Lymphomas and leukemias are the most common cancer in children and young adults and in utero exposure to carcinogens may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was administered to pregnant mice (15 mg/Kg b.w., gavage) on gestation day 17. Significant mortalities in young offspring were observed due to T-cell lymphoma. Lung and liver tumors also were observed in survivors at 10 months of age. To assess the role of the Aryl Hydrocarbon Receptor (AHR), we utilized crosses of B6129SF1/J (responsive) mice with strain 129S1/SvImJ (non-responsive). Offspring born to AHR non-responsive mothers had greater susceptibility to lymphoma, irrespective of offspring genotype. Responsive offspring displayed increased mortality if the mother was responsive. Lung adenomas showed Ki-ras mutations and exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. To examine the risk/benefit of maternal dietary phytochemical treatment against transplacental cancer, 2000 ppm indole-3-carbinol (I3C) was given to pregnant mice through diet from gestation day 9 till weaning. I3C significantly lowered mortality caused by lymphomas regardless of the maternal genotype, and also reduced lung tumor multiplicity in offspring born to AHR [superscript b-l/d] dams. Distribution of I3C in most maternal and fetal tissues was quantified following a single gavage of [¹⁴C]-I3C to the pregnant mice. DBP-DNA adducts were observed in both maternal and fetal tissues by ³³P postlabeling and HPLC analysis and were modulated by I3C and AHR genotype. I3C also modulated phase I and phase II enzyme protein expression in dams and gene expression in newborn thymus. I3C chemoprotection may involve modification of the bioavailability of DBP to the fetus and/or modulation of gene expression in the fetus as well. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice. These results raise the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults and, that the addition of chemoprotective agents to the maternal diet may reduce cancer risk among offspring. / Graduation date: 2006

Thesis (M.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Masters Abstracts International, Volume: 45-06, page: 3139. Adviser: Arch I. Carson. Includes bibliographical references.

Orientador: Noeme Souza Rocha / Banca: Michiko Sakate / Banca: Carla Adriene da Silva Franchi / Banca: Ana Lúcia Abreu Silva / Banca: Márcia Bersane Araújo de Medeiros / Resumo: Cromatografia Líquida de Alta Eficiência - HPLC foi adaptada para detectar e identificar inseticidas piretróides no tecido adiposo adjacente ao tumor maligno de mama de 10 cadelas, sem predileção por raça e idade. Após a cirurgia, as massas eram examinadas cuidadosamente para lesões neoplásicas malignas. Cinco gramas de tecido adiposo adjacente ao tumor foram colhidos para demonstração de contaminantes ambientais. Os piretróides identificados foram aletrina, cialotrina, cipermetrina, deltametrina e tetrametrina, com nível de contaminação de 40%. A histopatologia demonstrou sete cadelas (70%) como carcinoma complexo, duas (20%) com carcinoma simples e uma (10%) com carcinoma anaplásico. Desses tumores, (80%) apresentaram grau III e (20%) grau I de agressividade. O nível de contaminação foi observado nos tumores mais agressivos. Esta foi à primeira demonstração que se tem conhecimento que o nível de contaminates ambientais pode ser detectado no tecido adiposo de cadela com tumor maligno de mama, pela HPLC. O presente resultado sugere que contaminantes ambientais possam estar envolvidos com o processo de formação ou associação ao risco de desenvolvimento do câncer de mama de cadela, sendo um indicador para auxiliar na monitoração de piretróides. / Abstract: High Precision Liquid Chromatography - HPLC was adapted to detect and identify pyrethroid insecticides in adipose tissue adjacent to malignant tumor mammary gland tumor in 10 female dogs, without predilection for breed or age. After surgery, the masses were examined carefully for malignant neoplastic lesions. Five grams of adipose tissue adjacent to the tumor were collected for demonstration of environmental contaminants. The pyrethroids identified were allethrin, cyalothrin, cypermethrin, deltamethrin and tetramethrin, with a contamination level of 40%. The histopathology demonstrated seven female dogs (70%) as having complex carcinoma, two (20%) with simple carcinoma and one (10%) with anaplastic carcinoma. Of these tumors, (80%) presented aggressiveness degree III and (20%) degree I. The contamination level was observed in more aggressive tumors. This was the first known demonstration in which the level of environmental contaminants could be detected in adipose tissue of female dogs with malignant mammary tumor, by HPLC. The present result suggests that environmental pollutants can be involved with the formation process or association to the risk of development of female dog's breast cancer, being an indicator to aid in monitoring pyrethroids. / Doutor

No description available.

IL-33 participa em diversas doenças com funções pró-inflamatórias e protetoras, de acordo com o contexto do microambiente. Com relação a biologia tumoral, o papel de IL-33 ainda é controverso. Estudos demonstraram que IL-33 possui efeitos pró e anti-inflamatórios em diferentes modelos animais de câncer. A presença desta citocina no estroma favorece a imunossupressão pela ativação de células T reguladoras e células mieloides supressoras. IL- 33 pode em outras situações promover a imunogenicidade e a resposta imune antitumoral de tipo 1 através das células T citotóxicas e células Natural Killers. Contudo o efeito preciso de IL-33 em diferentes tipos de câncer permanece incerto. Sendo assim, compreender o papel de IL-33 na imunobiologia do câncer, poderia direcionar esta citocina como um possível alvo em imunoterapias contra o câncer. Considerando, portanto, a pluralidade desta citocina no desenvolvimento de uma resposta imune, no presente estudo buscamos avaliar os efeitos do tratamento com anti-IL-33 em modelo experimental de carcinoma espinocelular de pele em camundongos BALB/c de linhagem selvagem. Ao final dos protocolos de indução e tratamento, a análise histopatológica revelou que o tratamento com anti-IL-33 levou a menor incidência de carcinoma espinocelular in situ e diminuição das atipias celulares e, consequentemente, do grau de displasia. O tratamento com anti-IL-33 levou a aumento nos percentuais de células B e diminuição nas percentagens de linfócitos T CD4+, células dendríticas, células TREG e macrófagos isolados do microambiente tumoral. Ademais, o tratamento com anti-IL-33 levou a aumento na percentagem de linfócitos T CD4+ produtores de IFN- e menor percentagem de linfócitos T CD4+ e CD8+ produtores de IL-4 nos linfonodos. Em camundongos submetidos ao tratamento, observou-se menor produção de TGF- no microambiente tumoral, sem interferir de modo significativo com a produção de IFN-, IL-4, IL-10 e IL-17. Os nossos resultados indicam que o tratamento com anti-IL-33 poderia ser alvo de novos estudos em busca de estratégias terapêuticas para o carcinoma espinocelular de pele. / IL-33 participates in several diseases with pro-inflammatory and protective functions, according to the context of the microenvironment. Related to tumor biology, the role of IL-33 is still controversial. Studies have shown that IL-33 has pro and anti-inflammatory effects in different animal models of cancer. Its presence in the stromal and tumor serum increases the immunosuppression by the activation of regulatory T cells and myeloid-derived suppressor cells. On the other hand, the intracellular form in tumor cells promotes immunogenicity and the antitumor type 1 immune response through cytotoxic T cells and natural killer cells. However, the precise effect of IL-33 on cancer conditions remains uncertain. Thus, understanding its role in the immunobiology of cancer could target this cytokine as a marker in cancer immunotherapies. Considering, the range of IL-33 in the development of an immune response, this study aims to evaluate the effects of the anti-IL-33 treatment on wild type BALB/c mouse squamous cell carcinoma (SSCC) development. Histopathological analysis revealed that anti-IL-33 treatment decreased the dysplasia. In addition, anti-IL-33 treatment showed an increasing percentage of B cells and reduced the percentage of CD4+ T lymphocytes, dendritic cells, TREG cells and macrophages in the tumor microenvironment. In the lymph node, anti-IL-33 treatment induced a shift towards the TH1 type cytokine profile and reduced the percentage of IL-4 expressing CD4+ and CD8+ cells. Additionally, anti-IL-33 treatment showed a reduced TGF- production in the tumor microenvironment, but with no changes to the IFN-, IL-4, IL-10 e IL-17 production. Taken together these results indicate that anti-IL-33 treatment could be the subject of further studies of therapeutic strategies for squamous cell carcinoma of the skin.

Recent studies from our laboratory on the aromatic amine carcinogen, 4-aminobiphenyl (ABP) have shown a significantly lower prevalence of ABP-induced liver tumors in male mice lacking the N-acetyltransferases, and a dramatically lower prevalence in females than in males, but no association of tumor prevalence with strain or sex differences in levels of acute ABP-induced DNA damage. This thesis aimed to investigate the possible involvement of acute cytotoxic effects of ABP in the development of a tumor-promoting inflammatory environment. We found that wild-type male mice showed higher acute hepatotoxicity to ABP, as well as, a possible trend towards higher serum levels of the pro-inflammatory cytokine interleukin 6. This correspondence between acute ABP cytotoxicity and inflammatory response with ultimate tumor growth is consistent with a model whereby ABP not only initiates cells by damaging DNA but also promotes tumor growth in a gender-selective fashion that may be governed by gonadal hormone influences.

Recent studies from our laboratory on the aromatic amine carcinogen, 4-aminobiphenyl (ABP) have shown a significantly lower prevalence of ABP-induced liver tumors in male mice lacking the N-acetyltransferases, and a dramatically lower prevalence in females than in males, but no association of tumor prevalence with strain or sex differences in levels of acute ABP-induced DNA damage. This thesis aimed to investigate the possible involvement of acute cytotoxic effects of ABP in the development of a tumor-promoting inflammatory environment. We found that wild-type male mice showed higher acute hepatotoxicity to ABP, as well as, a possible trend towards higher serum levels of the pro-inflammatory cytokine interleukin 6. This correspondence between acute ABP cytotoxicity and inflammatory response with ultimate tumor growth is consistent with a model whereby ABP not only initiates cells by damaging DNA but also promotes tumor growth in a gender-selective fashion that may be governed by gonadal hormone influences.

Orientador: Luis Fernando Barbisan / Resumo: Perturbações no ambiente uterino e nos estágios iniciais da vida, por fatores nutricionais e/ou alterações hormonais, podem predispor os recém-nascidos a doenças crônicas na vida adulta. A restrição proteica gestacional (RPG) e a exposição ao Bisfenol A (BPA), nas fases pré e pós-natal, alteram o desenvolvimento mamário e aumentam a suscetibilidade a carcinogênese mamária. Assim, este trabalho investigou os possíveis efeitos da RPG e sua associação com a exposição pós-natal ao BPA sobre o desenvolvimento da glândula mamária e a suscetibilidade à carcinogênese mamária induzida pela 7,12-dimetilbenzantraceno (DMBA). Fêmeas prenhes da linhagem Sprague-Dawley foram alocadas em quatro grupos experimentais: dieta normoproteica (DNP); dieta hipoproteica (DHP); DNP+BPA e DHP+BPA. O BPA (1 mg/L) foi ministrado na água de beber à prole do dia pós-natal (DPN) 21 até o DPN 51. No DPN 51, fêmeas da prole (n=10/grupo) foram eutanasiadas para avaliação das glândulas mamárias, enquanto o restante (n=11/grupo) recebeu dose única de DMBA (30 mg/kg, i.g.), e foram eutanasiadas no DPN 250 para avaliação de tumores mamários. A RPG e a exposição ao BPA não alteraram o crescimento da árvore mamária, as unidades de brotos e ductos terminais (TEBs e TDs), a proliferação celular (Ki-67), a expressão do receptor de estrógeno β (RE-β) e área ocupada por fibras colágenas nas glândulas mamárias no DPN 51. Entretanto, nos grupos DHP e DNP+BPA houve redução na área correspondente ao tecido epitelial glandul... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Disturbances in the uterine environment and in the early stages of life, due to nutritional factors and/or hormonal changes, may predispose newborns to chronic diseases in adult life. Gestational protein restriction (GPR) and exposure to Bisphenol A (BPA), in the pre and postnatal phases alter breast development and increase susceptibility to mammary carcinogenesis. Therefore, the aim of this study was to investigate the possible effects of GPR and its association with postnatal exposure to BPA on mammary gland development and on susceptibility to 7,12-dimethylbenzanthracene (DMBA) induced mammary carcinogenesis. For this purpose, pregnant females of the Sprague-Dawley strain were allocated into four experimental groups: normoprotein diet (NPD); hypoproteic diet (HPD); NPD+BPA and HPD+BPA. BPA (1 mg/L) was given in drinking water to offspring from postnatal day (PND) 21 to PND 51. At the PDN 51, offspring females (n=10/group) were euthanized for mammary glands evaluation, while the remainder (n=11/group) received a single dose of DMBA (30 mg/kg, ig) and were euthanized at the PND 250 for breast tumors evaluation. GPR and BPA exposure did not alter the growth of the mammary tree, number of bud and terminal duct (TEBs and TDs), cell proliferation (Ki-67), expression of estrogen receptor β (ER-β) and collagen fibers area in the mammary glands at PDN 51. However, in the HPD and NPD+BPA groups was a decreased area corresponding to the glandular epithelial tissue and the associatio... (Complete abstract click electronic access below) / Mestre

Submitted by Muriele Bertagna Varuzza null (mbvaruzza@aluno.ibb.unesp.br) on 2018-02-27T20:55:50Z No. of bitstreams: 1 Dissertação Mestrado Muriele Bertagna Varuzza.pdf: 4268193 bytes, checksum: 9b5e69a8c4d6ccec96ff6ee74a116eca (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-03-05T17:34:50Z (GMT) No. of bitstreams: 1 varuzza_mb_me_bot.pdf: 4268193 bytes, checksum: 9b5e69a8c4d6ccec96ff6ee74a116eca (MD5) / Made available in DSpace on 2018-03-05T17:34:50Z (GMT). No. of bitstreams: 1 varuzza_mb_me_bot.pdf: 4268193 bytes, checksum: 9b5e69a8c4d6ccec96ff6ee74a116eca (MD5) Previous issue date: 2018-02-09 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Perturbações no ambiente uterino e nos estágios iniciais da vida, por fatores nutricionais e/ou alterações hormonais, podem predispor os recém-nascidos a doenças crônicas na vida adulta. A restrição proteica gestacional (RPG) e a exposição ao Bisfenol A (BPA), nas fases pré e pós-natal, alteram o desenvolvimento mamário e aumentam a suscetibilidade a carcinogênese mamária. Assim, este trabalho investigou os possíveis efeitos da RPG e sua associação com a exposição pós-natal ao BPA sobre o desenvolvimento da glândula mamária e a suscetibilidade à carcinogênese mamária induzida pela 7,12-dimetilbenzantraceno (DMBA). Fêmeas prenhes da linhagem Sprague-Dawley foram alocadas em quatro grupos experimentais: dieta normoproteica (DNP); dieta hipoproteica (DHP); DNP+BPA e DHP+BPA. O BPA (1 mg/L) foi ministrado na água de beber à prole do dia pós-natal (DPN) 21 até o DPN 51. No DPN 51, fêmeas da prole (n=10/grupo) foram eutanasiadas para avaliação das glândulas mamárias, enquanto o restante (n=11/grupo) recebeu dose única de DMBA (30 mg/kg, i.g.), e foram eutanasiadas no DPN 250 para avaliação de tumores mamários. A RPG e a exposição ao BPA não alteraram o crescimento da árvore mamária, as unidades de brotos e ductos terminais (TEBs e TDs), a proliferação celular (Ki-67), a expressão do receptor de estrógeno β (RE-β) e área ocupada por fibras colágenas nas glândulas mamárias no DPN 51. Entretanto, nos grupos DHP e DNP+BPA houve redução na área correspondente ao tecido epitelial glandular e a associação (DHP+BPA) aumentou a área ocupada pelo fat pad. A exposição ao BPA (DNP+BPA e DHP+BPA) aumentou os índices apoptóticos, a RPG aumentou a expressão do receptor de estrógeno α (RE-α) e a associação (DHP+BPA) aumentou os receptores de progesterona (RP) nas glândulas mamárias no DPN 51. Os grupos DHP, DNP+BPA e DHP+BPA apresentaram menor latência tumoral. Além disso, os grupos que receberam BPA apresentaram maior incidência e multiplicidade tumoral. Considerando esses resultados, podemos concluir que a RPG e o BPA aumentaram a suscetibilidade ao desenvolvimento de tumores mamários induzidos pela DMBA, mas a associação (DHP+BPA) não levou ao aumento do risco. / Disturbances in the uterine environment and in the early stages of life, due to nutritional factors and/or hormonal changes, may predispose newborns to chronic diseases in adult life. Gestational protein restriction (GPR) and exposure to Bisphenol A (BPA), in the pre and postnatal phases alter breast development and increase susceptibility to mammary carcinogenesis. Therefore, the aim of this study was to investigate the possible effects of GPR and its association with postnatal exposure to BPA on mammary gland development and on susceptibility to 7,12-dimethylbenzanthracene (DMBA) induced mammary carcinogenesis. For this purpose, pregnant females of the Sprague-Dawley strain were allocated into four experimental groups: normoprotein diet (NPD); hypoproteic diet (HPD); NPD+BPA and HPD+BPA. BPA (1 mg/L) was given in drinking water to offspring from postnatal day (PND) 21 to PND 51. At the PDN 51, offspring females (n=10/group) were euthanized for mammary glands evaluation, while the remainder (n=11/group) received a single dose of DMBA (30 mg/kg, ig) and were euthanized at the PND 250 for breast tumors evaluation. GPR and BPA exposure did not alter the growth of the mammary tree, number of bud and terminal duct (TEBs and TDs), cell proliferation (Ki-67), expression of estrogen receptor β (ER-β) and collagen fibers area in the mammary glands at PDN 51. However, in the HPD and NPD+BPA groups was a decreased area corresponding to the glandular epithelial tissue and the association (HPD+BPA) increased the fat pad. Exposure to BPA (NPD+BPA and HPD+BPA) increased apoptotic indexes, GPR increased estrogen receptors α expression (ER-α) while their association (HPD+BPA) increased progesterone receptors (PR) in the mammary glands. The groups HPD, NPD+BPA and HPD+BPA also showed lower tumor latency. In addition, the groups that received BPA presented higher tumor incidence and multiplicity. These results suggests that GPR and BPA exposure increased the susceptibility to mammary carcinogenesis induced by DMBA, but the association (HPD+BPA) did not increase the risk. / Processo Fapesp nº 2016/01220-2

O composto estudado neste trabalho foi o corante comercial CI Disperse Blue 291 (DB291), que contém o aminoazobenzeno 2-[(2-bromo-4,6-dinitrofenil)azo]-5-(dietilamino)-4-metoxiacetanilida. Esse produto é um azo-corante disperso usado largamente pelas indústrias têxteis para o tingimento de poliéster e pode ser encontrado em ambientes aquáticos oriundo da descarga de efluentes industriais, podendo levar à exposição de humanos por meio da ingestão de água ou alimentos contaminados. Portanto, faz-se importante a avaliação toxicológica do DB291. Este produto apresentou atividade mutagênica para linhagens de Salmonella typhimurium que possuem alta expressão das enzimas nitrorredutase e Ο-acetiltransferase. Tais enzimas também são expressas pelas bactérias da flora intestinal humana e de roedores e, desempenham importante papel na biotransformação de substâncias presentes na luz intestinal. O objetivo deste trabalho foi investigar a atividade do corante DB291 na indução de lesões pré-neoplásicas no cólon de ratos, avaliada pelo teste do cometa e pelo desenvolvimento de focos de criptas aberrantes (FCAs). Resultados com 2, 8, 16 e 24 semanas de tratamento demonstraram que o DB291 não foi capaz de induzir FCAs em ratos tratados por gavage com a dose de 50mg/kg de peso corpóreo, três vezes por semana em dias alternados. Entretanto, resultados com o teste do cometa demonstraram que o corante foi capaz de causar danos ao DNA das células da mucosa do cólon de ratos tratados por via intra-retal. Estes resultados sugerem que o DB291 possui atividade genotóxica in vivo. Considerando a resposta genotóxica para o teste do cometa, a alta atividade mutagênica no teste Salmonella microssoma e o recente relato de que o DP291 causou danos em células de fígado humano (HepG2), faz-se necessário a realização de testes de carcinogênese de longa duração para avaliação segura do seu potencial carcinogênico, não somente em cólon, mas em outros órgãos tais como fígado e bexiga. / The commercial disperse dye product CI Disperse Blue 291 , which contain the aminoazobenzene 2-[(2-bromo-4,6-dinitrophenyl)azo]-5-(diethylamino)-4-methoxyacetanilide (CAS registry no. 56548-64-2) is used for polyester fibers dyeing. It can be released in the aquatic environment through the discharge of industrial effluents. Humans can be exposed through the consumption of water and food contaminated with this product therefore its toxicological properties are important to be evaluated. This product showed elevated mutagenic activity with nitroreductase and Ο-acetyltransferase overproducing Salmonella strains. These enzymes are also expressed by human intestinal microflora, making intestines a possible target organ to the development of cancer after exposure to this product. The aim of this study was to investigate the effects of the commercial disperse dye product containing the CI Disperse Blue 291 on rat colon carcinogenesis, evaluated by the single cell gel assay (comet assay) and by aberrant crypt foci development. Results within different experimental periods showed the DB291 were not able to induce preneoplastic lesions in the colon of rats orally treated with 50mg/kg b.w., three times a week. The DB291 induced damages in the DNA of the rats colon mucosa, evaluated by the comet assay. These data indicate that the OB291 showed genotoxic activity in the colon mucosa cells. Considering these results, the mutagenic activity with Salmonella test and the recent data that the OB291 presents toxicity to human liver cells (HepG2), further long time carcinogenesis assays are needed to security evaluation of its carcinogenic potential, not only in colon, but also another organs like liver and kidney.