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

描述（由申请人提供）：柴油暴露与心脏病的严重恶化有关，但这些恶化的潜在机制以及子宫内和生命早期暴露的可能影响尚不清楚。我们发现，在子宫内和/或生命早期暴露于柴油废气的小鼠，成年后左心室肥厚增加，易患心力衰竭。具体来说，我们发现，在子宫内和/或生命早期暴露于柴油废气的雄性小鼠与暴露于过滤空气的小鼠相比，左心室肥厚，而在子宫内和出生后暴露于柴油废气的雌性小鼠射血分数降低。当雄性小鼠接受主动脉束带时，它们比过滤空气的对照组更快地发展为心力衰竭。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，使其在成年后易患心肌肥大和/或心力衰竭，这可能是一种性别特定的方式。因此，我们建议在子宫内暴露于柴油废气后检测新生儿和成年小鼠心脏的全基因组表观遗传修饰。我们还将研究这些修饰如何随性别而变化，以及在暴露后和主动脉横缩后立即改变全局RNA表达模式，主动脉横缩是心脏肥厚的有效诱导剂。我们预测，柴油废气将诱导表观遗传变化，改变基因的表达，赋予肥厚和心力衰竭的易感性。

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.