## 5 An Anthropological Perspective
In support of the above scenario, analyses carried out through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), targeting SNPs strongly associated with arsenic metabolization, showed that, contrary to alleles associated with increased toxicity risk, protective variants are much more frequent in exposed populations compared to a southern Chilean community [109]. Potential hints of human adaptation to PAHs exposure come from the comparison between the exome sequence (i.e., the sequence of nucleotides that make up the protein-coding portion of the genome) of the aryl hydrocarbon receptor (AHR) gene in Neanderthal, Denisovan and modern human individuals [110]. Once activated by endogenous or exogenous ligands, such as diet-derived metabolites and PAHs, respectively, the complex made up of AHR and other proteins passes from the cytoplasm to the nucleus. Here, following further biochemical mechanisms, the AHR regulates the CYP1A1/1A2/1B1 genes expression, thus initiating PAHs metabolism, with the resultant production of PAHs' reactive metabolites and DNA adducts. [PERSON] and colleagues found that modern humans carry the same allele at a codon of the AHR gene that is unique to our species, and which is associated with a reduced AHR activation by PAHs, specifically 2,3,7,8-tetrachlorobenzofuran (TCDF), B(a)P and benz(a)anthracene, compared to Neanderthal and other primates receptors. On the other hand, modern humans and Neanderthal AHR showed similar levels of activation by endogenous ligands. Based on the above results, the authors postulate that exposure to potentially toxic environmental AHR ligands, such as PAHs derived from controlled fires in caves, may have driven the selection of genetic variants conferring a reduced sensitivity to AHR exogenous ligands, and thus a lower DNA adduct synthesis [110]. As demonstrated also by the above-mentioned studies, molecular anthropologists are only starting to depict the role that environmental toxicants could have had in human evolution, and this is thanks to modern genomic technologies. Moreover, environmental toxicants can impact human biological variability at multiple levels, as shown by above-mentioned studies on the DNA methylation. Environmental pressures can shape DNA methylation variability across human groups, and methods have been developed to explore the epigenetic side of human diversity at different levels. In a study analyzing the DNA methylation profiles of three human populations at 450,000 CpG sites, the authors found that DNA methylation differences contribute to the phenotypic variability of these populations, and that 68% of differentially methylated CpG sites were significantly related to underlying genetic variation, while the remaining 32% was probably related to external stimuli able to induce epigenetic changes with an impact on subsequent generations (e.g., toxic xenobiotics, differences in dietary or hormone exposure, or stress response) [111]. Many toxicants are sources of differences within human populations [80]. In [PERSON] and colleagues' [112] investigation, for example, the authors compared the DNA methylation of individuals living in areas that were heavily sprayed with Agent Orange during the Vietnam War with that of individuals from non-contaminated areas. What they found is that past exposure to dioxin, the main ingredient of Agent Orange, led to DNA methylation changes among Vietnamese individuals from areas heavily sprayed, and in those whose parents participated in the war in sprayed zones.