Influencia de contaminantes ambientales en la gestación humana: causante de patologías en el adulto / Influence of environmental pollutants on human gestation: cause of adult pathologies

Resumen: En el presente articulo se revisan los mecanismos del imprinting epigenético mediante el cual se producen los efectos diferidos generados por la exposición prenatal o infantil temprana a agentes químicos contaminantes. Se revisaron las bases de datos Pubmed y Embase para identificar estudios publicados entre 2005 y 2018, junto a artículos considerados pioneros en este ámbito. Se incluyeron además, datos generados en nuestro Laboratorio. Como fuente de información secundaria se citan normas chilenas de concentraciones de algunos contaminantes en agua potable publicados por el Ministerio de Salud de Chile. Se describen cambios en la metilación de diversos genes causados por exposición prenatal o infantil temprana a algunos contaminantes ambientales relevantes en Chile: arsénico, plomo, ftalatos y fenoles, y se mencionan algunas de las enfermedades orgánicas y cambios neuroconductuales que se desarrollan más tarde en la vida como consecuencia de dichas exposi ciones. Se sugiere que un mayor conocimiento de los factores ambientales y una mejor educación de la población, permitirían una protección más adecuada de embarazadas y lactantes, en especial durante las ventanas de susceptibilidad y que los pediatras y obstetras, serían los profesionales mejor indicados para desarrollar estas acciones. Se sugiere además la necesidad de adecuar normas am bientales y aumentar la fiscalización de contaminantes y sus fuentes, para prevenir el deterioro de la salud de las futuras generaciones.

Abstract: This review explains the epigenetic imprinting mechanisms by which the delayed effects generated by prenatal or early childhood exposure to chemical pollutants are produced. Pubmed and Embase databases were reviewed to identify studies published between 2005 and 2018, along with articles considered pioneers in this field. We also included data generated in our Laboratory. As a source of secondary information, Chilean standards on concentrations of some pollutants in drinking water published by the Ministry of Health of Chile are cited. Changes are described in the methylation of diverse genes caused by prenatal or early childhood exposure to some relevant environmental po llutants in Chile such as arsenic, lead, phenols, and phthalates, and some of the organic diseases and neurobehavioral changes that occur later in life as a consequence of these exposures are mentioned. We suggest that a wider knowledge of environmental factors and better education of the population would allow a more adequate protection of pregnant women and infants especially during the win dows of susceptibility, and that pediatricians and obstetricians would be in the best position to deve lop these actions. We also suggest the need to adapt environmental standards and increase the control of pollutants and their sources to prevent health deterioration of future generations.

Geologic and anthropogenic sources of contamination in settled dust of a historic mining port city in northern Chile: health risk implications.

Chile is the leading producer of copper worldwide and its richest mineral deposits are found in the Antofagasta Region of northern Chile. Mining activities have significantly increased income and employment in the region; however, there has been little assessment of the resulting environmental impacts to residents. The port of Antofagasta, located 1,430 km north of Santiago, the capital of Chile, functioned as mineral stockpile until 1998 and has served as a copper concentrate stockpile since 2014. Samples were collected in 2014 and 2016 that show elevated concentrations of As, Cu, Pb, and Zn in street dust and in residents' blood (Pb) and urine (As) samples. To interpret and analyze the spatial variability and likely sources of contamination, existent data of basement rocks and soil geochemistry in the city as well as public-domain airborne dust were studied. Additionally, a bioaccessibility assay of airborne dust was conducted and the chemical daily intake and hazard index were calculated to provide a preliminary health risk assessment in the vicinity of the port. The main conclusions indicate that the concentrations of Ba, Co, Cr, Mn, Ni, and V recorded from Antofagasta dust likely originate from intrusive, volcanic, metamorphic rocks, dikes, or soil within the city. However, the elevated concentrations of As, Cd, Cu, Mo, Pb, and Zn do not originate from these geologic outcrops, and are thus considered anthropogenic contaminants. The average concentrations of As, Cu, and Zn are possibly the highest in recorded street dust worldwide at 239, 10,821, and 11,869 mg kg-1, respectively. Furthermore, the contaminants As, Pb, and Cu exhibit the highest bioaccessibilities and preliminary health risk indices show that As and Cu contribute to elevated health risks in exposed children and adults chronically exposed to dust in Antofagasta, whereas Pb is considered harmful at any concentration. Therefore, an increased environmental awareness and greater protective measures are necessary in Antofagasta and possibly other similar mining port cities in developing countries.

[Influence of environmental pollutants on human gestation: Cause of adult pathologies]. / Influencia de contaminantes ambientales en la gestación humana: Causante de patologías en el adulto.

This review explains the epigenetic imprinting mechanisms by which the delayed effects generated by prenatal or early childhood exposure to chemical pollutants are produced. Pubmed and Embase databases were reviewed to identify studies published between 2005 and 2018, along with articles considered pioneers in this field. We also included data generated in our Laboratory. As a source of secondary information, Chilean standards on concentrations of some pollutants in drinking water published by the Ministry of Health of Chile are cited. Changes are described in the methylation of diverse genes caused by prenatal or early childhood exposure to some relevant environmental po llutants in Chile such as arsenic, lead, phenols, and phthalates, and some of the organic diseases and neurobehavioral changes that occur later in life as a consequence of these exposures are mentioned. We suggest that a wider knowledge of environmental factors and better education of the population would allow a more adequate protection of pregnant women and infants especially during the win dows of susceptibility, and that pediatricians and obstetricians would be in the best position to deve lop these actions. We also suggest the need to adapt environmental standards and increase the control of pollutants and their sources to prevent health deterioration of future generations.

[The impact of tap water fluoridation on human health]. / Consecuencias de la fluoración del agua potable en la salud humana.

The purpose of this review is to describe the osteological, neurological, endocrine and dermatological effects of fluoride ingestion. Additional aims are to evaluate whether the Chilean tap water fluoridation program has had any impact on dental health, and analyze the basis for the Chilean elementary school milk fluoridation program, which is targeted at children living in places where tap water has a fluoride concentration less than 0.3 mg/L, without any artificial fluoridation process. We discuss the finding that both public measures have no direct or remarkable effect on dental health, since topical dental hygiene products are the main and most effective contributors to the prevention of dental decay. We also suggest that the permanent and systematic ingestion of fluorides imposes health risks on the population. Therefore, we recommend reevaluating the national fluoridation program for public tap water and the elementary school milk program.

Consecuencias de la fluoración del agua potable en la salud humana / The impact of tap water fluoridation on human health

The purpose of this review is to describe the osteological, neurological, endocrine and dermatological effects of fluoride ingestion. Additional aims are to evaluate whether the Chilean tap water fluoridation program has had any impact on dental health, and analyze the basis for the Chilean elementary school milk fluoridation program, which is targeted at children living in places where tap water has a fluoride concentration less than 0.3 mg/L, without any artificial fluoridation process. We discuss the finding that both public measures have no direct or remarkable effect on dental health, since topical dental hygiene products are the main and most effective contributors to the prevention of dental decay. We also suggest that the permanent and systematic ingestion of fluorides imposes health risks on the population. Therefore, we recommend reevaluating the national fluoridation program for public tap water and the elementary school milk program.

Equol and daidzein decrease migration, invasion and matrix metalloproteinase (MMPs) gene expression in prostate cancer cell lines, DU-145 and PC-3 / Equol y daidzeina disminuyen la migración, invasión y la expresión génica de metaloproteinasa de la matriz(MMPs) en las líneas celulares prostáticas cancerosas DU-145 y PC-3

This search is focused on the study of diet compounds that may have any potential chemopreventive effect against cancer. Some compounds that fulfill this requirement are phytoestrogens. Among them we find genistein (1), the most studied, daidzein (2) and equol (3) (figure 1). To compare the sensitivities of different prostate cancer cells to phytoestrogen treatment, sulphorhodamine B dye assay was performed to determine cell viability. DU-145 and PC-3 prostate cancer cell lines treated with various doses of phytoestrogen (0-12.5-25-50 and 100 μM) for different times (24, 48 and 72h). For cell invasion or migration assay cells were seeded in a Transwell chamber with or without coating Matrigel respectively. DU-145 and PC-3 cells were treated previously with phytoestrogen (50 μM) for 24h. The study showed that equol, daidzein and genistein inhibited migration and invasion in prostate cancer cell lines. Moreover, we analyzed the effects of phytoestrogens in MMP-2 and MMP-9 mRNA expression by RT-PCR. The results indicated that equol, daidzein and genistein diminished the expression of MMP-2 and MMP-9 in a cell-dependent manner. Our data suggested that equol, daidzein and genistein inhibited migration and invasion in prostate cancer cell lines. Moreover, the results also suggest that down-regulation of MMP-2 and MMP- 9 might be involved in the inhibition of invasion of PC-3 and DU-145 cells after genistein, daidzein and equol treatment.

Este trabajo se centra en el estudio de los compuestos de dieta que pueden tener potencial efecto quimiopreventivo contra el cáncer. Algunos de estos compuestos son los fitoestrógenos. Entre ellos encontramos la genisteína (1), el más estudiado, la daidzeína (2) y el equol (3) (figura 1). Para comparar el efecto de estos fitoestrogenos sobre las líneas celulares de cáncer de próstata, DU-145 y PC-3, se utilizó el ensayo de sulforodamina B para determinar la viabilidad celular tras los tratamientos con diferentes concentraciones de fitoestrógenos (0-12.5-25-50-100 μM) durante diferentes tiempos (24, 48, 72 h). Para analizar el efecto sobre la migración celular, las células DU-145 y PC-3 fueron tratadas previamente con una concentración de fitoestrógrno (50 μM) durante 24 horas y sembradas en una cámara Transwell sin recubrir. El estudio mostró que el equol, daidzeína y genisteína inhibió en MMP-2 y MMP-9 expresiones de genes en líneas celulares de cáncer de próstata, la PC-3 y DU-145. Los resultados indicaron que la daidzeína disminuyó la expresión de MMP- 2 y MMP-9 en DU-145 células. Nuestros datos sugieren que equol, daidzeína y genisteína inhiben la migración y la invasión de líneas celulares de cáncer de próstata.

Propuesta de políticas públicas que relacionen el ambiente como determinante del estado de salud poblacional e individual: resumen ejecutivo de propuestas para los candidatos a la presidencia de la república y al parlamento / Public politics proposal considering environment as population and individual health determinant executive summary of proposals to the candidates to the republic presidency and parliament

El Departamento de Medio Ambiente del Colegio Médico de Chile ha concordado una serie de medidas que a su juicio deben ser implementadas por las nuevas autoridades políticas de Chile elegidas, con el fi n de corregir aquellos problemas ambientales que son determinantes de salud poblacional e individual. La implementación de estas medidas deberá impactar positivamente en la salud y calidad de vida de los habitantes de Chile, disminuir la mortalidad aguda y o diferida causada por exposición a diversos contaminantes ambientales. En especial, deberá afectar positivamente a las futuras generaciones al disminuir la exposición prenatal o infantil temprana a agentes que determinan el desarrollo de enfermedades o cambios conductuales más tarde en la vida. Estas proposiciones fueron entregadas a todos los candidatos presidenciales y explicadas en reuniones con cada uno de los 4 candidatos presidenciales que tienen las mejores opciones de de ser electos, de acuerdo a encuestas realizadas en el país.

The Environment Department of the Colegio Médico de Chile (Chilean College of Physicians) agreed a series of measures that should be implemented by the new elected Chilean political authorities, with the purpose of correction the environmental problems which are population and individual health determinants. The implementation of these measures should positively impact Chilean population health and quality of life and decrease acute or delayed mortality caused by exposure to various pollutants. Especially, it should positively affect future generations preventing prenatal or infant exposure to agents determining the development of diseases or behavioural changes later in life. These proposals were delivered to all presidential candidates, and explained in meetings with each of the four presidential candidates with the best perspectives to be elected, according to opinion polls carried out in the country.

Daidzein-estrogen interaction in the rat uterus and its effect on human breast cancer cell growth.

Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17ß (E(2); subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 µg/mL) or E(2) on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast.

Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study / Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction.Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective.This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

Introducción. El levonorgestrel, un progestágeno sintético usado para endometriosis, dismenorrea y anticoncepción de emergencia, es rápida y completamente absorbido en el tubo digestivo. Su metabolismo es principalmente hepático, mediante las enzimas CYP3A4 y CYP3A5. Objetivo. El presente estudio tuvo como objetivo evaluar la asociación entre la farmacocinética de levonorgestrel y las variantes alélicas de CYP3A4*1B y CYP3A5*3. Materiales y métodos. En un grupo de 17 mujeres adultas sanas, que firmaron un consentimiento informado, se practicó genotipificación para CYP3A4*1B y CYP3A5*3 mediante PCR. Posteriormente, las voluntarias fueron sometidas a un estudio farmacocinético donde, luego de 12 horas de ayuno, recibieron una dosis de 0,75 mg de levonorgestrel. Se extrajeron muestras sanguíneas seriadas (0 a 24 horas) y se determinaron las concentraciones de levonorgestrel mediante un método validado de UPLC-ms/ms, para luego obtener los parámetros farmacocinéticos. Todos los procedimientos consideraron los aspectos éticos de la Declaración de Helsinki y las buenas prácticas clínicas. Resultados. Las frecuencias genotípicas observadas para el grupo de estudio fueron 11,8 % para *1B/*1B; 5,8 % para *1/*1B, y 82,4 % para *1/*1 de CYP3A4*1B. Para CYP3A5*3, las frecuencias genotípicas fueron 70,5 % para *3/*3; 23,5 % para *1/*3, y 6,5 % para *1/*1. Se observa una interesante variabilidad entre las voluntarias que sugiere una relación con las variantes genéticas CYP3A, pero que no permite establecer una asociación estadísticamente significativa, presumiblemente debido al bajo número de individuos homocigotos mutados de CYP3A4 y silvestres de CYP3A5. Conclusiones. Los polimorfismos genéticos podrían ser factores relevantes en la determinación de la variabilidad entre pacientes en las concentraciones plasmáticas de levonorgestrel, lo cual, sin embargo, no pudo ser establecido estadísticamente en este estudio. Por lo tanto, resulta necesario continuar este tipo de estudios con mayor número de voluntarios para establecer una asociación entre la variabilidad observada y la presencia de estos polimorfismos.

[Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study]. / Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto.

INTRODUCTION: Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). OBJECTIVE: This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. MATERIALS AND METHODS: A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. RESULTS: Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. CONCLUSIONS: Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

Efectos sobre la salud y el medio ambiente de las actividades mineras en Chile: contaminación del Estero Pupío y agua potable del pueblo de Caimanes: ¿se origina desde el tranque de relaves mineros El Mauro? / Health and environmental effects of mining activities in Chile: Pupio River and Ddinking water pollution in the town of Caimanes: does it originate from the El Mauro mining tail?

Se describe la presencia de concentraciones elevadas de mercurio en el agua potable del pueblo de Caimanes y la presencia de concentraciones muy elevadas de manganeso, mercurio, hierro, níquel y molibdeno en el estero Pupío. La evidencia sugiere que estos niveles elevados de elementos tóxicos provienen de filtraciones del tranque de relaves El Mauro en la IV Región de Chile. Se describen los efectos diferidos de la exposición crónica y prenatal a estos elementos tóxicos.

The presence of high amounts of mercury in drinking water in the town of Caimanes and presence of very high concentrations of manganese, mercury, iron, nickel and molybdenum in the Pupio river is reported. Evidence suggests that these increased concentrations of toxic elements result from the El Mauro mining tail filtrations in the IV Region of Chile. The delayed effects of chronic and prenatal exposure to these toxic agents are described.

Genistein selectively inhibits estrogen-induced cell proliferation and other responses to hormone stimulation in the prepubertal rat uterus.

Sex hormone replacement therapy helps improve quality of life in climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk for cancer in these organs. The lower incidence of mammary cancer in Asian women than in western women has been attributed to high intake of soy isoflavones, including genistein. Our previous work in the prepubertal rat uterus model showed that genistein (0.5 mg/kg body weight subcutaneously) caused an estradiol-like hypertrophy in myometrial and uterine luminal epithelial cells and an increase in RNA content in luminal epithelium; however, it did not induce cell proliferation, uterine eosinophilia, or endometrial edema. The present study investigated, in the same animal model, the effect of genistein administration (0.5 mg/kg body weight subcutaneously) before treatment with estradiol-17ß (0.33 mg/kg body weight subcutaneously) on uterine responses that were not induced by genistein. Pretreatment with this phytoestrogen completely inhibited estradiol-induced mitoses in uterine luminal epithelium, endometrial stroma, and myometrium and partially inhibited estradiol-induced uterine eosinophilia and endometrial edema. These findings indicate that genistein protects against estrogen-induced cell proliferation in the uterus and suggest that future studies should investigate the possibility of using this agent to decrease the risk for uterine cancer after hormone replacement therapy in climacteric women.

Effect of prenatal exposure to lead on estrogen action in the prepubertal rat uterus.

Lead is a widely spread environmental pollutant known to affect both male and female reproductive systems in humans and experimental animals and causes infertility and other adverse effects. The present paper investigated the effects of prenatal exposure to lead on different parameters of estrogen stimulation in the uterus of the prepubertal rat. In prenatally and perinatally exposed rats, estrogen-induced endometrial eosinophilia, endometrial stroma edema, and eosinophil migration towards the endometrium, and uterine luminal epithelial hypertrophy are enhanced while several other responses to estrogen appear unchanged. These effects may contribute to decrease in fertility following prenatal exposure to lead. The striking difference between most of these effects of prenatal exposure and the previously reported effects of chronic exposure to lead suggests that prenatal exposure to lead may neutralize the effects of chronic exposure to lead, providing partial protection of cell function against the adverse effects of chronic exposure to lead. We propose that the mechanism involved, named imprinting or cell programming, persisted through evolution as a nongenetic adaptive mechanism to provide protection against long-term environmental variations that otherwise may cause the extinction of species not displaying this kind of adaptation.

Efectos de la radiación electromagnética no ionizante sobre lasalud y el caso específico de los efectos en la salud humana de la telefonía celular / Health effects of non-ionizing electromagnetic radiation, and the specific case of the effects of mobile telephony

Los efectos en salud de la radiación electromagnética ionizante son bien conocidos; sin embargo hay menos reconocimiento de los efectos en salud causados por exposición a radiación electromagnética no ionizante. La primera parte del presente trabajo se refiere a los efectos en salud de las radiaciones electromagnéticas no ionizantes, independiente de su origen, puesto que no hay diferencias apreciables entre los efectos producidos por los diversos tipos de radiación electromagnética no ionizante y por lo tanto, son también válidas para aquellas emitidas por la telefonía celular. Se describe una asociación estadísticamente significativa de varias enfermedades a radiación electromagnética de frecuencia baja (ELF) proveniente de tendidos o transformadores de alta tensión, radiación electromagnética ELF del tendido eléctrico domiciliario y de artefactos electrodomésticos, exposición ocupacional a radiación electromagnética principalmente ELF, y radiación electromagnética de radiofrecuencia (RF) proveniente de antenas de transmisión de televisión. A continuación se analizan los efectos ya demostrados de la telefonía celular (los teléfonos y sus antenas repetidoras). Luego se analizan los grados de certeza de un estudio del Estado de California (USA) para relacionar las diversas enfermedades causadas por radiación electromagnética no ionizante. Este estudio confirmó la alta o mediana probabilidad de una relación causa-efecto de la radiación electromagnética con las siguientes enfermedades: leucemia en adultos y niños, cáncer cerebral en adultos y niños, cáncer de mama femenino y masculino, abortos espontáneos, suicidio, enfermedad de Alzheimer, esclerosis lateral amiotrófica y enfermedades cardiovasculares incluyendo infarto del miocardio. Se describen cuales son estas enfermedades de acuerdo al origen de estas radiaciones y se analizan cuales pueden ser los mecanismos biológicos que determinan la génesis de éstas...

The health effects of ionizing electromagnetic radiation are well known; neverthless there exist less recognition on the health effects of exposure to non-ionizing electromagnetic radiation. The first part of the present report refers to health effects of non-ionizing electromagnetic radiation, independently of its origin, since there are not important differences among effects caused by the different kind of non-ionizing radiations, therefore, they are valid for those emmited by the mobile telephony. A statistically significant association is described among various diseases and extremely low frequency electromagnetic radiation (ELF) from high tension electric conductors or transformers, intradomiciliary electric lines or electrodomestic appliances, occupational exposure to electromagnetic fields, mainly ELF, and radiofrequency (RF) electromagnetic radiation from television transmission. Already demonstrated effects of mobile telephony (cellular telephones and their antenas). The degrees of certainty from a study of the State of California (USA) is analyzed to relate various diseases caused by non-ionizing radiation. This study confirmed high or moderate probability of a cause-effect relationship for adult and child leukemia, brain cancer in adults and children, female and male breast cancer, spontaneous abortions, suicide, Alzheimer disease, amiotrophic lateral sclerosis and cardiovascular diseases including myocardial infarction. Various diseases are related to the different origin of the radiation, and the biological mechanisms involved in disease generation are analyzed. Research performed in the USSR and afterwards in Russia on health effects of mobile telephony are summarized, these investigations originated the regulation in this country and afterwards in West Europe, and influenced the decisions of WHO on its carcinogenicity...

Biological activity of genistein and soy extracts: selective induction of some but not all estrogenic responses in the prepubertal rat uterus / Actividad biológica de Genisteína y extractos de soya: inducción selectiva de algunas pero no todas las respuestas estrogénicas en el útero de la rata prepúber

The existence of multiple kinds of estrogen receptors (ERs), involved in independent groups of responses, allows their dissociation and opens the possibility to selectively induce beneficial responses but not those considered at risk (cell proliferation). Based on the low hormone-dependent cancer mortality in Eastern Asia, attributed to high dietary intake of estrogenic isoflavones, we investigated whether genistein (G) or soybean extracts (S) selectively induce some, but not all estrogenic responses in the rat uterus, comparing its activity to that of estradiol-17 (E2). Prepubertal rats were treated with E2, G, concentrated S (Sc), diluted S (Sd), or vehicle, and uterine responses to estrogen were evaluated. Luminal epithelial and myometrial cell hypertrophy, and luminal epithelial RNA increase, were induced by E2, G or S. Uterine eosinophilia, endometrial edema and proliferation of 4 uterine cell-types were induced by E2 only. Results reveal that G and S induce some responses to estrogen but not others, suggesting their use as agents not displaying carcinogenic risk.

La existencia de múltiples tipos de receptores de estrógeno (ERs), involucrados en el desarrollo de grupos independientes de respuestas a estrógeno, permite su disociación y abre la posibilidad de inducir en forma selectiva respuestas benéficas pero no aquellas consideradas de riesgo (proliferación celular). Basado en la baja mortalidad por cánceres hormono-dependientes en el Este Asiático, atribuidos a una alta ingesta dietaria de isoflavonas estrogénicas, nosotros investigamos si la genisteína (G) o extractos de soja (S) inducen en forma selectiva algunas, pero no todas, las respuestas estrogénicas en el útero de rata, comparando su actividad con la del estradiol-17beta (E2). Ratas prepuberales fueron tratadas con E2, G, S concentrado (Sc), S diluido (Sd) o vehículo, y las respuestas estrogénicas en el útero fueron evaluadas. Las hipertrofias celulares en epitelio luminal y miometrio, y el aumento de ARN en células del epitelio luminal fueron inducidas por E2, G o S. La eosinofilia uterina, el edema en estroma endometrial y la proliferación de 4 tipos celulares uterinos fueron inducidos sólo por E2. Los resultados revelan que G y S inducen algunas respuestas estrogénicas pero no otras, sugiriendo su uso terapéutico como agentes estrogénicos que no presentan riesgo de cáncer.

Exposición prenatal a drogas de abuso: efectos diferidos e imprinting (desprogramación celular) / Prenatal exposure to drugs of abuse: delayed effects and imprinting (Cell Deprogramming)

El uso de drogas de abuso es un grave problema de salud y problema social en todo el mundo. Se conocen muy bien los efectos en salud de la exposición aguda o crónica a drogas de abuso. También que causan efectos directos en la placenta o en órganos en desarrollo de los embriones, causando malformaciones congénitas. Existe sin embargo muy poca información sobre efectos diferidos de la exposición a estos agentes durante las últimas etapas del desarrollo fetal o las primeras etapas de desarrollo postnatal.Estos agentes causan alteraciones irreversibles en la diferenciación y programación celular, que pueden ser consideradas como malformaciones bioquímicas y funcionales, responsables de alteraciones funcionales orgánicas o neuroconductuales que favorecenel desarrollo de enfermedades más tarde en la vida. En el presente trabajo se describen los efectos persistentes de la exposición a drogas de abuso ilícitas (opiáceos, cocaína, ketamina, tolueno, cannabinoides y anfetamina y sus derivados) y a drogas de abusolegalmente permitidas (alcohol etílico - nicotina y consumo de tabaco no se describen por formar parte de publicación previa en Cuadernos). Exposición a estos agentes favorece el desarrollo de una serie de enfermedades y alteraciones de la conducta más tarde en la vida. Además, se presenta evidencia que la exposición prenatal a varios químicos (plomo, el plaguicida malatión, bisfenol) y a varias drogas de abuso (opioides, etanol, cannabinoides) determinan cambios persistentes que favorecen el desarrollo de adicciones a drogas de abuso más tarde en la vida. Se concluye que, además de los problemas sociales y de salud derivadas del uso por adultos de drogas de abuso, la exposición fetal causa cambios que determina el desarrollo de varias enfermedades más tarde en la vida, incluyendo adicción a drogas de abuso. En consecuencia, la legislación gubernamental que restrinja el acceso y uso de estas drogas...

The use of drugs of abuse is a serious health and social problem through all the world. The eff ects of acute and chronic exposure of drugs of abuse on health are well known. They also cause direct eff ects on placenta o the developing embryo organs, causing congenital malformations. There is however very scarce information on the delayed eff ects of exposure to these agents during the last stages of fetal development or the early stages of postnatal development. These agents cause irreversible alterations in cell diff erentiation and programming, that could be considered as biochemical and functional malformations, responsible of functional organic or neurobehavioral alterations that favors the development of diseases later in life. The present report describes persistent effects of prenatal exposure to illicit drugs of abuse (opiates, cocaine, ketamine, toluene, cannabinoids, and amphetamine derivates) and to legal drugs of abuse (ethyl alcohol; nicotine and tobacco smoking are not reviewed since they were analyzed in a previouspublication in Cuadernos). Exposure to these agents favors the development of a myriad of diseases and behavioral alterations later in life. In addition, evidence is presented that prenatal exposure to various chemicals (lead, the pesticide malathion, bisphenol) andseveral drugs of abuse (opioids, ethanol, cannabinoids) determine persistent changes that favor the development of addictions to drugs of abuse later in life. It is concluded that, besides the known health and social problems derived by adults use of drugs of abuse, fetal exposure causes changes that determine the development of various diseases later in life, including drug addiction.Therefore, the dictation of Governmental regulations to decrease access to and use of these drugs, including the “softest” drugs such as cannabinoids, is fundamental to protect future generations health...

Efectos de exposición aguda a cadmio en la acción de estrógenos en útero de rata impúber / Effects of acute exposure to cadmiun on response to estrogen in the prepuberal rat uterus

Background: Few information is available about uterine effects of Cadmium (Cd) exposure, where toxic agents affecting the female genital tract interact with estrogen (E) receptors, modifiying myometrial activity and the menstrual cycle, causing dysmenorrhea, infertility and spontaneous abortion. No information exists whether prenatal or early postnatal exposure may cause any gynecologic persistent adverse effect. Our finding of a second mechanism of E interaction and differences between E receptors in the various uterine cell types suggests that Cd may affect differently E interaction in each cell-type. Objective: Evaluate a possible selective effect of acute Cd exposure on E action in the uterus during prepuber age. Method: Female prepuber rats exposed to Cd 4 mg/kg and 2 hours later, treated with Estradiol-17² 0,3 mg/kg. A myometrial sample was obtained under anaesthesia 24 hours after E treatment and histologically processed for the quantification of E responses on different uterine cell-types. Results: Cd exposure potentiates E-induced uterine eosinophilia and endometrial edema and inhibits E-induced cell hypertrophy in circular myometrium and cell proliferation in luminal myometrium. Cd, in the absence of hormone stimulation, causes a slight cell hypertrophy in circular myometrium. Conclusions: Acute exposure to Cd affects differently various responses to E in the different uterine cell-types. Future studies should verify whether this effect explains Cd-induced infertility, postpubertal sex organ development and whether prenatal or early postnatal exposure to Cd induces delayed persistent effects.

Antecedentes: Existe poca información sobre efectos del cadmio (Cd) en el útero. En mujeres altera la actividad miometrial, el ciclo menstrual y causa dismenorrea, abortos espontáneos, infertilidad y mortinatos. No existe información si la exposición prenatal o postnatal temprana causa efectos ginecológicos diferidos persistentes. Los tóxicos que afectan el útero suelen interactuar con receptores de estrógeno (E). Nuestro hallazgo de un segundo mecanismo de acción de E y de diferencias entre receptores de E de los diversos tipos celulares uterinos hacen posible que el Cd interactúe con los E en forma diferente en cada tipo celular. Objetivos: Buscar un posible efecto selectivo de la exposición aguda a Cd con algunas respuestas a E en útero de rata durante la edad prepuberal. Métodos: Ratas hembra impúberes recibieron 4 mg Cd/kg p.c. y 2 h después se trataron con 0,3 mg estradiol-17(3/kg p.c; los úteros fueron obtenidos bajo anestesia a las 24 h del tratamiento con E. Los úteros se procesaron para la cuantificación de respuestas a E en cada tipo celular por separado. Resultados: La exposición a Cd incrementa la eosinofilia uterina y edema endometrial inducidos por E; inhibe las siguientes respuestas a E: hipertrofia celular en miometrio circular, proliferación celular en epitelio luminal y miometrio. En ausencia de hormona, el cadmio causa una leve hipertrofia celular en miometrio circular. Conclusiones: La exposición aguda a Cd afecta de manera diferente las respuestas a E en los diversos tipos celulares uterinos de rata prepuberal. Futuros estudios deberán verificar si este efecto explica la infertilidad causada por exposición a Cd, afecta el desarrollo postpuberal de los órganos sexuales, e investigar si la exposición prenatal o postnatal temprana induce efectos diferidos persistentes, como puede ocurrir en población infantil prenatalmente expuesta a Cd.

¿Es posible encontrar un fitoestrógeno para la terapia de reemplazo hormonal, que disminuya el riesgo de cáncer?: tema de Proyecto Anillos de Investigación del Programa Bicentenario en Ciencia y Tecnología / Is it possible to find a phytoestrogen for hormone replacement therapy, decreasing cancer risk?: subject of Research Team Grant in Science and Technology from the Bicentennial Program in Science and Technology

Se describe una nueva línea de investigación que tiene como objetivo investigar principios activos presentes en especies vegetales chilenas, para identificar alguna(s) que produzcan los efectos farmacológicos deseables para su uso como terapia de reemplazo hormonal en mujeres peri o postmenopáusicas, pero que no aumenten, o incluso disminuyan, el riesgo de desarrollar cáncer mamario o endometrial. Esta posibilidad se basa en el hallazgo previo de nuestro equipo de investigadores de un nuevo tipo de receptores estrogénicos responsables de respuestas estrogénicas no genómicas y de nuestro hallazgo de diferencias entre los receptores estrogénicos citosólico-nucleares clásicos de los diferentes tipos celulares uterinos. Si existiera, como anteriormente se creía, un solo tipo de receptor de estrógenos, no sería posible el desarrollo de este nuevo fármaco estrogénico selectivo que buscamos, pues todos los receptores tendrían la misma afinidad por este agente, el que en consecuencia, induciría todas las respuestas a la estimulación estrogénica (incluyendo aquellas que deseamos prevenir, como las que presentan riesgo de desarrollo de cáncer), o que actuaría como antiestrógeno, antagonizando todas las respuestas a los estrógenos en el útero.

A new research line aimed at the investigation of active agents from Chilean plant species is described. The purpose is to indentify those agents inducing expected pharmacological effects in a hormone replacement therapy in peri- or post-menopausal women, but not increasing, or even decreasing, the risk for development of mammary or endometrial cancer. This possibility is based on previous findings from our research team of a new kind of estrogen receptors, responsible of non-genomic responses to estrogen, and our finding of differences between the classical cytosol-receptor estrogen receptors from the different uterine cell-types. If there exists one kind of estrogen receptors only in the uterus, as it was formerly accepted, then it is not possible to develop the selective estrogenic drug we search for, because all receptors would display the same affinity for this agent; therefore, it would induce all responses to estrogen stimulation (including those we wish to prevent, such as those presenting risk of cancer development), or would act as antiestrogen, antagonizing all responses to estrogen in the uterus.

Efectos diferidos de contaminantes ambientales y otros agentes en salud reproductiva y sexualidad: un desafío pendiente de la toxicología de la reproducción para la salud de las futuras generaciones / Delayed effects of environmental pollutants and other agents on reproductive health and sexuality: a pending challenge of reproductive toxicology for future generations health

La exposición perinatal a diversos contaminantes ambientales y a otros agentes químicos afecta en formairreversible la diferenciación y programación de diversos tipos celulares, alterando cualitativa y cuantitativamentesus receptores hormonales mediante el mecanismo del imprinting, afectando su función y determinando el desarrollo de diversas patologías más tarde en la vida. En el presente trabajo se describen los agentes más conspicuos que actúan por este mecanismo afectando de por vida la salud reproductiva y la sexualidad. La investigación de este mecanismo, la identificación de sus agentes inductores y el desarrollo de medidas legislativas y administrativas para minimizar el daño constituyen un desafío pendiente para mejorar la saludreproductiva de las futuras generaciones.

Perinatal exposure to various environmental pollutants and other chemical agents irreversibly affects thedifferentiation and programming of various cell-types. This process quantitatively and qualitatively alters their hormone receptors through the mechanism of imprinting, affecting their function and determining the development of various pathologies later in life. The present report describes the most conspicuous agents acting through this mechanism, affecting for life reproductive health and sexuality. The study in detail of this mechanism, the identification of imprinting-inducing agents and the development of legislative and administrative measures to minimize damage constitute a pending challenge to improve future generations reproductive health.