BUTTERWORTH BE, POPP JA, CONOLLY RB AND GOLDSWORTHY TL. 1999, Guengerich 2001, van Leeuwen and Zonneveld 2001, Oda 2004). Do acúmulo de mutações somática em protoconcogenes e genes supressores de tumor. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. KING C, WANG C, GORELICK N AND FREDERICK C. 1995. irreversíveis e predispõe a célula normal à evolução maligna e à imortalidade El daño en la célula puede tener una naturaleza genética o epigenética. et al., 1992; Klaunig et al., 2000; Dixon e Kopras, 2004). Epidemiological studies of cancer incidence demonstrated that the risk of developing cancer varies between population groups and these differences are associated with lifestyle factors and habits (Garner 1998, Lai and Shields 1999, Gutiérrez and Salsamendi 2001). 1998. ASHBY J. Nature 386: 761-763. Este periodo, a su vez, puede ser subdividido en dos fases, una fase local, en la que el tumor se encuentra todavía localizado en las estructuras ACHANZAR WE, BRAMBILA EM, DIWAN BA, WEBBER MM AND WAALKES MP. Bell: Cáncer de piel en trabajadores alquitrán y parafina 1895. Mutagenesis 13: 405-408. 1990, Pitot and Dragan 1991). 1995. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. 2001). Durante la primera etapa de la carcinogénesis se producen alteraciones irreversibles del genotipo de la célula normal, como resultado de lo cual pasa al estado predispuesto a la transformación (célula latente). People with a high quantity of phase I and a low quantity of phase II enzymes have a higher probability of synthesising intermediate compounds and exhibiting more DNA damage (Rojas et al. SHARMA RA AND FARMER PB. 2001, Waddell 2002): a) It has not been confirmed if rodent models are representative of carcinogenesis in humans. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Park et al. 2000, Oesch et al. Cancer Lett 93: 9-16. In 1890, a high incidence of bladder cancer in chemical and rubber industry workers was observed across Europe. (EN), An. VAN LEEUWEN IM AND ZONNEVELD C. 2001. 1994. 2021 May;71 (3):209-49. fIntroducción. 2001). 1992,Nguyen-ba and Vasseur 1999, Klaunig et al. 1999. 2003). The first group includes nutritional habits (food preservation and preparation), socio-economic status, lifestyle, physical agents (ionising and non-ionising radiation), chemical compounds (natural and synthetic) and biological agents ( Helicobacter pylori, Epstein Barr virus, human T lymphotropic viruses I and II, human papilloma virus and the hepatitis B virus, parasites such as Schistosoma haemotobium, Clonorchis sinensis and Opisthorchis vivarium; growth factors) (Pitot and Dragan 1991, Barrett and Anderson 1993, Farmer 1994, Weisburger 1999, Minamoto et al. However, substances such as nitrosamines and beryllium do not strongly correspond to their results in the Ames test (Gonzalez 2001, Payne and Kemp 2003). Bqco. Metabolic detoxification: implications for thresholds. ABSORPTION AND METABOLISM OF CHEMICAL CARCINOGENS. 2004. Genotoxicity in the rodent urinary bladder. Carcinogénesis química corresponde a la activación por mutación en un oncogén. YAMAGIWA K AND ICHIKAWA K. 1918. Clin Cancer Res 10: 4901-4912. If we delay their differentiation they become initiated and accumulate in tissues as clones of abnormal cells (Trosko 2003). IARC Sci Publ 116: 279-305. También puede contactarnos! ISHIKAWA T, IDE F, QIN X, ZHANG S, TAKAHASHI Y, SEKIGUCHI M, TANAKA K AND NAKATSURU Y. La carcinogénesis consta de tres etapas: iniciación, promoción y progresión. Low DNA repair is a risk factor in skin carcinogenesis: a study of basal cell carcinoma in psoriasis patients. é idêntica às restantes células, no entanto sofreu mutações que favorecem a sua Os benefícios estão, por vezes associados a desvantagens, os efeitos resultantes da exposição a compostos químicos enquadram-se entre a morte imediata e um longo processo de carcinogênese química. p53R2 is induced by p53 and p73, while R2 synthesis occurs during S phase. The identification of adducts suggests that chemical carcinogens are absorbed, metabolized and distributed by tissues, thus fleeing from the body's detoxification and repair mechanisms (Garner 1998, Airoldi et al. Fue la primera teoría unificada sobre el origen de los tumores, que incluyó logros en el campo de la carcinogénesis química, por radiación y viral. Mutations linked to adducts can appear through deletion, frameshift, or by nucleotide substitution (Garner 1998). 1978. Environ Health Perspect 104: 569-577. desenvolvimento neoplásico sem ter ocorrido iniciação. En ella se implican por tres procesos fundamentales para la célula: metabolismo, reparación del ADN y proliferación celular. 2005). Hoy hablaremos los carcinógenos químicos y las etapas necesarias para que una sustancia química de origen a una neoplasia. b) The impossibility of simultaneously controlling exposure to other chemicals, and analysing the influence of those environmental and physiological factors that influence the evolution of the disease. mutations in proto-oncogenes and tumour suppressing genes. Prog Clin Biol Res 340: 113-122. MILLER 3RD MC, MOHRENWEISER HW AND BELL DA. Metabolism of carcinogenic amino derivatives in various species and DNA alkylation by their metabolites. Adv Cancer Res 50: 25-70. Biomedicine 24: 306-316. Initiation is an additive process, neoplasic development depends on the carcinogenic dose, increasing the dose increases the incidence and the multiplicity of resultant neoplasias and reduces the latent period of its manifestation. A sociedade obtém numerosos benefícios da utilização de compostos químicos. During progression, cell proliferation is independent from the presence of stimulus (Lutz 2000, Gutiérrez and Salsamendi 2001). Cad Saúde Pública 13 (Suppl): 27-38. TEORIA DEL CAMPO DEL CANCER. VOGELSTEIN B AND KINZLER KW. Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics. de mutações, o ritmo de crescimento celular e a expressão fenotípica dos genes 1992, Weisburger 1998, Williams 2001). Yet, when mixed and in equal doses, they induced neoplasic development. Mutations in the caretakergenes, which are considered to be typical tumour suppressors, compromise genome stability and, more specifically, increase the probability of mutation in the gatekeepers which include both tumours suppressor genes and oncogenes (Vogelstein and Kinzler 2004, Blagosklonny 2005). RICHARDSON FC, BOUCHERON JA, DYROFF MC, POPP JA AND SWENBERG JA. 62, Núm. mutações e de erros na replicação do ADN. 1984, Gutiérrez and Salsamendi 2001). The role of cell proliferation in chemical carcinogenesis. Finalmente, la cuarta etapa es el resultado del proceso tumoral. proliferação celular, invasibilidade, metastização, e modificações nas características A comparative morphological evaluation of 1500 experiments. Cancer Res 44: 4217-4223. Carcinogenesis 21: 345-351. Methods, and the apparent persistence of initiated cells. The p53 family participate in NER by inducing the expression of GADD45, xeroderma pigmentosum group E gene [XPE] and XPC (Hwang et al. originando duas novas células iniciadas (Trosko, 2003). Oncogene 19: 4283-4289. Br J Cancer 44: 1-14. A utilização de diferentes metodologias possibilita o reconhecimento e a compreensão dos mecanismos básicos envolvidos no desenvolvimento do cancro. Mutat Res 477: 414-419. 2005. A acumulação de danos no ADN tem particular importância nas células Ej., Mutaciones genéticas o aberraciones cromosómicas) o cambios en el número de copias de genes o la integridad de los cromosomas. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence. There are innumerable anatomic, physiological and biochemical resemblances between rodents and humans that justify their use in carcinogenicity testing (Maronpot and Boorman 1996, Balmain and Harris 2000). Opin Chem Biol 5: 383-388. 12 0 obj
acontecimentos normais como são a depurinação e a desaminação do ADN (Gomes- progressão o equilíbrio é alterado e surge a neoplasia (Mehta, 1995; Kanojia e Vaidya, 2005). 2006. 1992, Cohen and Lawson 1995). A mutação actua de forma aleatória, por sua vez a Sección. DNA damage has been well established as the event which kick-starts chemical carcinogenesis (Santella et al. Not all cells exposed to promoters take part in the promotion stage, only cells which are stimulated to divide, that are undifferentiated, and have survived apoptosis, can contribute to instability between growth and cell death and lead to the appearance of a malign neoplasia (Trosko 2001). Oral Oncol 37: 477-492. 1997. contrário actuam em simultâneo sobre vários tecidos (Yuspa e Hennings, 1983; Scott et Human life is led under very different conditions from these experimental procedures. son enlaces a estos estudios en los que se puede hacer clic. Nucleic Acids Research 34: 840-852. Genetic, epigenetic, dysgenetic, and non-genetic mechanisms in tumorigenesis. Dev Biol (Basel) 106: 53-57. A expansão clonal das células 1975. Beta oxidación. Most of the morphological, biochemical and genetic changes currently observed should be considered as the expression of the adaptation of neoplasic cells to survive in a familiar but hostile environment. ¿Qué estudia la carcinogénesis? Os resultados obtidos a partir de distintos trabalhos BONNET JL, DUSSER M, BOHATIER J AND LAFFOSSE J. Although p53R2 and R2 are similar, they differ in their N-terminal amino acid sequence and regulation. Esta contradição A carcinogênese, também denominada oncogênese, trata-se do processo de formação de uma neoplasia. Genetic alterations and DNA repair in human carcinogenesis. ETAPAS DE LA CARCINOGÉNESIS Cuando el clínico se encuentra ante un tumor, no observa más que un pequeño momento de lavida del proceso canceroso, el denominado periodo clínico. Carcinogenesis no sólo causa cambios persistentes el genotipo de las células, sino que también tiene un efecto colector sobre el tejido, órgano, y los niveles de organismo, en algunos casos, la creación de un entorno propicio para la supervivencia de las células transformadas y el posterior crecimiento y la progresión neoplásica. R. Huebner y Todaro G. (R. Huebner y G.Todaro), que sugirió que el aparato genético de células cada uno genes normales están presentes en función de activación prematura o aparejo que puede ser una célula normal convertirse en un canceroso. 1995. 1992, Klaunig et al. primeira e na última etapa deste processo, ou seja, na iniciação e na progressão, ocorrem Nat Rev Cancer 5: 113-125. SIMONS JW. Genetic variability in susceptibility and response to toxicants. Each pathway utilizes unique enzymatic mechanism. 1999, Tennant et al. and mortality worldwide for 36 cancers in 185 countries. These can stretch from 5 to 7 years if we take into account the posterior analysis of the results obtained via the different methods (Tennant et al. HARMS K, NOZELL S AND CHEN X. 2000). The uses of carcinogen-DNA adduct measurement in establishing mechanisms of mutagenesis and in chemoprevention. A iniciação pode surgir por mutações espontâneas desencadeadas por Mol Cell Biol 19: 12-20. Si considera que alguno de nuestros contenidos es incorrecto, está desactualizado o es cuestionable, selecciónelo y presione Ctrl + Intro. (Simons, 1995; Hanahan e Weinberg, 2000). Initiation and promotion at different ages and doses in 2200 mice. 1998. proliferação, mas não a diferenciação (Trosko, 2001). tempo para se manifestar clinicamente. 1992, Gutiérrez and Salsamendi 2001). Due to the high correlation that exists between mutagenecity and carcinogenicity, the Ames test is frequently used to evaluate the carcinogenic potential of chemicals. 2001). BLAGOSKLONNY MV. Oncol Rep 6: 925-932. 1984. Mol Cell Biol 19: 1673-1685. Os estudos realizados em modelos animais, em ensaios in vitro e em estudos Nos trabalhos experimentais de carcinogénese química com exposição The role of individual susceptibility in cancer burden related to environmental exposure. Mutat Res 424: 237-247. 2004). 1999). Am J Public Health 84: 1223-1228. HENGSTLER JG, ARAND M, HERRERO ME AND OESCH F. 1998. Todo el contenido de iLive se revisa médicamente o se verifica para asegurar la mayor precisión posible. FRIEDBERG EC. O conceito de promoção foi introduzido quando se identificaram substâncias The hallmarks of cancer. GUENGERICH FP. Organ specificity and tumor promotion. CARCINOGENESIS QUIMICA. p21 acts as an inhibitor of cyclin-dependent kinases providing a functional link between p53 and cell cycle (Bertram 2001). The conclusions reached from several experiments enabled the conclusion to be drawn that initiation is caused by irreversible genetic changes which predispose susceptible normal cells to malign evolution and immortality (Beremblum and Shubik 1947, Stenbäck et al. CARCINOGENESIS. COHEN SM AND ELLWEIN LB. Mutat Res 547: 1-4. OESCH F, HERRERO ME, HENGSTLER JG, LOHMANN M AND ARAND M. 2000. Para que una sustancia química, ajena al ser vivo, tenga efecto sobre los mecanismos biológicos, debe suceder una reacción, de naturaleza química o fisicoquímica. , These compounds modulate growth and cell death, potentate the effects of genotoxic compounds, do not show a direct correlation between structure and activity, and their action is limited by their concentration. Chemical carcinogenesis. 1999. 2000, Ohshima et al. A promoção é uma etapa 2000. Naturaleza química de los ácidos grasos y los acilgliceroles. According to Pritchard et al. 2). WebEste es el tipo de cáncer de páncreas más común. In Vivo 15: 467-478. COSTA M, YAN Y, ZHAO D AND SALNIKOW K. 2003.Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cells signalling. ROBBINS D AND COTRAN R. 2005. The chicken chorioallantoic membrane assay is used to study angiogenesis during tumour growth (Tufan and Satiroglu-Tufan 2005). Mutat Res 477: 79-87. Cell proliferation is essential for this stage, if cellular division occurs before DNA repair systems can act then the injury becomes permanent and irreversible. A sua transformação, através de mecanismos genéticos e Peroxidations also occur parallel to metabolic reactions with the continuous production of reactive oxygen species (ROS) (Weisburger 1999, Klaunig et al. La carcinogénesis está ligada a la mutagénesis (producción de un cambio en la secuencia del DNA), lo cual es evidente para los carcinógenos químicos (que provocan cambios en la secuencia de los nucleótidos), y para las radiaciones, como los rayos-X (que causan ruptura de los cromosomas, y translocaciones). 3.2. La transformación es el resultado de la interacción de una célula normal con un agente transformante (carcinógeno). Initiation can begin with spontaneous mutations, supported by normal occurrences such as DNA depurination and deamination. 2003. Adducts assume importance in chemical carcinogenesis because of the way they change DNA, possibly inducing an incorrect transcription and causing mutations of the new DNA chain. K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers-a review. Embora a iniciação espontânea seja mais rara do que a induzida vivos. Cancer Biol Ther 4: 621-627. The specificity of the activation systems of different tissues regulate neoplasic development and is dependent on genetic polymorphism, which requires the expression and distribution of the enzymes involved in phase I and II reactions, and the resulting susceptibility to cancer development (Schut and Castonguay 1984, Hayes 1995, Henglster et al. Endogenous factors include immune system damage and inflammation caused by uncertain aetiology (e.g. COHEN SM AND LAWSON TA. The contribution of the mouse in hazard identification studies. A progressão caracteriza-se pela irreversibilidade, instabilidade genética, d) Through genetic modification, it is possible to identify those mechanisms associated with neoplasic development. PCNA, a cofactor for DNA polymerase d, is another p53 target gene and has been shown to interact with hMSH2 to facilitate hMSH2 transfer to mismatched bases (Flores-Rozas et al. Mutat Res 488: 195-209. stream
Genetic, epigenetic, dysgenetic and non-genetic mechanisms in tumorigenesis. Alejandra Camargo TOXICOLOGÍA DE LOS ALIMENTOS CARCINOGÉNESIS QUÍMICA 2. Carcinogenic assays on rodents identify potential carcinogens for humans. The more that nearby cells increase the number of cell divisions through regenerative procedures, the more likely it is that they will end up being prematurely recruited for the cell cycle and that the time available for reparation DNA will be inferior - this increases the probability of mutations occurring (Cohen 1991, Melnick et al. Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. Thresholds of carcinogenicity of flavors. BABENKO VN, BASU MK, KONDRASHOV FA, ROGOSIN IB AND KOONIN EV. TEORIA GENETICA DEL CANCER. 1999, Khan and Dipple 2000). 2003. 1992). Toxicol Pathol 28: 382-387. Phenotypic diversity in experimental hepatomas: the concept of partially blocked ontogeny. Charlotte Auerbach and chemical mutagenesis. Non-genotoxic carcinogens act as promoters and do not need metabolical activation. Environ Health Perspect 61: 69-96. Carcinogenicity and mutagenicity testing, then and now. GAYLOR DW AND CHEN JJ. Cáncer de escroto en limpiadores de chimeneas 1885. La aparición de estas lesiones ocurre como resultado de causas endógenas, como errores de replicación, inestabilidad química de las bases de ADN y su modificación bajo la acción de radicales libres, y bajo la influencia de factores externos causantes de naturaleza química y física. hMSH2 functions in mismatch recognition and binds mismatched bases (Lamers et al. monoclonal a partir de uma célula estaminal. The order of exposition to these substances was fundamental for carcinogenesis. Cáncer de piel en conejos con alquitrán de hulla (3,4 BP) 1930. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals. Se produce un efecto tóxico a nivel genético y daño en el ADN. 2000. COHEN SM. Chemical basis of inflammation-induced carcinogenesis. Cancer Detect Prev 24: 1-12. Prog Clin Biol Res 374: 213-229. FARBER E. 1984. COHEN SM. In studies of chemical carcinogenesis with prolonged exposure and using high doses almost all of the promoter agents induce neoplasias without initiation(Pitot and Dragan 1991, Gutiérrez and Salsamendi 2001). A perfect concordance. tem de possuir potencial proliferativo e sofrer mutações nos genes que regulam a sua Interestingly, these epigenetic changes in chromatin can also alter the sensitivity of DNA sequences to mutation, thus rendering genes more susceptible to toxic insult (Dixon and Kopras 2004). A neoplasia initiated by the inactivity of a gatekeeper gene can progress quickly as a consequence of its effect on genes that directly control cell death (Kinzler and Volgestein 1997). crescimento e a morte celular, e conduzirem ao aparecimento de um conjunto de células El portal iLive no proporciona asesoramiento médico, diagnóstico ni tratamiento. 1996, Butterworth and Bogdanffy 1999, Klaunig et al. Promoters delay the natural inhibition of the quiescent cells or in G0 by gap junctions (Barrett and Anderson 1993, Simons 1999, Bertram 2001, Trosko 2001). Medium-term bioassays for carcinogens. 2001. b) Although many chemical carcinogens for animals do not cause cancer in humans, many of humancarcinogens were discovered from assays in animals such as: aflotoxins, diethylstilbestrol or vinyl chloride. , Universidade de Tras os Montes e Alto Douro, CECAV , Department of Veterinary Sciences, Portugal, , Vila Real, 1996. Se han identificado varios centenares de HAP en el medio ambiente. 2000). The role of transgenic mouse models in carcinogen identification. 2002. Clin Adv Hematol Oncol 2: 147-151. pamo@utad.pt, , Vila Real, Cancer cells exhibit a mutator phenotype. They do not react directly with DNA, do not raise adducts and show negative on mutagenicity tests carried out in vivo and in vitro (Butterworth et al. Mitogenic compounds need to be present in certain concentrations to promote their activity. In most of the cases it is assumed to vary between tissues and between different species (Grisham et al. By the end of the nineteenth century it had become evident that occupational exposure to certain chemicals or mixtures of chemicals had carcinogenic effects (Luch 2005). Semin Cancer Biol 14: 441-448. In the pre-Watson and Crick era, before carcinogens were known to bind to DNA, the cancers produced by chemical carcinogens were believed to be due to their interaction with proteins in specific tissues (Miller and Miller 1952). Os danos no ADN podem ser corrigidos por mecanismos de 1986, Frowein 2000). The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. The role of interindividual variation in human carcinogenesis. 2003, Dixon and Kopras 2004). The premise that those carcinogenic compounds experimentally tested are harmful for man is not always valid (Swenberg et al. Meanwhile, others researchers studied carcinogenesis of the bladder, liver, kidney, pancreas and lung usinglaboratory animals. The experiment has a previously established duration and the animals that survive are sacrificed at the end of the experiment (van Leeuwen and Zonneveld 2001, Pitot 2001, Payne and Kemp 2003). c) The doses are too high and may cause a proliferative response in normal cells. The relationship between chemical substances in the workplace and the development of certain neoplasias in various occupational groups led to the conception of experimental models to better understand the biopathological processes inherent to carcinogenesis (Weinstein 1991, Cohen et al. La progresión es la tercera etapa del crecimiento tumoral. This classification is based on their involvement in maintaining genome integrity and DNA repair, respectively (Lai and Shields 1999). At first, these occurrences were associated with epigenetic mechanisms, but nowadays it is widely agreed that promotion also involves genetic changes (Simons 1995, Hanahan and Weinberg 2000). These radicals are associated with several chronic diseases including chemical carcinogenesis (Klaunig et al. By the end of the 1960s, increasing evidence pointed to a correlation between the DNA binding capacity of a particular carcinogen and its biologicalpotency (Luch 2005). 1999). 2004). The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development (King et al. Proc Natl Acad Sci USA 96: 424-428. Relative potency of chemical carcinogens in rodents. PAYNE SR AND KEMP CJ. Environ Health Perspect 76: 65-70. A partir de entonces, el benzopireno ha servido de molécula modelo en el estudio de la carcinogénesis química y se ha demostrado que su absorción intestinal se favorece altamente tras disolverse con los lípidos de la dieta (Vetter et al., 1985). SIMONS JW. LUTZ WK. 2000). 2000. CARCINOGENESIS QUÍMICA EN LA PIEL También los agentes químicos y ambientales se han señalado como sospechosos de ejercer una acción cancerígena, tal los subproductos de la combustión del tabaco. The increase in DNA damage is specifically important to stem cells, because they survive for a long time and exist in several tissues (Potter 1978, Simons 1999, Trosko 2001, Williams 2001). BEREMBLUM I AND SHUBIK P. 1947. Correlation of DNA adduct levels with tumor incidence: carcinogenic potency of DNA adducts. 2001. The biological activity of p53 protein is dependent on its ability to bind transcriptional regulatory elements in DNA. Las ideas obsoletas sobre la fugacidad del proceso tumoral dieron paso a teorías más modernas. POIRIER MC, SANTELLA RM AND WESTON A. The number of adducts formed by carcinogens is changeable and each of them may cause a specific damage to DNA (Straub and Burlingame 1981, Farmer 1994, Otteneder and Lutz 1999). 1992, Maronpot and Boorman 1996, Airoldi et al. Toxicol Lett 126: 155-158. Carcinogenic effects of hyperthermia. Lack of p53-mediated G1 arrest in response to an environmental carcinogen. NGUYEN-BA G AND VASSEUR P. 1999. Res Microbiol 154: 375-385. promotores fenobarbital, 12-Ο-tetradecanoilforbol-13-acetato, benzeno, asbestos e arsénico, sem a prévia aplicação de agentes iniciadores, conduz só por si, ao Although the process of carcinogenesis is similar for man and experimental animals, the different chemical compounds to which humans are exposed throughout their lives alter the speed of the process and the frequency of mutation, the speed of cell growth and the phenotypical expression of the changed genes. There are several routes towards DNA repair. The loss of p53 function activates proto-oncogenes and inactivates tumour suppressor genes therefore performing an exceptional role in chemical carcinogenesis (Luch 2005). En los últimos diez años, la teoría oncogénica de la carcinogénesis y el cáncer ha adquirido un aspecto moderno y se puede reducir a varios postulados básicos: Carcinogenesis tiene otro lado del problema, que se refiere a mecanismos para contener la transformación maligna y en relación con la función de los denominados anti-oncogenes (genes supresores) que proporcionan efecto de inactivación normal sobre la proliferación y la inducción de apoptosis favorable. It is estimated to happen at a frequency of around 10-5 to 10-6 through nucleotides and cell division. Carcinogénesis de la segunda etapa: la etapa de activación o promoción, cuya esencia es la proliferación de la célula transformada, la formación de un clon de células cancerosas y un tumor. 1997). 2000). Por outro lado, a susceptibilidade individual e os mecanismos de defesa BARRET JC AND WISEMAN RW. etapas da carcinogênese; avaliação de carcinogeneicidade; carcinogênicos químicos; carcinogênese química, Paula A. OliveiraI; Aura ColaçoI; Raquel ChavesII; Henrique Guedes-PintoII; Luis F. De-La-Cruz P.III; Carlos LopesIV,V, IDepartment of Veterinary Sciences, CECAV, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal, IICenter of Genetics and Biotechnology-CGB, University of Trás-os-Montes and Alto Douro (UTAD), Department of Genetics and Biotechnology, 5000-801 Vila Real, Portugal, IIIDeparment of Physiology, Faculty of Veterinary, Santiago University, Granxa Street, Campus Universitario, 27002 Lugo, Spain, IVDepartment of Pathology, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal, VDepartament of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Largo Professor Abel Salazar, 2, 4099-003 Porto, Portugal. I. 1986. Species susceptibilities to chemical carcinogenes: a critical appraisal of the roles of genetic and viral agents. Cancer Lett 123: 185-191. Statistical learning methods have recently been explored as a new approach for genotoxicity prediction without any restrictions on the features of structures or types of molecules. 1991. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Although stem cells are not identifiable in most tissues, it is believed that every tissue has a population of stem cells (Player et al. reparado, o dano torna-se permanente e passa a estar “fixo”. Conjugation reactions enable these enzymes to decompose the polar group in glucose, amino acids, glutathione and sulphate, which are less toxicmetabolites that are more soluble in water and more easily expelled by the urine and bile (Galati et al. genotípicas e fenotípicas (Trosko, 2003). YUSPA SH, HENNINGS H, LICHTI U AND KULESZ-MARTIN M. 1983. químicas que carecendo de actividade carcinogénica apreciável conseguiam estimular o mutations in proto-oncogenes and tumour suppressing genes. These experiments are labelled as themolecular epidemiology of cancer or molecular dosimetry (Bondy 2004, Yang and Schlueter 2005). diferenciação terminal (Farber, 1984; Yuspa e Poirier, 1988; Klaunig et al., 2000; 1998,Trosko 2001). These assay groups of males and females, of mice and rats, are exposed to two or three doses of the agent being tested while a non-exposed (control) group is also used (Weisburger 1999). al., 1984; Yuspa e Poirier, 1988; Gutiérrez e Salsamendi, 2001). SCOTT RE, WILLE Jr JJ AND WIER ML. KHAN QA, VOUSDEN KH AND DIPPLE A. Bull Acad Natl Med 182: 33-46. From exposure to effect: a comparison of modeling approaches to chemical carcinogenesis. KLAUNIG JE, KAMENDULIS LM AND XU Y. Numerosos ejemplos de traducciones clasificadas según el tipo de actividad de "carcinogénesis química" - Diccionario español-inglés y asistente de traducción inteligente. J Natl Cancer Inst 94: 1888-1891. Progression is characterised by irreversibility, genetic instability, faster growth, invasion, metastization, and changes in the biochemical, metabolical and morphological characteristics of cells (Pitot and Dragan 1991, Butterworth et al. epigenéticos, em lesões malignas é a última das etapas da carcinogénese, e a mais Bolt et al. In contrast, inactivity by caretaker genes does not support the starting phase of a neoplasia, instead favouring the genetic instability which results in an increase in mutations across all genes, including the gatekeeper. la carcinogénesis es causada por alteraciones genéticas y epigenéticas que alteran la integridad del genoma, y que le permiten a la célula transformada violentar mecanismos como la senescencia celular, la apoptosis, el control de la proliferación, la estabilidad de la matriz extracelular, la dependencia de señales tróficas específicas del tejido … Toxicol Pathol 24: 801-814. GUITTET O, HAKANSSON P, VOEVODSKAYA N, FRIDD S, GRASLUND A, ARAKAWA H, NAKAMURA Y AND THELANDER L. 2001. 2000,Williams 2001). Public opinion considers cancer to be an increasingly threatening disease, affecting people of all ages. 1991. (English), Resumo Cancer Res 51: 6493-6505. Instead of focusing on specific structural features or a particular group of related molecules, these methods classify molecules into genotoxic positive or non-genotoxic agents based on their general structural and physicochemical properties, regardless of their structural and chemical types (Li et al. , 1984, Yuspa and Poirier 1988, Gutiérrez and Salsamendi 2001). desenvolvimento neoplásico (Melnick et al., 1996; Trosko, 2001). J Nutr 29: 552S-555S. carcinogÉnesisandrea martinez acostageraldine sanabria cuencafacultad de medicina2010 KOIVUSALO M, JAAKKOLA JJ, VARTIAINEN T, HAKULINEN T, KARJALAINEN S, PUKKALA E AND TUOMISTO J. MASTERS JR. 2000. Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway. 2000. 1999. They have enabled us to understand diseases, to discover etiological factors and to test many treatments (Maronpot and Boorman 1996). Fundamientos de cięncia toxicológica. (Beremblum e Shubik, 1947; Stenbäck, 1981; Mehta, 1995; Dybing e Sanner 1999; WANG TC, CHIOU CM AND CHANG YL. 2000. promoção, ocorre uma alteração na expressão dos genes, com a proliferação selectiva 2002. 1999, Dybingand Sanner 1999, Gonzalez 2001, Gonzalez and Kimura 2001, Gutiérrez and Salsamendi 2001, Lutz 2002). Salsamendi, 2001). Between 70 and 90% of known chemical carcinogens show positive results on the Ames test. The cell cycle and chemical carcinogenesis. 7). Finally, we will describe a selection of the methods available for evaluating the carcinogenic potential of chemical compounds. The use of chemical compounds benefits society in a number of ways. Some promoter agents are specific for a particular tissue, but others act simultaneously upon several tissues (Yuspa et al. A true threshold dose in chemical carcinogenesis cannot be defined for a population, irrespective of the mode of action. MILLER EC AND MILLER JA. Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver. The factors responsible for cancer development are classified as exogenous and endogenous (Camargo et al. Each of these stages is exceedingly complex in itself. The role of croton oil applications, associated with a single painting of a carcinogen, in tumor induction of the mouse's skin. The search for critical genes regulated by p53 led to the discovery of the p21 gene. A symposium summary and perspective on comparative molecular biology of cancer. CARCINOGENESIS • La mayoría se origina en un clon aberrante. Predictive toxicology: benchmarking molecular descriptors and statistical methods. LUCH A. In their role as genomic protectors, it is not surprising that the p53 family have a part to play in DNA repair (Fig. The understanding of these stages and the factors involved in them is very important for the development of biomarkers that allow early diagnosis, and also to know the stage of tumor development. La última de estas etapas, progresión, es exclusiva de la transformación maligna e implica la capacidad de invadir tejidos vecinos o a distancia. On the cases in which the control animals do not show neoplasias, the results are considered significant if 10% of the animals exposed to the carcinogen develop neoplasias (Pitot 2001). IARC Sci Pub 147: 211-225. Carcinogenesis 7: 853-858. BMC Cancer 9: 26-36. 2007. Several experiments have proved that chemical compounds, which create ROS in excess, encourage initiation, promotion and neoplasic progression through genotoxicity (Galati et al 2000, Shacter and Weitzman 2002). TROSKO JE. INTRODUCCIÓN • El cáncer es considerado el problema más grave de salud por las siguientes razones: Es una condición común y ocurre en una de cada cuatro personas Se mueren más personas que la padecen, incluso con tratamiento intensivo El cáncer causa un severo sufrimiento físico y . Demethylation of promoter regions at the CpG sequences can lead to an over-expression of proto-oncogenes, and silencing ofgene expression can occur as a result of hypermethylation, sometimes leading to chromosome condensation (Klaunig et al. , The role of DNA adducts in chemical carcinogenesis. Carcinogénesis Etapas de la carcinogenesis: Iniciación: En ella se implican por tres procesos fundamentales para la célula: metabolismo, reparación del ADN y proliferación celular. [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. 2003. Nat Genet 26: 375-378. 2001. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 23: 75-97. Three stages of carcinogenesis are described: initiation, promotion and progression. OHSHIMA H, TAZAWA H, SYLLA BS AND SAWA T. 2005. Mutat Res 402: 331-337. 1998, Gutiérrez and Salsamendi 2001, Trosko 2001). ), genetic makeup, age, endocrine balance and physiological condition (Cohen et al. Free Radic Biol Med 37: 582-593. Carcinogen adducts: use in diagnosis and risk assessment. E-mail: Oncology 33: 73-76. Tenemos pautas de abastecimiento estrictas y solo estamos vinculados a sitios de medios acreditados, instituciones de investigación académica y, siempre que sea posible, estudios con revisión médica. 1999. 1983, Butterworth et al. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. 2000, Gutiérrez and Salsamendi 2001, Luch 2005). Prediction of Rodent Carcinogenicity for 30 Chemicals. 2000, Oesch et al. Anticancer Res 19: 4781-4789. La carcinogénesis, es decir, el desarrollo del cáncer se produce en varias etapas. Cellular and molecular mechanisms of multistep carcinogenesis: relevance to carcinogen risk assessment. The use of chemical compounds benefits society in a number of ways. The ciliated protozoan Tetrahymena pyriformis may be used in bioassays to evaluate the cytotoxic impact of many chemical compounds (Bonnet et al. agente promotor que ao aumentar as divisões celulares favoreça a ocorrência de 1992. 4). La información publicada en el portal es solo para referencia y no debe utilizarse sin consultar a un especialista. alterações na estrutura do genoma (Simons, 1995; Pitot, 2001). The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Toxicol Sci 68: 275-279. p53 and p73 induce the expression of p53R2, a gene which is homologous with the R2 regulatory subunit of ribonucleotide reductase (RNR) (Nakano et al. A angiogénese, como acontecimento epigenético, é fundamental durante a CARCINOGENESIS QUIMICA ANTECEDENTES HISTORICOS 1775. células imortais até ser induzida a sua diferenciação ou morte; se impedirmos a sua 1999, Huff 1999, Bertram 2001). entre a mutação e a selecção clonal. Laser capture microdissection, microarrays and the precise definition of a cancer cell. Alteración: Habrá activación sostenida, no necesita estímulos para conservar . Prácticamente cada tumor contiene mutaciones tanto en la forma anti-tumorigénico de las deleciones y micromutaciones, en el que los genes supresores de daño de inactivación son mucho más común que la activación de mutaciones en oncogenes. Gatekeeper genes regulate neoplasic development by inhibiting its growth or killing it (Kinzler and Vogelstein 1997). The all-important next step was to systematically investigate and reproduce these diseases in experimental surroundings. The loss of pRb protein function provokes an increase in the cell proliferation rate and an absence of terminal differentiation. 2005. A carcinogênese química inclui três etapas definidas como iniciação, promoção e progressão. HANAHAN D AND WEINBERG RA. 1998. To overcome the advantages of these methods, and those previously mentioned regarding in vivo assays, new methods were developed using human tissues and biologicalfluids to obtain specific biomarkers, which combined with the epidemiological studies gave results that are more reliable. Several studies have been developed in order toevaluate the differences between several exogenous and endogenous factors on individual susceptibility to carcinogenesis (Table I) (Barrett 1993, Bartsch and Hietanen 1996, Maronpot 1996, Lutz 1998, 1999, Ishikawa et al. Mod Pathol 4: 371-382. FARMER PB. These have lead to incorrect interpretations when animal models are used in the research and analysis of carcinogenic properties of chemical compounds (Guengerich 2000, Gonzalez 2001, Gonzalez and Kimura 2001). Yet, it is difficult to understand the individual contribution of a certain chemical within a complex situation like environmental contamination. 2004. The most well understood epigenetic mechanisms involve DNA methylation and histone acetylation, methylation, and phosphorylation (Fig. aparente tem duas explicações possíveis: ou o efeito genotóxico não foi identificado nos Thus it is best to think of mutated cancer genes as contributing to, rather than causing, cancer (Vogelstein and Kinzler 2004). GRISHAM JW, KAUFMANN WK AND KAUFMAN DG. Las reacciones más comunes en la carcinogénesis, esenciales para la aparición y el desarrollo de un tumor son cambios en el nivel y la relación de aminas biogénicas en el sistema nervioso central, particularmente el hipotálamo, que afectan, entre otras cosas, de la mejora mediada por la hormona de la proliferación celular, y trastornos de hidratos de carbono y grasa intercambio, cambios en la función de varias partes del sistema inmune. Cells which are proliferating have less time to repair the damaged DNA and remove covalent bonds that chemicals establish with the DNA - known as adducts (Heidelberger 1977, Richardson et al. La aparición de una célula cancerosa en el cuerpo no conduce inevitablemente al desarrollo de una enfermedad tumoral y a la muerte del organismo. Nature and nurture - lessons from chemical carcinogenesis. das características que contribuem para a malignidade e a sua inibição impede o WEISBURGER JH. Para la inducción del tumor, es necesaria una acción prolongada y relativamente continua del promotor. SANTELLA RM, GAMMON M, TERRY M, SENIE R, SHEN J, KENNEDY D, AGRAWAL M, FARAGLIA B AND ZHANG F. 2005. The detection of chemical carcinogens in an alternative medium-term bioassay. Carcinogenesis 21: 371-377. Fase tóxicodinámica. Based on data accumulated from experiments in recent years, and according to Gutiérrez and Salsamendi (2001), they provide the following factors which favour these assays: a) All substances that revealed carcinogenic activity in humans, apart from rare exceptions, are also positive in rodent assays. MILLER JA AND MILLER EC. alterados. 2000). Strategies for inhibiting multistage carcinogenesis based on signal transduction pathways. Para que se lleve a cabo el proceso metastásico, se requiere The molecular biology of cancer. Características de las etapas del proceso de carcinogénesis Etapa de Iniciación. Neste último caso pode pensar-se num efeito indirecto do The main carcinogenic compound seems to be ptaquiloside, which induces mammary tumors, intestinal tumors and hematuria in rats. Changes in the genome's structure occur across the three stages of neoplasic development (Simons 1995, Pitot 2001, Luch 2005). 1994. En términos generales, la carcinogénesis se considera hasta la fecha como resultado de la interrupción de la homeostasis celular, que se expresa en una pérdida de control sobre la reproducción y para mejorar los mecanismos de defensa celular de la acción de las señales de apoptosis, es decir, la muerte celular programada. selecção favorece o crescimento das células com maior autonomia, ou seja, com o ciclo Nat Rev Mol Cell Biol 1: 233-236. Errors in DNA replication are also associated with initiation. Cells, which are part of benign neoplasias, grow more slowly, and in general, they do not disturb normal tissue function, unless they compress vital structures (Player et al. 2003. p27(Kip1) (Cdkn1b)-deficient mice are susceptible to chemical carcinogenesis and may be a useful model for carcinogen screening. mutações nos proto-oncogenes e genes supressores de tumor. These assays use prokaryotic and human cells, have differing levels of complexity, and can overcome the ethical aspects related to animal experimentation (Masters 2000). 1996, Trosko 2001). 2003). We will classify different types of carcinogens in function of their active mechanisms and we will describe the molecular targets of carcinogens. Mammalian p53R2 protein forms an active ribonucleotide reductase. Some years later, and based on these observations, a guide distributed to Danish chimney sweeps recommended that these professionals take a daily bath to avoid such an occurrence (Hayes 1995, Gutiérrez and Salsamendi 2001). Analysis of modifying factors in chemical carcinogenesis. 1999, Gutiérrez and Salsamendi 2001). Cancer 40: 430-433. Carneiro et al., 1997; Trosko, 2001). The histopathological observation of neoplasias, be they induced or spontaneous, enables us to better evaluate carcinogenesis, but it may not be enough to identify more subtle alterations such as molecular changes (Huff 1992, Maronpot 1996). cancer stages; carcinogenesis evaluation; chemical carcinogens; chemical carcinogenesis. The role of stem cells and gap junctional intercellular communication in carcinogenesis. 1995, Maronpot and Boorman 1996). 2003. A ocorrência de danos no ADN é o primeiro evento da carcinogénese química With the discovery of different mechanisms involved in carcinogenesis, this definition is now incomplete (Butterworth and Bogdanffy 1999). Mutat Res 433: 15-22. It can be done via the excision of bases, or nucleotides, recombined repair or mismatch repair (Farmer 1994, Moustacchi 1998, Miller et al. For them, carcinogenesis was a complex process including one phase called initiation and another called promotion, with one or more genetic changes necessary for cancer development. Further delineation of the rate limiting step. 62, Núm. Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid. Ahora se ha establecido que el cáncer o el cáncer - una enfermedad del aparato genético de la célula, que se caracteriza por procesos patológicos crónicos a largo plazo, o más simplemente, la carcinogénesis, que se desarrollan en el cuerpo durante décadas. primeiro passo para nela se transformar, depois de ocorrerem sucessivas alterações 2005). Adduct repair is coordinated by several enzymes and controlled by different genes. When applied in low doses, none of these substances have carcinogenic properties by themselves. 11 am Grupo#2 Integrantes * Isis Martinez 20101002441 *keila Machado 20061900327 *Julia Elvir 20121007439 *Kelin Zuniga 20131004387 *Maria Duran 20131004889. Between 1980 and 1990, the discoveries made via the molecular biology of proto-oncogenes and tumour suppressor genes strengthened the case behind this supposition (Cohen 1998). NAKANO K, BALINT E, ASHCROFT M AND VOUSDEN KH. CAMARGO JLV, SALVADORI DMF, ROCHA NS, BAEBISAN LF AND RIBEIRO LR. Drinking water mutagenicity and gastrointestinal and urinary tract cancers: an ecological study in Finland. MIRSALIS JC, STEINMETZ KL, HAMILTON CM, BAKKE JP AND GARIN KE. La teoría oncogénica de la carcinogénesis ha permitido acercarse a la comprensión de por qué diferentes factores etiológicos causan una enfermedad intrínsecamente. La carcinogénesis de vejiga urinaria en los roedores de urotelial tumors chemically induced in the urinary bladder laboratorio es un proceso que envuelve una serie de etapas are morphologically and histologically similar to the human There is a positive correlation between the quantity of adducts detected in animal models and the number of neoplasias developed (Yuspa and Poirier 1988, Williams 2001, Baird and Mahadevan 2004). Animal models deficient in p53 protein and ras genes are more sensitive to the identification of genotoxic carcinogens (Sills et al. The 10 Walter Hubert Lecture. HAYSES JD AND PULFORD DJ. 1999. Universidad Universidad Juárez Autónoma de Tabasco Materia ANATOMÍA PATOLÓGICA (F1508) Libros listados Patologia Estructural Y Funcional Robbins y Cotran. La historia de la carcinogénesis química etiología multifactorial, alteraciones multietapas, multianuales, multigenéticas y enfermedad multitrayecto. Todos los derechos reservados. GUTIÉRREZ JB AND SALSAMENDI AL. J Braz Ass Advan Science 51: 22-26. f) Synergic effects are not taken into account with other chemical compounds. Da ativação descontrolado de um único prot-concogene 2003). Esta evolución de las propiedades del tumor se denomina "progresión tumoral". Cancer Res 14: 327-339. SARASIN A AND MEUNIER-ROTIVAL M. 1976. 1998. Aunque el proceso incluye Mutat Res 489: 17-45. Br J Cancer 1: 379-382. The results obtained using rodents act as back-up against any false negatives obtained through in vitro researches and can be used to prevent, or reduce, human exposure to a suspected carcinogen (Payne and Kemp 2003). menos tempo disponível para os reparar (Richardson et al., 1986; Frowein, 2000). Mechanisms for the initiation and promotion of carcinogenesis: a review and a new concept. Crit Rev Biochem Mol Biol 30: 445-600. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals (Grisham et al. 2001. Toxicol Lett 120: 269-280. No entanto, as células em proliferação têm ¿Cuáles son las tres etapas de la carcinogénesis? MOSTAFA MH, SHEWEITA SA AND O'CONNOR PJ. 2004. 1999. Carcinogenesis 21: 1611-1618. 1991, Butterworth et al. 1992, Ashby 1996, Weisburger 1998, Frowein 2000, Bertram 2001, Lutz 2001, Williams 2001, Baird and Mahadevan 2004). BAIRD WM AND MAHADEVAN B. The p53R2 and R1 complex functions as an active RNR (Guittet et al. Out of all of these, proto-oncogenes, tumour suppressor genes and cell cycle regulator genes assume a particular importance (Mehta 1995, Nguyen-ba and Vasseur 1999, Klaunig et al. Chemicals associated with tumours of the kidney, urinary bladder and thyroid gland in laboratoryrodents from 2000 US National Toxicology Program / National Cancer Institute bioassays for carcinogenicity. aditivo, o desenvolvimento neoplásico depende da dose do carcinogénico, aumentando Promoter compounds do not interact directly with DNA and unchain biological effects without being metabolically activated (Yuspa et al. Es un hecho que las manifestaciones agudas, principalmente cutáneas, conjuntivales y respiratorias, resultado de la exposición a los contaminantes atmosféricos, son las que más atraen la atención; los efectos a mediano y largo plazos son los más peligrosos, y por lo mismo son los que requieren una atención permanente.
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