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

J Am Heart Assoc. 2017 Apr 11;6(4):e005796. doi: 10.1161/JAHA.117.005796.

Abstract

Background: Particulate matter (PM; PM2.5 [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 PM2.5 exposure alone could alter cardiac structure and function at adulthood.

Methods and results: Female FVB mice were exposed either to filtered air or PM2.5 at an average concentration of 73.61 μg/m3 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/dtmax/end-systolic volume), frequency-dependent acceleration of relaxation), and blunted contractile response to β-adrenergic stimulation in PM2.5-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 PM2.5-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 PM2.5-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 Ca2+-ATPase, phosphorylated phospholamban, and Na+/Ca2+ exchanger were decreased.

Conclusions: In utero PM2.5 exposure triggers an acute inflammatory response, chronic matrix remodeling, and alterations in Ca2+ handling proteins, resulting in global adult cardiac dysfunction. These results also highlight the potential involvement of epigenetics in priming of adult cardiac disease.

Keywords: air pollution; calcium signaling; cardiac; cardiovascular function; heart failure; in utero; myocardial; myocyte; particulate matter.

MeSH terms

  • Action Potentials / drug effects
  • Age Factors
  • Animals
  • Animals, Newborn
  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology
  • Atrial Remodeling / drug effects*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Epigenesis, Genetic / drug effects*
  • Female
  • Gestational Age
  • Heart Failure / chemically induced*
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Rate / drug effects
  • Inhalation Exposure / adverse effects*
  • Maternal Exposure / adverse effects*
  • Mice
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Particle Size
  • Particulate Matter / toxicity*
  • Phosphorylation
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Sirtuin 2 / genetics
  • Sirtuin 2 / metabolism
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism
  • Ventricular Function, Left / drug effects*
  • Ventricular Remodeling / drug effects

Substances

  • Calcium-Binding Proteins
  • Particulate Matter
  • Sodium-Calcium Exchanger
  • phospholamban
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B
  • Sirt1 protein, mouse
  • Sirt2 protein, mouse
  • Sirtuin 1
  • Sirtuin 2
  • Calcium-Transporting ATPases