Imprinted Genes and the Environment: Links to the Toxic Metals Arsenic, Cadmium and Lead

Abstract

Imprinted genes defy rules of Mendelian genetics with their expression tied to the parent from whom each allele was inherited. They are known to play a role in various diseases/disorders including fetal growth disruption, lower birth weight, obesity, and cancer. There is increasing interest in understanding their influence on environmentally-induced disease. The environment can be thought of broadly as including chemicals present in air, water and soil, as well as food. According to the Agency for Toxic Substances and Disease Registry (ATSDR), some of the highest ranking environmental chemicals of concern include metals/metalloids such as arsenic, cadmium, and lead. The complex relationships between toxic metal exposure, imprinted gene regulation/expression and health outcomes are understudied. Herein we examine trends in imprinted gene biology, including an assessment of the imprinted genes and their known functional roles in the cell, particularly as they relate to toxic metals exposure and disease. The data highlight that many of the imprinted genes have known associations to developmental diseases and are enriched for their role in the TP53 and AhR pathways. Assessment of the promoter regions of the imprinted genes resulted in the identification of an enrichment of binding sites for two transcription factor families, namely the zinc finger family II and PLAG transcription factors. Taken together these data contribute insight into the complex relationships between toxic metals in the environment and imprinted gene biology.

Maternal cadmium, iron and zinc levels, DNA methylation and birth weight

“…Using the unbiased Illumina HumanMethylation450 BeadChip, maternal cigarette smoking, a common source of fetal Cd exposure, has been associated with altered DNA methylation at multiple CpG sites including 11 imprinted genes such as AHRR , GFI1 , IGF2 and CYP1A1 in cord blood leukocyte DNA [ 33 , 34 ]. In studies with small sample sizes [ 12 , 35 ], in utero Cd exposure specifically was associated with CpG methylation differences in umbilical cord blood leukocyte DNA at multiple CpG sites mapping to genes involved in xenobiotic metabolism and inflammation [ 12 ], some of which may be sex-specific [ 36 , 37 ]. Female-specific effects of Cd exposure have previously been reported in relation to birth weight, hypothesized to be due to lower iron in females that is associated with increased Cd intestinal absorption [ 38 ].…”

Triple-negative breast cancer in African-American women: disparities versus biology

“…Signalling networks activated by insulin, such as AKT–mTOR, are associated with aggressive cancer biology. Unsafe neighbourhoods and an unequal burden of environmental exposures contribute to stress, lack of access to healthy food (food deserts, which in turn promotes obesity), lack of exercise and exposure to carcinogens and heavy metals (such as cadmium, lead and arsenic) that are thought to promote abnormal imprinting and epigenetic changes 86–89 , which in turn may promote aggressive biology. EMT, epithelial–mesenchymal transition.…”

Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort

“…Although protein disruption/misfolding, generation of oxidative stress, and endocrine disruption are known effects of toxic metal exposure, mechanisms causing these effects are still largely unknown (Satarug and Moore 2012; Sanders, Smeester et al 2014; Smeester, Yosim et al 2014). A growing body of in vitro and in vivo evidence supports that environmental exposure to toxic metals, including Pb, can alter DNA methylation (Takiguchi, Achanzar et al 2003; Reichard, Schnekenburger et al 2007; Jiang, Xu et al 2008; Pilsner, Hu et al 2009; Bailey and Fry 2014; Faulk, Liu et al 2014; Li, Xie et al 2015; Nye, Hoyo et al 2015).…”