Persistent organic pollutants : aberrant DNA methylation underlying potential health effects

Wild caught fish, especially marine fish, can contain high levels of persistent organic pollutants (POPs). In the Netherlands, especially eel from the main rivers have high POP levels. This led to a ban in 2011 on eel fishing due to health concerns. Many of the marine POPs have been related to adverse health effects such as endocrine disruption, neurodevelopmental problems, immune suppression and cancer. Although some mechanisms of action of POPs are clear, like dioxins binding to the aryl hydrocarbon receptor and OH-PCBs binding to thyroid transport proteins, not all adverse health effects can be explained by these mechanisms of action. Epigenetic phenomena, such as DNA methylation, have been proposed as a possible molecular mechanism underlying adverse health effects. DNA methylation is a heritable modification, which refers to the addition of a methyl group to cytosine in a CpG dinucleotide. Observational studies have indeed shown that POPs can affect global DNA methylation, although results are inconsistent. Some animal studies as well as in vitro experiments suggest that POPs can affect gene-specific DNA methylation, however, the biological significance and relevance for humans is not clear. Therefore, this thesis aimed to 1) study the accumulation of POPs in men consuming eel from high-polluted areas 2) elucidate whether seafood-related POPs can induce aberrant DNA methylation and 3) to determine whether DNA methylation is related to functional endpoints and gene expression in vitro. For this purpose eight POPs that are abundantly present in seafood were chosen, namely 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorobiphenyl (PCB) 126 and 153, perfluorooctanesulfonic acid (PFOS), hexabromocyclododecane (HBCD), 2,2′,4,4′- tetrabromodiphenyl ether (BDE-47), tributyltin (TBT), and methylmercury (MeHg). Chapter 2 describes the in vitro effects of these POPs and mixtures thereof in H295R adrenocortical carcinoma cells. Relative responses for 13 steroid hormon