Preconception paternal and maternal smoking alters gene expression in the early murine embryo and offspring lung function

Epidemiological evidence shows that tobacco smoking during the puberty susceptibility window impairs the respiratory health of future children, but the underlying mechanisms remain unclear. We hypothesized that parental smoking during puberty affects first transcriptional events in the early embryo. We investigated whether the expression profile of transcripts in blastomeres connects to altered lung function of offspring in a mouse model of pubertal parental smoking. 3-wk-old male and female C57BL/6J mice were exposed to mainstream cigarette smoke (CS) (research cigarettes 3R4F) for 2 weeks to 1puff/min and 4 weeks to 4puffs/min for 1 h/d for 5 d/wk followed by mating to air-controls. Blastomeres were harvested for RNASeq. Offspring aged 3 wks were challenged with house dust mite extract (HDM) or PBS (i.n.) for 3 wks. Lung function was measured (FinePoint RC) at baseline and after methacholine provocation. Blastomeres fertilized by CS-exposed fathers showed 6 up-regulated (Fam81a) and 3 down-regulated genes (Pdgfa). In blastomeres from mothers CS-exposed during puberty, 5 up-regulated and 16 down-regulated genes were detected. In the first days of life, male offspring from CS-exposed fathers had a higher weight gain, which was decreased in female offspring from CS-exposed mothers. CS-exposure of mothers induced higher airway hyperreactivity in HDM-challenged offspring than paternal exposure to CS. We observed sex-specific changes in embryonic transcripts and weight gain in a parent-of-origin manner. Further evidence is required to determine whether the dysregulated genes in blastomeres are precursors for the altered weight gain and lung function in offspring.