In Utero Particulate Matter Exposure Produces Heart Failure, Electrical Remodeling, and Epigenetic Changes at Adulthood

Abstract

Background

Particulate matter (PM; PM _2.5 [PM with diameters of <2.5 μm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM _2.5 exposure alone could alter cardiac structure and function at adulthood.

Methods and Results

Female FVB mice were exposed either to filtered air or PM _2.5 at an average concentration of 73.61 μg/m ³ for 6 h/day, 7 days/week throughout pregnancy. After birth, animals were analyzed at 12 weeks of age. Echocardiographic (n=9–10 mice/group) and pressure‐volume loop analyses (n=5 mice/group) revealed reduced fractional shortening, increased left ventricular end‐systolic and ‐diastolic diameters, reduced left ventricular posterior wall thickness, end‐systolic elastance, contractile reserve ( dP/dt _max/end‐systolic volume), frequency‐dependent acceleration of relaxation), and blunted contractile response to β‐adrenergic stimulation in PM _2.5‐exposed mice. Isolated cardiomyocyte (n=4–5 mice/group) function illustrated reduced peak shortening, ± dL/ dT, and prolonged action potential duration at 90% repolarization. Histological left ventricular analyses (n=3 mice/group) showed increased collagen deposition in in utero PM _2.5‐exposed mice at adulthood. Cardiac interleukin ( IL)‐6, IL‐1ß, collagen‐1, matrix metalloproteinase ( MMP) 9, and MMP13 gene expressions were increased at birth in in utero PM _2.5‐exposed mice (n=4 mice/group). In adult hearts (n=5 mice/group), gene expressions of sirtuin (Sirt) 1 and Sirt2 were decreased, DNA methyltransferase (Dnmt) 1, Dnmt3a, and Dnmt3b were increased, and protein expression (n=6 mice/group) of Ca ²⁺‐ATPase, phosphorylated phospholamban, and Na ⁺/Ca ²⁺ exchanger were decreased.

Conclusions

In utero PM _2.5 exposure triggers an acute inflammatory response, chronic matrix remodeling, and alterations in Ca ²⁺ handling proteins, resulting in global adult cardiac dysfunction. These results also highlight the potential involvement of epigenetics in priming of adult cardiac disease.