## 3 Human Genetic Diversity
### PAHs Exposure and Human Genetic Diversity  
PAHs metabolism is a complex process consisting of two major phases (Figure 2): In the first phase, following ingestion or inhalation, the xenobiotic compound is epoxidated by enzymes belonging to the cytochromes P450 family, with the formation of diols and dihydrodiols [31]. Dihydrodiols can thus bind to the DNA, to give rise to DNA adducts, starting the mutagenic processes and eventually leading to cancer [73]. Then, in the second phase, the intermediate diols conjugate with glutathione, thanks to glutathione s-transferase enzymes. This leads to the formation of polar compounds, which can be easily excreted by renal or biliary routes [74]. The liver is the major site of the metabolism of PAHs. However, in the case of ingestion, gut micro flora and intestinal cytochrome P450 enzymes can also contribute to the process [31]. Epidemiological studies showed that polymorphisms at several genes influence levels of biomarkers of exposure to PAHs in several human populations (Tables 2 and S2 for further details). As suggested by much evidence, PAH-DNA adducts may be a potential source of heritable prezygotic DNA damage in spermatozoa. [PERSON] and colleagues [68] detected PAH-DNA adducts in ejaculated sperm of infertile adults environmentally exposed to low levels of PAHs, showing that the consumption of PAH-rich meals at least three times a week contributed significantly to an increase in DNA adduct formation. Moreover, the authors demonstrated an association between specific XRCC1 polymorphisms and an increase in sperm adduct levels. XRCC1 encodes a protein that is essential to providing an efficient repair of the DNA, and thus polymorphisms at this gene may be useful to identify individuals susceptible to DNA damage resulting from PAHs exposure. Myeloperoxidase (MPO), an enzyme central to the microbicidal activity of neutrophils, and \(N\)-acetyltransferase 2 (NAT2), which functions to both activate and deactivate drugs and carcinogens, are involved in Phase I and Phase II of PAH metabolism, respectively, while ERCC5 is a single-strand-specific DNA endonuclease that participates in DNA excision repair. The SNPs in these genes have been shown to affect the PAH-driven formation of the DNA adduct. In a study [69] of more than one hundred healthy female non-smokers from Golestan Province, a region in north-eastern Iran, characterized by very high levels of exposure to PAH probably due to diet and methods of food preparation, the DNA adduct level in blood was significantly lower in homozyggotes for NAT2 slow alleles,  
Figure 2: Schematic representation of the metabolic phases following PAHs ingestion. In the first phase, following ingestion or inhalation, PAHs are epoxidated by enzymes belonging to the cytochromes P450 family, with the formation of diols and dihydrodiols. Dihydrodiols can thus bind to the DNA, to give rise to DNA adducts. Then, in the second phase, the intermediate diols conjugate with glutathione, thanks to glutathione s-transferase enzymes. This leads to the formation of polar compounds, which can be easily excreted. which are responsible for a less efficient detoxification of carcinogen-reactive metabolites, and the ERCC5 (rs1047768) non-risk-allele genotype. In contrast, DNA adduct level was higher in the MPO (rs2333227) homozygote risk-allele genotype. In a cohort of non-smoking Polish mothers and newborns, [PERSON] and colleagues [36] observed a significant interaction between maternal exposure to airborne PAHs, measured by personal air monitoring, and SNPs in selected B(a)P metabolism genes on cord blood B(a)P-DNA adducts. These genes included: maternal CYP1A1 and GSTT2, and newborn CYP1A1 and CYP1B1. CYP1A1 and CYP1B1 are involved in metabolizing the parent B(a)P compound to the reactive B(a)P 7,8-diol-9,10-epoxide (BPDE) metabolite, which is involved in the formation of B(a)P-DNA adducts. In contrast, GSTT2 is involved in shifting B(a)P metabolism so as to prevent the formation of the reactive BPDE.