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Introduction
Modulation of the epigenome has been proposed as a key mechanism through which exposure to environmental stressors during development can program altered gene expression to impact health in later life. Developmental exposure to malnourishment (Lee 2015), toxic metals (Castillo et al. 2012), and endocrine disruptors (Susiarjo et al. 2013) impacts metabolic health, and is associated with alterations to the epigenome in early life, although finding loci that maintain these epigenetic changes into adulthood has proved challenging. Identifying such loci might provide important insights into the mechanisms of this long-term programming effect.
Imprinted genes are expressed preferentially from one of their two parental alleles, dependent on allele-specific epigenetic profiles established during gametogenesis at imprinting control regions (germline ICRs) (Bartolomei and Ferguson-Smith 2011). These sites of differential methylation between the maternal and paternal alleles are protected from the wave of global demethylation that occurs immediately after fertilization, providing a parent-of-origin-specific epigenetic signature. Given that epigenetic profiles at germline ICRs are generally stable throughout life, these loci have been considered candidates for providing a long-term memory of early-life exposures. Additionally, dysregulation of imprinted gene expression can have potent effects on growth and metabolism, suggesting that changes to their epigenetic regulation could directly contribute to effects on metabolic health associated with developmental exposures. Despite the widespread use of imprinted genes as biosensors of environmentally induced epigenetic changes, it has not been determined whether ICRs are more or less sensitive to perturbation than other loci in the genome. Resolving this would provide insight into the mechanisms through which exposures interact with the epigenome.
In the current study, we address this question in humans in the context of cadmium (Cd) exposure. Cd is a toxic metal that is poorly metabolized, accumulating in the liver and kidneys. The primary routes of exposure are inhalation, typically from cigarette smoke and contaminated dust, and ingestion, particularly of cereals and vegetables that absorb Cd from contaminated soil (Järup and Åkesson 2009). Low-level chronic exposure in adulthood has been associated with metabolic disorders, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (Hyder et al. 2013), cardiovascular disease (Agarwal et al. 2011), and reduced bone mineral density, causing an increased incidence of bone fractures and osteoporosis (Järup and Åkesson 2009). Postnatal exposure to Cd has also...