Early life exposure to cigarette smoke primes lung response to later life exposure in a mouse model

Cigarette smoke (CS) exposure in early life causes long-lasting lung function defects even years after the exposure itself. Long term regulation of genes by epigenetic marks may be one of the mechanisms maintaining the cellular memory of early life exposure and influencing the response to additional exposures later in life. Here, we investigated the effects of early life CS exposure on mouse lung epigenetic marks across time, and how those marks were altered by re-exposure later in life. We found that early life exposure to CS induced a differential susceptibility to later life exposure – when exposed to CS in adulthood, animals with early life exposure had higher immune cell infiltration in the lung compared to those without early life exposure. Whole genome DNAm and ATACseq data show that epigenetic marks associated with early life CS exposure in the lung wane over time, but are re-established upon re-exposure at over 100 genes, including important epigenetic remodelers and immune related genes. Our results show that CS exposure in early life primes the cellular response to later life exposure, which may occur through modifications to the epigenome. DNA methylation is unlikely to be the main regulator, as DNAm changes are not maintained to adulthood in the absence of re-exposure. Future work examining specific transcription factors and histone modifications will be needed in order to design interventions to break the molecular links between early life CS and long lasting alterations to lung function.