In Utero Exposure to Second‐Hand Cigarette Smoke Promotes Epigenetically‐Mediated Cardiac Dysfunction in High‐Fat Fed Male Mice

Abstract

We investigated whether in utero exposure to second‐hand cigarette smoke (SHS) would adversely affect cardiac structure/function in the exposed offspring fed a high‐fat diet. Pregnant mice (C57B1/6J) were exposed to SHS or air (4 hr/d) from gestational days 6–19. The male offspring (age: 65 days) from the SHS and air exposure groups were fed either normal chow, or high‐fat liquid diet (35% fat; HFD) for 16 weeks (n=12/group). Cardiac function was measured by echocardiography at baseline (30 days) and at the end of pair feeding. Mice were then sacrificed and heart tissue collected for histological and mRNAseq analysis. There was no significant difference in body weight or heart weigh/tibial length between the in utero SHS+HFD and in utero air+HFD treated offspring. However, compared to in utero air+HFD mice, in utero SHS+HFD mice had decreased left ventricular internal diameters and volumes during diastole (3.95±0.09 vs. 4.34±0.24 mm; 67.8±1.5 vs. 85.4±4.4 μl, P<0.05) and systole (2.91±0.07 vs. 3.34±0.15 mm; 32.5±1.9 vs. 46.3±5.1 μl, P<0.05), accompanied by increases in left ventricular wall thickness during diastole (0.72±0.03 vs. 0.66±0.03 mm, P<0.01) and septal thickness during systole (1.2±0.06 vs. 0.99±0.05 mm, P<0.05) and increased fractional shortening. There was also a significant increase in collagen in the hearts of the in utero SHS+HFD mice. These data are consistent with the development of concentric cardiac hypertrophy in in utero SHS+HFD mice. mRNAseq analysis of cardiac tissue revealed 100 up‐regulated and 120 down‐regulated genes in in utero air+HFD vs in utero SHS+HFD. Top Wiki Pathway terms included genes linked to adaptive cardiac hypertrophic responses: adrenergic receptor a1a, MAP2K1, MAP2K3, CDK7, CHUK, PDPK1 and IKBKE, microRNAs in cardiomyocytes, exercise induced changes in circadian rhythm (upregulated BMAL1, downregulated Per2) and signaling via estrogens, TNF alpha and MAP kinases. GO pathways identified included cardiac muscle contraction, protein acetylation and regulation of DNA methylation. We conclude that in utero exposure to SHS produces epigenetically‐regulated differential cardiac responses following challenge with obesogenic high fat diet. (NIH P20 GM103514).Support or Funding InformationNIH P20 GM103514