con el metabolismo de xenobióticos, la proliferación, la migración y la invasión. Nuestro objetivo es revisar los efectos del HCB en la glándula mamaria y el cáncer mamario, resumiendo los principales mecanismos de acción. El HCB aumenta el desarrollo tumoral y activa vías de señalización de c-Src/receptor del factor de crecimiento epidérmico (EGFR), mientras que disminuye la fosforilación de tirosina 537/receptor de estrógenos alfa (RE-alfa), promoviendo un fenotipo de mayor malignidad y metástasis pulmonar en diferentes modelos con animales. En la glándula mamaria de rata genera un microambiente estrogénico por activación del RE-alfa y las vías de insulina/factores de crecimiento similares a la insulina (IGF). En células de cáncer mamario humanas MCF-7 (RE-alfa) induce proliferación celular, promoviendo la progresión del ciclo, aumentando la ciclina D1 y la interacción p27/c-Src. En MDA-MB-231 (-RE-alfa) estimula la migración e invasión, así como la expresión de metaloproteasas y factor de crecimiento transformante beta 1 (TGF-beta 1). Estos estudios indican que las alteraciones en el microambiente estrogénico podrían influir el comportamiento biológico de la glándula mamaria y los tumores, lo que provoca lesiones preneoplásicas o aumento en la malignidad tumoral mamaria. Nuestros hallazgos sugieren que el HCB podría ser un factor de riesgo para la progresión del cáncer de mama humano.

El organofosforado clorpirifos como disruptor estrogénico y factor de riesgo para el cáncer de mama / The organophosphorus chlorpyrifos as endocrine disruptor and breast cancer factor risk

El clorpirifos (CPF) es un insecticida de amplio espectro que se utiliza en Argentina y en otros países de Latinoamérica. Se emplea para el control de plagas en la producción de frutas, hortalizas, cereales y plantas ornamentales. El principal mecanismo de acción descripto para este insecticida es la inhibición de la acetilcolinesterasa. Sin embargo, reportes más recientes sugieren múltiples efectos del plaguicida independientes de la inhibición de esa enzima. El objetivo de este trabajo es transmitir a la comunidad los resultados de nuestras investigaciones obtenidos utilizando diferentes dosis de CPF en distintos modelos experimentales, tanto in vitro como in vivo. En relación a esto, hemos evidenciado una acción del CPF sobre el sistema redox celular que conduce al incremento de especies reactivas del oxígeno y consecuentemente a la activación de diferentes vías de señalización. Además, hemos determinado que el insecticida CPF puede comportarse como un disruptor endócrino modulando la acción de los estrógenos y alterando la normal estructura del tejido mamario. Nuestros resultados alertan sobre el impacto que este compuesto podría tener sobre la salud, sugiriendo la necesidad de revisar su uso dado que manifiesta acciones a dosis encontradas en el ambiente.

Chlorpyrifos (CPF) is a broad spectrum insecticide used in Argentina and other Latin American countries. It is commonly used for pest control in the production of fruits, vegetables, cereals and ornamental plants. The main mechanism of action described for this insecticide is the inhibition of acetylcholinesterase activity. However, more recent reports suggest multiple effects for this pesticide in an independent way from the inhibition of this enzyme. The objective of this work is to convey to the community the results of our investigations obtained using different doses of CPF in various experimental models, both in vitro and in vivo. In this connection, we have shown a CPF action on the cellular redox system which leads to increased reactive oxygen species and the consequent activation of different signaling pathways. In addition, we have determined that the insecticide CPF acts as an endocrine disruptor modulating the action of estrogen and altering the normal structure of breast tissue. Our findings warn about the impact that this compound might have on health, suggesting the need to review its use since adverse actions were found at environmentally relevant doses.

Mitochondrial apoptotic pathways

Apoptosis or programmed cell death (PCD) is a physiological process characteristic of pluricellular organisms leading to self-destruction of the cell. It is therefore involved in development, homeostasis and host defense. However, a significant difference has been shown between mammalian cell apoptosis and non-mammalian cell apoptosis: mitochondria are implicated only in the former. Execution of PCD includes the release of several proapoptotic proteins from the intermembrane space of mitochondria. They could exert their actions through a caspase dependent as well as a caspase independent way. On the other hand, regulation of PCD is mainly given by the Bcl-2 family members, which are in turn essentially regulated by activation of death receptors and/or DNA damage. Nowadays, execution of apoptosis is better known than its regulation. Nevertheless, we are still far of a complete understanding of the apoptotic process

Intravascular brachytherapy: a model for the calculation of the dose

In this study we present the radiation dose distribution for a theoretical model with Montecarlo simulation, and based on an experimental model developed for the study of the prevention of restenosis post-angioplasty employing intravascular brachytherapy. In the experimental in vivo model, the atherosclerotic plaques were induced in femoral arteries of male New Zealand rabbits through surgical intervention and later administration of cholesterol enriched diet. For the intravascular irradiation we employed a 32P source contained within the balloon used for the angioplasty. The radiation dose distributions were calculated using the Monte Carlo code MCNP4B according to a segment of a simulated artery. We studied the radiation dose distribution in the axial and radial directions for different thickness of the atherosclerotic plaques. The results will be correlated with the biologic effects observed by means of histological analysis of the irradiated arteries