Involvement of global methylation in the development of lung allergic inflammation, in intrauterine undernourished rats, at different ages

Abstract

It has been demonstrated that adverse environmental factors in prenatal period can disrupt the normal pattern of fetal growth and development, leading to a phenotype more susceptible to diseases, such as hypertension, glucose intolerance, insulin resistance, hyperlipidemia, hyperinsulinemia, obesity, chronic obstructive pulmonary disease, in adulthood. In fact, failure of the maternal-placental supply to match fetal nutrient demand results in a range of fetal adaptations and developmental changes. Although these adaptations may be benecial for short-term survival, they can lead to permanent alterations in body structure and metabolism and thereby to cardiovascular and metabolic diseases in adult life. In previous works, our group demonstrated that global intrauterine undernutrition caused hypocellularity in bone marrow and peripheral blood, in Wistar rats. Besides, the reduction in adhesion molecules expression, in collagen (extracellular matrix), and the generation of inflammatory mediators caused a reduction in leukocyte migration, in these rats. In this model, we also observed reduction in lung allergic inflammation induced by ovalbumin. However, in this situation, this response was age-dependent. Considering the epigenetic mechanisms are crucial for chromatin structure reprogramming and gene expression during development and cell differentiation, we hypothesized that molecular mechanisms, including epigenetic alterations due to global undernutrition throughout the gestational period might be involved in the mechanisms of the attenuation of inflammatory response, acute and lung allergic, observed in Wistar rats. So, we propose the study of these mechanisms in a classic model of intrauterine malnutrition (characterized by 50% reduction in maternal food supply throughout the pregnancy) and the use of current techniques for elucidating the proposed hypothesis. For this purpose, allergic lung inflammation will be induced in 8- and 12-wk-old rats that were born to undernourished or nourished dams. The allergic lung inflammation will be characterized by total and differential cells infiltration in bronchoalveolar lavage fluid (BALF) and into the lung interstitium; by evaluation of lipid mediators and cytokines levels in lung tissue. To assess the involvement of global methylation on the development of lung allergic inflammation, in intrauterine undernourished rats, we will analyze lung pattern of global DNA methylation, and gene and protein expression of DNMT1, in lung tissue, in intrauterine nourished and malnourished rats, at 8 and 12 weeks of age. (AU)