## 4 The Epigenetic Impact of Seafood Contaminants
### The Impact of the Exposure to PAHs on DNA Methylation  
Both in vitro and in vivo analyses have revealed the ability of these substances to disrupt human DNA methylation patterns [42] (Tables 4 and S4 for further details). The developing fetus is particularly susceptible to PAH-induced DNA damage, and studies support the hypothesis that this may be due also to epigenetic dysregulations caused by these chemicals. In a study of non-smoking African-American and Dominican women from New York City [93], the authors found that prenatal exposure to PAHs measured using a personal air monitor was associated with lower global DNA methylation levels measured in umbilical cord blood DNA. [PERSON] and colleagues [94] analyzed samples of visceral adipose tissue of non-smoking female patients with myoma. They showed that the DNA methylation level of IRS2 gene increased as the concentrations of PAHs in adipose tissue increased. Interestingly, the IRS2 gene mediates the effects of insulin on various cellular processes, and it has been associated with several diseases, such as type 2 diabetes. Furthermore, promoter methylation of the IRS2 gene turned out to mediate the transcriptional silencing of this gene in the same study, and this led the authors to suggest that exposure to PAHs might contribute to the pathogenesis of insulin resistance through the methylation-mediated suppression of IRS2. PAHs can accelerate human aging through epigenetic modifications. In their study of Chinese and Caucasian populations, [PERSON] and collaborators [96] first developed a DNA methylation age predictor based on the methylation status of many CpG sites across the genome, and then defined two aging indicators: \(\Delta\)age, defined as methylation age minus chronological age; and aging rate, defined as the ratio between methylation age and chronological age. Evaluating the association of PAHs exposure biomarkers with the above-defined aging indicators, the authors found that the increase in several urine PAHs metabolites was associated with an increase in both \(\Delta\)age and aging rate. Possible hints of PAHs-mediated DNA methylation changes that may affect neurodevelopment emerged also from a study of pregnant women living close to a coal-fired power plant in China [95]. In that study, the authors analyzed cord blood samples for PAH-DNA adducts and assessed global DNA methylation by measuring genomic long interspersed nuclear elements (LINE1) methylation. LINE1 is one of the transposable repetitive elements, repetitive DNA sequences scattered across the genome and found in most eukaryotic organisms, which can change their position. Changes in LINE1 methylation can disrupt gene expression, and have been associated with birth defects, such as NTDs. In [PERSON] and collaborators' study, a significant inverse relationship was observed between PAH-DNA adducts and LINE1 DNA methylation. Interestingly, the latter was a positive predictor of IQ (Intelligence Quotient) scores at 5 years of age in women enrolled before the closure of the power plant. Neural tube defects (NTDs) are common and severe congenital malformations that arise from a failed or disordered closure of the neural tube during embryogenesis. Studies have linked NTDs to abnormal genome-wide DNA methylation. Authors found that PAX3, a gene encoding a transcription factor involved in development, is hypermethylated in NTD cases, and that the mean DNA methylation level of this gene in fetal neural tissue is positively correlated with median concentrations of PAHs in maternal serum [97]. Moreover, mean DNA methylation levels in the promoter region and 5' UTR of ZIC4 gene tended to be inversely associated with levels of HMW-PAHs in the livers of NTD fetuses in a recent survey [44]. ZIC4 encodes a zinc finger protein whose absence can hamper cerebellum development in both humans and mice. Concerning potential mechanisms underlying DNA methylation changes driven by Hg and PAHs, several findings support different hypotheses.