In utero and early life diesel exposure, epigenetic modification and heart failur

描述(由申请人提供)：接触柴油与心脏病的严重恶化有关，但这些恶化的潜在机制以及宫内和早期接触的可能影响尚不清楚。我们发现，在子宫和/或生命早期暴露于柴油废气的小鼠，成年后会出现左心室肥厚增加和心力衰竭的倾向。具体地说，我们发现，与暴露在过滤空气中的小鼠相比，在子宫和/或生命早期暴露于柴油废气的雄性小鼠会出现左心室肥厚，而暴露在子宫和出生后的雌性小鼠会出现射血分数降低。当雄性小鼠接受主动脉环扎术时，它们比过滤空气对照组进展得更快，从而导致心力衰竭。我们假设，在子宫内暴露于柴油废气中会在暴露的动物的心脏中产生表观遗传修饰，这些修饰在成年后容易发生心肌肥大和/或心力衰竭，可能是一种性别特有的方式。因此，我们建议在子宫内暴露于柴油废气后，检查新生和成年小鼠心脏全基因组的表观遗传修饰。我们还将研究这些修饰如何随着性别的不同而变化，并在暴露后立即改变全球RNA表达模式，以及横主动脉狭窄后，横动脉收缩是心肌肥厚的有效诱因。我们预测，柴油尾气将引起表观遗传变化，改变导致肥厚和心力衰竭易感性的基因的表达。

DESCRIPTION (provided by applicant): Diesel exposure has been associated with significant exacerbations in heart disease but the underlying mechanisms by which these exacerbations are mediated and the possible effects of in utero and early life exposure are poorly understood. We have found that mice exposed to diesel exhaust in utero and/or early in life develop increased left ventricular hypertrophy and a predisposition to heart failure as adults. Specificall, we have found that male mice exposed to diesel exhaust in utero and/or early in life develop left ventricular hypertrophy compared to those exposed to filtered air, while female mice exposed in utero and postnatally develop decreased ejection fraction. When the male mice undergo aortic banding, they progress more rapidly to heart failure than the filtered air controls. We hypothesize that in utero exposure to diesel exhaust creates epigenetic modifications in the hearts of exposed animals that predispose to myocardial hypertrophy and/or heart failure as adults, in possibly a gender specific fashion. Accordingly, we propose to examine genome wide epigenetic modifications in neonatal and adult mouse hearts after in utero exposure to diesel exhaust. We will also examine how these modifications vary by gender and alter global RNA expression patterns immediately after exposure and after transverse aortic constriction, a potent inducer of cardiac hypertrophy. We predict that diesel exhaust will induce epigenetic changes that alter expression of genes that confer susceptibility to hypertrophy and heart failure.