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Medical radiation is vital in acquiring a patient diagnosis, but some clinicians are concerned with the perceived risks associated with ionizing radiation. This risk is heightened when incorporating in utero exposures due to the risk to the developing foetus. Although other organ systems have been studied, there is a paucity of data on the effects to the respiratory system from in utero exposures. The aim of this thesis was to understand the long-term effects on the respiratory system from in utero exposures, but as a first step, it was important to determine what levels patients receive whilst admitted to hospital. Two polar populations were chosen based on their predicted exposure levels during hospitalisation; one with high levels, intensive care unit (ICU) patients, and one with low levels, pregnant patients. Most patients cumulatively received < 1mSv with median exposures of 0.99 mSv (ICU patients) and 0.02 mSv (pregnant patients). However, both cohorts had patients that surpassed 10 mSv. To assess the effects from in utero exposures on the respiratory system, two animal models were conducted both exposed during late gestation, one healthy model and one acute lung injury model. In the health animal model, cardiovascular outcomes were also measured, however, ionizing radiation (50, 300, 1000 mGy) did not appear to influence these two organ systems from the outcomes measured. In the acute lung injury model, lipopolysaccharide (3mg/Kg) stimulated an acute lung inflammatory response, however, there was also no overt effect of radiation from the outcomes measured (10, 100, 1000 mGy). In both models, ionizing radiation did cause growth restriction up to 16 weeks of age, but this was only observed from doses above 100 mGy. Overall, the levels of ionizing radiation patients receive is low and from diagnostic exposures during pregnancy, there does not appear to be any strong effects on the developing foetus. / Thesis / Doctor of Philosophy (PhD) / Radiation is necessary in medicine to observe the internal structures of the body, but it can sometimes cause unwanted biological changes within the body. This risk is heightened when considering exposure to developing baby because of the dynamic changing it is naturally going through and possible lifetime left to experience effects. This thesis aimed to understand what levels of radiation patients receive in hospital, observing one population predicted to receive high levels (Intensive care patients) and one predicted to receive low levels (pregnant patients). Overall, the majority of patients in the two cohorts received less than the recommended yearly public limit of 1 millisievert (mSv). The second aim was to observe the effects on the growth, lungs and hearts of the babies in an animal model when they are exposed during pregnancy. Radiation had no overall effect on the lungs or heart but can reduce body weight at moderate (100 milligrays (mGy) and high (1000 mGy) exposures.

The interaction between the embryo and fetus with the maternal environment can have both short- and long-term consequences on health and development after birth. In some cases, these changes may be detrimental to the individual, but in other cases these developmental changes may be beneficial and manipulated to produce desired effects. Our interest is to use this concept of fetal programming to improve skeletal muscle development and meat production in ruminants. To achieve this, we targeted the period of gestation when fetal muscle fiber formation occurs. Primary muscle fibers form during embryonic development, and it is this small number of primary muscle fibers that will serve as templates for secondary fiber formation that occurs in the fetus during mid-gestation. Supplementing amino acids that influence blood flow within the reproductive tract is one potential way to provide fetuses with added nutrients during gestation, and this supplementation strategy may be especially useful when the maternal diet is compromised. L-citrulline was chosen for this work because of its long half-life in maternal circulation. This work utilized twin-bearing ewes with a moderate dietary energy restriction to assess the effects of mid-gestational L-citrulline supplementation on umbilical blood flow, placental function, neonatal lamb size, and lamb performance. We hypothesize that i.v. administration of L-citrulline will increase uterine and placental blood flow in gestating ewes and this will improve fetal growth, development, and overall postnatal performance. Blood flow parameters were not influenced by treatment (P>0.05). Circulating levels of progesterone and pregnancy-specific protein B (PSPB) were used as indicators of placental function and were unaffected by treatment administration (P>0.05). A treatment by time interaction was detected in both analyses, but no differences between treatments were detected within any time points. There was no effect of treatment on lamb weights or survival to weaning (P>0.05). Lamb sex effects are absent with the exception that body weights were greater in ewe lambs (P>0.05). There was no effect of treatment on any carcass traits or visceral organ weights assessed, though there was an effect of sex on dressing percentage and pancreas weight with wethers having a greater dressing percentage and heavier pancreases per kg body weight than that of ewes (P<0.05). In summary, contrary to our hypothesis L-citrulline supplementation to pregnant ewes under a minor to moderate metabolic challenge had no impact on blood flow and provided no programming benefit to the lambs. / Master of Science / The global population continues to grow, along with the consumption of animal protein. This can be met with increasing the numbers of animals within our food production systems, however, there is also increasing pressure for livestock production systems to produce more while utilizing less space and resources. And simultaneously, we face growing concerns about climate change, its impacts on agriculture, and the role of agriculture in both the cause and any future solution. To combat both these issues, the efficiency of our livestock systems needs to improve with each individual animal becoming much more efficient. This increase in efficiency can occur in many ways including reproductive efficiency, feed efficiency, and in overall producing more meat per individual. The improvement in efficiency of an animal can begin in the womb. Livestock in meat production spend 35-40% of their life within the uterus being nourished by their mother. The interactions the embryo and fetus have with the maternal environment during this time can have both short- and long-term impacts on health and development after birth. In some cases, these changes may be detrimental to the individual, but in other cases these developmental changes may be beneficial and manipulated to produce the desired effects. Thus, it is important to understand the impact of these fetal-maternal interactions as it directly affects both fetal growth and growth and development after birth. This concept is known as fetal programming. Our interest is to use this concept to improve skeletal muscle development and meat production in cattle and sheep. To achieve this, we targeted the period of pregnancy when fetal muscle formation occurs. Primary muscle fibers form early in pregnancy, and it is this small number of primary muscle fibers that will serve as templates for secondary fiber formation that occurs in the fetus during mid-pregnancy. Supplementing amino acids that influence blood flow within the reproductive tract is one potential way to provide fetuses with added nutrients during pregnancy, and this supplementation strategy may be especially useful when the maternal diet is compromised. L-citrulline was chosen for this work because of its long half-life in maternal circulation. This work utilized twin-bearing ewes with a moderate dietary energy restriction to assess the effects of L-citrulline supplementation on blood flow, placental function, newborn lamb size, and lamb performance. We hypothesize that intravenous administration of L-citrulline will increase uterine and placental blood flow in pregnant ewes and this will improve fetal growth, development, and overall postnatal performance. There was no beneficial effect on blood flow to the fetus and on placental function. Additionally, there were very minimal effects on carcass traits or internal organ weights assessed. In summary, contrary to our hypothesis L-citrulline supplementation to pregnant ewes under a moderate metabolic challenge had no impact on blood flow and provided no programming benefit to the lambs. We can conclude that the potential benefit of amino acid supplementation was not realized in our sheep model.

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O sobrepeso/obesidade é uma condição multifatorial e poligênica que pode resultar em desequilíbrio calórico. Uma vez instalada, a obesidade tende a se manter, de modo que a prevenção figura como principal recurso e, a compreensão das causas, essencial. Este estudo teve o objetivo de avaliar a associação da expressão de genes relacionados à obesidade, inflamação e perfil lipídico em gestantes com sobrepeso/obesidade e eutróficas, na adiposidade dos recém-nascidos. Trata-se de um estudo prospectivo, inserido em estudo coorte de base populacional, realizado em 33 Unidades Básicas de Saúde e em hospital municipal de Araraquara (SP). Foram acompanhadas desde o início do pré-natal até o pós-parto, 78 gestantes, das quais 46 delas eram obesas ou com sobrepeso e 32, eutróficas. Trimestralmente, realizava-se aplicação de questionário digital sociodemográfico, de estilo de vida e morbidade, exames de ultrassonografia e exames de sangue para determinação de: glicemia de jejum, insulina, colesterol total, LDL, HDL, VLDL, triglicérides e PCR-us, hemoglobina glicada e hemograma completo). A análise da expressão gênica materna foi realizada apenas no terceiro trimestre, utilizando o método de extração por fenolclorofórmio para obter RNA a partir do sangue total, e a expressão gênica relativa foi analisada em triplicata por RT-qPCR no equipamento 7500 Fast Real PCR System (Applied Biosystems®, USA). A adiposidade do neonato foi estimada por pletismografia por deslocamento de ar (PEA POD®), na alta hospitalar. O presente estudo é inédito e mostrou que tanto o fator genético (expressão gênica dos genes LEPR, STAT3, PPARG, TLR4, IL6, NFkB e TNF) como fatores nutricionais e metabólicos maternos (IMC pré-gestacional, ganho de peso, HOMA-IR e diabetes mellitus gestacional) estão relacionados com a adiposidade do concepto logo após ao nascimento. O desenvolvimento fetal é um processo biológico complexo, regulado tanto por fatores maternos quanto fetais, incluindo influências genéticas e ambientais. Os mecanismos genéticos influenciam a regulação anti e pró-inflamatória que têm impacto na saúde materna. Expressões de sete dos dez genes investigados mostraram-se estatisticamente associados com a adiposidade do recém-nascido, independente de alguns genes serem mais ou menos expressos em gestantes obesas/sobrepeso. Portanto, o entendimento das diferentes vias do processo inflamatório, imunológico e sinalização da resistência à insulina são intimamente relacionados e dependentes. A elucidação dos fatores envolvidos no início da vida, observados neste estudo, e que podem ser prevenidos no pré-natal, devem ser cruciais para as políticas de saúde pública, na prevenção da obesidade infantil. / Overweight/obesity is a multicausal and polygenic condition that can result in energy imbalance. Once obesity tends to persist, prevention is the more effective strategy and understanding its causes is essential. This study aimed to evaluate the association of the gene expression related to obesity, inflammation and lipid profile in overweight/obese and eutrophic pregnant women and in newborn adiposity. It is a prospective study, inserted in a cohort study with population-based data, which was carried out at 33 Health Units and at a municipal maternity in Araraquara, Sao Paulo, Brazil. Seventy-eight pregnant women were followed since conception until postpartum, of whom 46 were obese or overweight and 32 were eutrophic. Every trimester, a sociodemographic, lifestyle and morbidity questionnaire was applied, ultrasonography and blood tests (fasting glucose, insulin, total cholesterol, LDL, HDL, VLDL, triglycerides and hs-CRP, glycated hemoglobin and complete blood count). The analysis of maternal gene expression was performed only in the third trimester, using the phenolchloroform extraction method to obtain RNA from whole blood, and relative gene expression was analyzed in triplicate by RT-qPCR in the 7500 Fast Real PCR System (Applied Biosystems®, USA). Newborn adiposity was estimated by air displacement plethysmography (PEA POD®) at hospital discharge. As far as we know this is the first study that verified that both genetic factors (LEPR, STAT3, PPARG, TLR4, IL6, NFkB and TNF gene expressions) and maternal nutritional and metabolic factors (pre-gestational BMI, gestational weight gain, HOMA-IR and gestational diabetes) are related to newborn adiposity at birth. Genetic mechanisms that participate in pro and anti-inflammatory regulation impact on maternal health, that may consequently play a role in the complex biological process of fetal development, that depends not only from maternal and fetal factors, but also of genetic and environmental influences. Expression of seven from ten genes investigated were statistically associated with newborn adiposity, regardless that some genes were more and other less expressed in obese/overweight pregnant women. Understanding immune and inflammatory pathways and insulin resistance signaling is crucial because its close association to maternal and newborn obesity, as observed in this study. The elucidation of factors involved in early life, as shown, should guide prenatal care in public health policies to prevent childhood obesity.

A indoleamina 2,3-dioxigenase (IDO) é uma enzima, produzida pelas células trofoblásticas e, por sua capacidade de catabolizar o triptofano, inibe a proliferação das células T maternas, participando desta forma como importante mecanismo da tolerância materno-fetal. Contudo, pouco se sabe se a ação da IDO é influenciada por outras substâncias presentes no micro-ambiente uterino e, por esta razão, formulou-se a hipótese de que esta enzima poderia ter sua ação alterada nesse contexto e, desta forma, avaliou-se o comportamento da expressão da IDO frente à adição de alguns desses componentes presentes no útero gestante. Neste trabalho, células uterinas, de placentas e de embriões de ratas e camundongos fêmeas prenhes e não prenhes foram mantidas em cultivo e a elas adicionadas estradiol, progesterona, interferon , triptofano e 1-metil-D- triptofano, avaliando-se a expressão da IDO pela técnica de citometria de fluxo nos períodos de 4, 24 e 48 horas. Os resultados demonstraram que as diferenças mais significativas na expressão da IDO entre as ratas prenhes e não prenhes, foram observadas após a adição de progesterona (19,24%), interferon (11.22%) e triptofano (23,53%), nas ratas prenhes. Já nos camundongos fêmeas prenhes e não prenhes, as maiores expressões de IDO foram observadas no primeiro grupo pela adição de progesterona (11,33%), estradiol (9,98%) e interferon (21,78%). Considerando esses resultados, podemos concluir que a expressão da IDO pelas células uterinas, placentárias e embrionárias em cultivo sofre influência dos fatores testados, o que permite novas hipóteses para melhor compreensão da participação dessa enzima na tolerância materno-fetal, particularmente em relação a sua interação com hormônios e citocinas presentes no útero gestante. Além disso, poderá colaborar na elaboração de possíveis tratamentos de enfermidades, relacionadas à manutenção e sucesso da gestação onde haja envolvimento do sistema imunológico materno e dos mecanismos de tolerância. / Indoleamine 2,3-dioxygenase (IDO) is an enzyme produced by trophoblast cells and due to its ability to catabolize tryptophan, inhibits the proliferation of maternal T cells, thus playing an important role as one of the mechanisms of maternal-fetal tolerance. However, little is known whether the action of IDO is influenced by substances present in the pregnant uterine microenvironment. This study evaluated the behavior of the IDO expression in cultured placental and embryonic cells from mice and rats in face of the addition of estradiol, progesterone, interferon, tryptophan and 1-methyl-D-tryptophan, by flow cytometry, at 4, 24 and 48 hours periods. The results showed that high expressions of IDO were observed in pregnant rats cells after the addition of progesterone (19.24%), interferon (11.22%) and tryptophan (23.53%). In mice, high expressions of IDO were observed in the pregnant group cells by the addition of progesterone (11.33%), estradiol (9.98%) and interferon- (21.78%). Considering these results, we may conclude that the expression of IDO by cultured placental and embryonic cells from mice and Wistar rats is indeed influenced by factors present in pregnant uterus, which provides additional information to better understand IDO role in the maternal-fetal tolerance, particularly on its interactions with reproductive hormones and cytokines. Additionally, it may contribute to the establishment of possible treatments for pregnancy-losses related to the maternal immune system response and mechanisms of tolerance.

O sucesso da gestação depende da adequada comunicação materno-fetal, que em algumas espécies têm um contato mais íntimo devido à capacidade migratória de populações de células trofoblásticas. Nos bovinos esse mecanismo é realizado pelas células trofoblásticas gigantes (CTGs), com invasão limitada até a lâmina basal do epitélio materno. Apesar dessa leve invasão das CTGs, é possível encontrar células fetais circulantes no sangue periférico da vaca gestante, levando ao microquimerismo fetal. Além de toda uma sinalização local e sistêmica e mudanças conformacionais, a migração das CTGs também é dependente da tolerância imunológica do epitélio materno que possui uma baixa expressão de MHC de classe I. Em contrapartida, o trofoblasto expressa MHC de classe Ib para impedir a ativação das células natural killers uterinas (uNK) contra ele mesmo. Neste contexto, o objetivo desse trabalho foi estudar a ocorrência e contribuir para o entendimento dos mecanismos da migração celular na placenta bovina, com marcadores exclusivos do cromossomo Y e de um modelo de clone transgênico expressando a proteína GFP. A hipótese testada foi que o microquimerismo fetal observado mediante a detecção do gene TSPY no sangue periférico da vaca gestante de embrião macho, e de GFP nos tecidos placentários maternos, associado à expressão de MHC classe 1b (Qa2) na interface materno-fetal. Para tanto, 153 embriões produzidos por fertilização in vitro (FIV) foram transferidos, resultando em 34 embriões machos e 31 fêmeas no dia 62 de gestação, quando foi realizada a coleta de sangue periférico da receptora. Dentre estas gestações, foram selecionadas de 25 machos, 4 fêmeas e 5 perdas gestacionais (confirmadas no D39 por ultrassonografia) para detecção de TSPY. Também foram produzidas gestações de clones transgênicos, expressando GFP com 30, 60 e 90 dias que foram utilizadas para a detecção de mRNA e a proteína GFP. Nas gestações de FIV 60% dos embriões machos, 50% das fêmeas e 40% das perdas gestacionais foram positivos para TSPY. A detecção de TSPY nas gestações de fêmeas possivelmente é resultante da persistência do microquimerismo de gestações anteriores. Nas gestações de clones transgênicos, observou-se a presença de mRNA e proteína GFP no endométrio, também indicando migração nesta região ou o transporte da GFP, e outros conteúdos do trofoblasto, para o epitélio materno. Nos placentônios, usando anticorpo anti-GFP pode-se ver a marcação positiva tanto no trofoblasto como no epitélio materno, possivelmente decorrente de liberação das CTGs no estroma endometrial após a fusão. As CTGs, quando em formação sincicial, têm a sua expressão de GFP diminuída, o que também foi observado, utilizando-se anticorpo anti-Qa2 (antígeno murino para MHC classe Ib). O epitélio materno e o trofoblástico também foram marcados para Qa2. Mediante as técnicas utilizadas, observamos que o microquimerismo pôde ser identificado nas gestações analisadas com o uso dos marcadores TSPY no sangue e o GFP nos tecidos placentários maternos. Este estudo mostra que na placenta bovina ocorre uma migração de células fetais além do epitélio materno e abre novas perspectivas para estudos das características da interação materno-fetal ainda pouco explorada nos bovinos. / The pregnancy success depends of adequate materno-fetal communication, that in some species are have a more intimate contact due migratory capacity of trophoblastic cells populations. In bovines, this mechanism is realized by trophoblast giant cells (TGC) with limited invasion until basal lamina of maternal epithelium. Besides this light invasion of TGCs, is possible to encounter circulate fetal cells in peripheral blood of pregnant cow, leading to fetal microchimerism. Beyond local and systemic sinalization and conformational changes, TGC migration is also dependent of immunologic tolerance of maternal epithelium that possess a downregulation of classe I MHC. In complement, the trophoblast express classe Ib MHC to inhibit natural killers cells activation. In this context, the objective of this work was to study the occurrence and contribute for knowledge cellular migration mechanisms in bovine palcenta, with Y-specific markers and a model of transgenic clone expressing GFP. The tested hypothesis was that fetal microchimerism observed by detection od TSPY gene in peripheral blood of cow pregnant of male embryo, and of GFP in maternal placental tissues associated by expression of class Ib MHC (Qa2) in materno-fetal interface. For this, 153 embryos produced by in vitro fertilization (IVF) were trasnfered, resulting in 34 male embryos and 31 female in day 62 of pregnancy, when recipient peripheral blood was collected. Among these pregnancies, 25 males, 4 females and 5 pregnancy losses (confirmed at 39 days of pregnancy by ultrassonography) was selected for TSPY detection. Also were produced pregnancies of transgenic cloned, embryos expressing GFP, with 30, 60 and 90 days of pregnancy that utilized for GFP mRNA and protein detection. In IVF pregnancies, 60% of male embryos, 50% of females and 40% of pregnancy losses were positive for TSPY. The detection of TSPY in female pregnancies possible is resultant of persistence of microchimerism of anterior pregnancies. In transgenic cloned pregnancies, was observed presence of GFP mRNA and protein in endometrium, also indicating migration in this region or GFP transport, and another trophoblast content, to maternal epithelium. In placentomes, using anti-GFP antibody, could be observed positive immunolabeling in trophoblast and maternal epithelium, possible due CTGs liberation in endometrial stroma after fusion. The CTGs, in syncytium formation, have a downregulation of GFP, that also be observed, utilizing anti-Qa2 antibody (murine antigen of classe Ib MHC). The maternal and trophoblastic epithelium also was Qa2 immunolabed. By utilized techniques, microchimerism could be indentified in analyzed pregnancies with use of markers for TSPY in maternal blood and GFP in maternal placental tissues. This study show that in bovine placenta occurs fetal cell migration further maternal epithelium and show new perspectives for studies of materno-fetal interaction characteristics until under explored in bovines.

Breast cancer is a persistent public health problem. Interesting hypothesis suggests that its risk can be modulated in early life periods, a phenomenon known as fetal programming. In this context, most fetal programming studies focus on maternal influence, due to the greater interaction between mother and fetus in both fetal and lactation periods. However, recent studies show that paternal preconception diet has also a major role in the offspring\'s susceptibility to metabolic chronic non-communicable diseases. Therefore, this direct doctoral project aimed to assess whether the paternal consumption of different high fat diets during the development period of the reproductive system of male rats increased the susceptibility of female offspring to mammary carcinogenesis. In addition we sought to evaluate which mechanisms could be involved in this process. We used male rats of the Sprague-Dawley strain (n = 20/group) that consumed high fat diet with 60% of calories from lipids from lard (LB group) or corn oil (CB group), or AIN-93G control diet (CO group) for nine weeks, during development and sexual maturation periods. These rats were mated with females who consumed only commercial diet in 1:1 ratio. Their 50 days old offspring were subjected to mammary carcinogenesis model using 7,12-dimethylbenz[a]anthracene (50mg/kg). Paternal consumption of high fat diet of animal or plant source had opposite effects, with the paternal consumption of diet with high content of saturated fatty acids (LB) increasing and consumption of diet with high content of n-6 polyunsaturated fatty acids (CB) reducing the risk of breast cancer development in female offspring. These effects were due to changes in the expression of 89 miRNAs in the father\'s sperm and 23 miRNAs in the offspring\'s mammary gland, with overlapping of three miRNAs (miR-1897-5p, miR- 219-1-3p and miR-376a #) that were altered in both tissues. Additionally, female offspring of males fed diets with high content of saturated fatty acids showed less differentiation of the mammary gland, higher levels of cell proliferation, lower levels of apoptosis and altered expression of keys proteins that regulate important cellular functions, such as epithelial to mesenchymal transition. Finally, these females had also altered lipid profile of the fat pad similar to their male parent as well as epigenetic changes that may be related to the etiology of breast cancer. Thus, we conclude that the high-fat preconception paternal diet programmed the susceptibility of female offspring to mammary carcinogenesis, but this effect was dependent on the type of fatty acid consumed and the observed effects possibly results from changes in miRNA expression profile. / O câncer de mama é um persistente problema de saúde pública. Hipótese intrigante sugere que a suscetibilidade à doença pode ser modulada em períodos precoces da vida, fenômeno conhecido como programação fetal. Nesse sentido, a maior parte dos estudos de programação fetal refere-se à influência materna, dada a intensa interação existente entre mãe e feto tanto no período fetal, quanto na lactação. Entretanto, estudos recentes mostram que a dieta paterna pré-concepcional também tem um papel de grande importância na suscetibilidade da prole à uma série de doenças crônicas não-transmissíveis de origem metabólica. Portanto, o presente projeto de doutorado direto teve como objetivo avaliar se o consumo paterno de diferentes dietas hiperlipídicas, durante o período de desenvolvimento do sistema reprodutivo de ratos machos, aumentaria a suscetibilidade da prole feminina à carcinogênese mamária. Adicionalmente buscou-se avaliar quais mecanismos poderiam estar envolvidos nesse processo. Utilizaram-se ratos machos da linhagem Sprague-Dawley (n=20/grupo) que consumiram dieta hiperlipídica com 60% de calorias provenientes de lipídeos de banha (grupo LB) ou óleo de milho (grupo CB), ou dieta controle AIN-93G (grupo CO), por nove semanas, durante os períodos de desenvolvimento e maturação sexual. Esses ratos foram acasalados com fêmeas, que consumiram apenas dieta comercial, na proporção 1:1. Sua prole de 50 dias foi submetida ao modelo de carcinogênese mamária com o uso de 7,12-dimetil-benza[a]antraceno (50mg/kg). O consumo paterno de dietas hiperlipídicas de origem animal ou vegetal conferiram efeitos opostos, com o consumo de dieta com alto teor de ácidos graxos saturados (LB) aumentando e o consumo de dieta com alto teor de ácidos graxos poli-insaturados n-6 (CB) diminuindo o risco de desenvolvimento de câncer de mama na prole feminina. Esses efeitos foram associados à alteração da expressão de 89 miRNAS no espermatozoide dos pais e 23 miRNAs na glândula mamária da prole, com sobreposição de 3 miRNAs (miR-1897-5p, miR-219-1-3p e miR-376a#) que estavam alterados em ambos tecidos. Adicionalmente, a prole feminina de machos que consumiram dieta com alto teor de ácidos graxos saturados apresentou menor diferenciação da glândula mamária, maior nível de proliferação celular, menor nível de apoptose e alteração da expressão de proteínas chaves da regulação celular, como na transição epitélio-mesenquimal. Finalmente, essas fêmeas também apresentaram perfil lipídico alterado semelhante à do seu progenitor masculino, bem como modificações epigenéticas que podem estar relacionadas à etiologia do câncer de mama. Assim, concluímos que a dieta paterna hiperlipídica pré-concepcional programou a suscetibilidade da prole feminina à carcinogênese mamária, porém esse efeito é dependente do tipo de ácido graxo consumido e os efeitos observados possivelmente decorrem de alterações no perfil de expressão de miRNAs.