Los contaminantes ambientales bifenilos policlorinados (PCB) y sus efectos sobre el Sistema Nervioso y la salud Translated title: The polychlorinated biphenyls (PCBS) environmental pollutants and their effects on the Nervous System and health

Abstract

La contaminación ambiental es un grave problema mundial que actualmente preocupa a la comunidad internacional. Las grandes ciudades industrializadas, como la de México, son las más contaminadas. Sin embargo, la contaminación llega hasta zonas alejadas de donde se produce y afecta los ecosistemas. La contaminación es responsable de una alarmante y creciente lista de enfermedades en el hombre, los animales y las plantas. Los bifenilos policlorados (PCB) se catalogaron dentro de los 12 contaminantes orgánicos más tóxicos para los organismos vivos. Sus propiedades físicas hicieron que se usaran ampliamente en la industria. No son biodegradables y se acumulan en el ambiente, se transfieren dentro de la cadena alimenticia y tienden a concentrarse más al final de ésta, por lo que en los alimentos se determinaron concentraciones que sobrepasaban los límites establecidos por el Organismo de Protección del Ambiente de los Estados Unidos. Se demostró que los PCB afectan la función de los sistemas endocrino, inmunológico y nervioso, entre otros. El mecanismo de acción descrito para los PCB, es por medio de la activación del receptor aril hidrocarburo, un factor de transcripción citosólico dependiente de ligando. Los PCB actúan como ligandos y son lipofílicos, por lo que entran a la célula y llegan al núcleo para unirse al ADN, lo cual altera la trascripción de genes específicos y provoca alteraciones genéticas que conducen a cambios en los procesos y funciones celulares. Los PCB interfieren con la producción y regulación de las hormonas esteroides y tiroideas al actuar como antagonistas o agonistas de los receptores hormonales. Afectan la función reproductora y alteran diferentes aspectos de la sexualidad. Como otros grupos de investigación, el nuestro ha observado que la administración de PCB a ratas gestantes causa un incremento de la mortalidad de las crías, pérdida fetal, peso corporal bajo y una reducción en el número de machos por camada. Los PCB actúan como inmunotoxinas que causan la atrofia del timo y afectan la respuesta inmune. Los PCB y sus metabolitos son carcinogénicos debido a la generación de especies reactivas de oxígeno que pueden producir daño oxidativo al ADN, provocar aberraciones cromosómicas y generar cáncer de mama, hígado, tracto biliar, gastrointestinal, cerebral, etc. Los organismos son más vulnerables a la exposición de los PCB durante las etapas tempranas del desarrollo embrionario. Los PCB atraviesan la placenta y llegan al feto, permanecen en la leche materna y mantienen niveles altos en las crías. Los PCB afectan así el desarrollo del Sistema Nervioso, los órganos y los tejidos, y pueden llevar a la pérdida fetal. También se asocian a deficiencias en el neurodesarrollo del niño y a alteraciones neuropsicológicas en la atención, el aprendizaje y el desarrollo psicomotor. La exposición aguda o crónica a los PCB se asocia con cefalea, insomnio, nerviosismo, irritabilidad, depresión y ansiedad. Los PCB participan en el proceso de neurodegeneración al afectar el sistema dopaminérgico. En el nivel neurofisiológico, afectan la transmisión sináptica excitatoria e inhibitoria hipocampal; inhiben la potenciación a largo plazo y la plasticidad sináptica; alteran mecanismos de señalización celular como el GABAérgico, en el aprendizaje y la memoria, y producen alteraciones cognoscitivas. Nuestro grupo demostró que la administración de los PCB durante la gestación inhibe la actividad de la enzima sintasa del óxido nítrico y provoca cambios neuronales morfológicos degenerativos en los núcleos paraventricular y supraóptico hipotalámicos. Las evidencias de los estudios realizados con los PCB son concluyentes en cuanto a que la exposición a estos tóxicos ambientales interfiere con el funcionamiento de diferentes órganos y sistemas y a que son un factor de riesgo para un amplio número de alteraciones neurodegenerativas. Actualmente, las poblaciones están expuestas a concentraciones que exceden los niveles límite tolerables recomendados por la Organización Mundial de la Salud. Nuestro grupo está analizando las alteraciones de estos contaminantes en el nivel neuroendocrino y en algunos aspectos del aprendizaje y la memoria. Dada la relevancia de los efectos de los PCB en la salud y de la falta en México de una valoración de los niveles de los PCB existentes en personas y alimentos, es importante que las instituciones de salud fomenten y apoyen las investigaciones en esta área.

Translated abstract

Environmental pollution is a world-wide issue which is a matter for concern among the international community. Great industrialized cities are the most polluted and Mexico City is among them. However, pollution affects places which are far away from contaminated urban areas, thus damaging eco-systems. Environmental pollution is responsible for an alarming and increasing list of illnesses in humans, animals and plants. This has generated an international interest in this problem. From the 187 chemical agents considered toxic for living organisms, the Inter-Government Committee for the Negotiation of Persistent Organic Pollutants (Pops) has catalogued 12 as the most hazardous for life. Among them are the so-called polychlorinated biphenyls (PCBs). PCBs are a family of 209 structurally chlorinated compounds made up of chlorine, carbon and hydrogen. These compounds are chemically and thermally stable, insoluble in water, non-flammable, electrically resistant, with low volatility at normal temperatures, and bio-degradable only at high temperatures (1200°C). One of their main disadvantages is that they are subject to a process of bioaccumulation where their concentration increases along the food chain. Their physical properties make them widely used in industry, mainly in the electrical and building areas. Not long after PCBs were manufactured, it was determined that food for human intake such as milk, fish and eggs, to mention just a few, presented higher PCBs concentrations than those allowed by the Organism for US Environmental Protection (0.0005mg/l). It has been demonstrated that PCBs can cause damage to the endocrine, immunologic and Nervous Systems, among others. The underlying mechanism of action of these compounds is through the activation of the aril hydrocarbon receptor (AhR), a ligand-dependent cytosolic transcription factor. PCBs act like ligands and, given their lipophilic properties, enter cells by passive diffusion. Two co-chaperone proteins are bound to AhR to form an oligomer which dissociates when binding to a PCB. After ligand binding, a heterodimer is formed which translocates into the nucleus and links to specific DNA regions; this in turn regulates the transcription velocity of specific genes and produces genetic alterations that modify processes and functions in the cell. PCBs belong in the group of chemicals considered endocrine disruptors. Damage caused by these compounds can be irreversible. In the endocrine system they interfere with the production and regulation of steroid and thyroid hormones, acting as agonists or antagonists of hormone receptors. They impair endocrine metabolic pathways, such as those of thyroid hormones (T3 and T4), and inhibit carrier proteins such as transthyretin. Contaminants that harm the endocrine system also affect the reproductive function and disrupt various aspects of sexuality. In males, PCBs inhibit the synthesis of testosterone, alter masculinity, reduce sperm motility and the capacity of binding and penetrating the ovule, induce changes in the shape of the penis as well as its size, retard or inhibit testicle descent, and can generate testicular cancer. In females, they can cause early menarche (first menstruation), enhanced duration of menstrual bleeding, urogenital malformations, endometriosis, spontaneous abortion, fetal death, premature delivery and low-weight in offspring. Our group, as well as other research groups, has encountered that PCB administration to gestating rats causes an increment in offspring mortality, fetal miscarriages, low bodily weight of the offspring and a reduction in the number of males per litter. The immunological system is sensitive to chemicals such as PCBs which originate an immunological response; they act as immunotoxins that cause thymus atrophy, affect innate immunity, compromise host resistance and immunity mediated by B and T cells, as well as humoral immunity. PCBs and their metabolites are carcinogenic and act as general cancer promoters by enhancing the effects of other substances through the generation of oxygen reactive compounds that can induce DNA oxidative damage. Chronic PCB exposure can cause chromosomal aberrations; these compounds have been related to all types of cancer: mammary gland, liver, biliary tract, gastrointestinal, skin (especially malignant melanomas), lung, pancreas and brain. There is evidence that organisms are more vulnerable to PCB exposure during the early embryonic stages. These compounds can cross the placenta and affect the fetus; when they are present in human milk they keep the offspring under high PCB levels thus altering development. In addition, they can contribute to the interruption of growth and development of brain, organs and tissues. As a result, malfunctions or miscarriage occur. PCBs are involved in the neurodegeneration process since they affect dopaminergic neurons in caudate nucleus, ventral tegmental area and substantia nigra. These compounds disrupt neuronal mechanisms such as vesicular transport and dopamine release which lead to cellular death similar to that described for diseases such as Parkinson's. Perinatal exposure to PCBs is associated with neurodevelopmental deficiencies of infants which consist of dysfunctions at the neuropsychological level such as in verbal learning (syllables, words and concepts), performance functions, changes in attention and psychomotor development. Acute or chronic exposure to PCBs is associated with cephalea, insomnia, nervousness, irritability, depression and anxiety; these symptoms in turn modify behavior. At the neurophysiological level, these contaminants impair excitatory and inhibitory synaptic transmission in the hippocampus, inhibit long-term potentiation and synaptic plasticity, alter some mechanisms of cell signaling (GABAergic pathway), and deteriorate learning and memory. Recently, these compounds have been related to cognitive alterations. Our group demonstrated that the administration of PCB-77 and Aroclor 1254 during gestation inhibits the enzymatic activity of nitric oxide synthase (NOS) in 10-day postnatal pups. These rats presented degenerative morphological neuronal changes such as shrinking, picnosis, loss of neurites, neuronal death and decrease in the number of nitrergic neurons in the paraventricular and supraoptic hypothalamic nuclei. We also reported that in these nuclei a decrease in immunoreactivity to vasopressin and neuronal NOS is observed. The evidence in PCB studies is conclusive. The exposure to these environmental toxins interferes with the functioning of various organs and systems such as the endocrine and Nervous Systems, not only in humans but also in animals. These contaminants pose a risk factor for a wide number of neurodegenerative alterations.