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Abstract

The thesis investigates associations between the biomarkers of lead (Pb) exposure (and mercury (Hg), where applicable) and genetic variability in in vulnerable populations, including pregnant women and their newborns from Italy, Slovenia, and Croatia, as well as Slovenian men of reproductive age. The research utilizes data from the Public Health Impact of Long-term, Low-level Mixed Element Exposure in Susceptible Population Strata (PHIME) project and the Slovenian Human Biomonitoring (HBM) project, both characterized by low to moderate levels of potentially toxic non-essential Pb and Hg exposure with adequate levels of essential zinc and selenium. We examined how genetic factors influence susceptibility or resilience to low- to moderate-level Pb (and Hg) exposure, with the central focus on key single nucleotide polymorphisms (SNPs) in the ALAD (δ-aminolevulinic acid dehydratase), VDR (vitamin D receptor), and APOE (apolipoprotein E) genes. Associations were estimated and tested using multiple linear regression models, with the adjustment for selected available cofounders.
In both populations, the presence of the ALAD2 allele was associated with lower blood Pb concentrations. Furthermore, SNP ALAD rs1800435 (ALAD1/2) was shown to impact blood Pb levels in varying ways depending on the level of exposure by comparing Slovenian men living in historically Pb polluted environment vs non-polluted environment. Our results also confirm that other ALAD SNPs—namely rs1805312, rs1805313 and rs1139488—can as well significantly influence Pb levels. Additionally, combinations of ALAD SNPs, were found to account for a substantially higher degree of variability in blood Pb levels compared to individual SNPs alone, underscoring the importance of examining multiple genetic variants together, if possible biases are negligible.
The research also addressed the role of VDR SNPs in Pb toxicokinetics, finding no significant effect of selected SNPs or their haplotypes on blood Pb levels in either population. This lack of association may stem from the complex physiological role of vitamin D, particularly in pregnant women, where calcitriol production occurs independently of sun exposure or dietary intake. While VDR polymorphisms are known to influence the formation of Ca-binding proteins and affect bone density, the intricate interactions between calcitriol, calcium, and Pb—combined with the polymorphic nature of the VDR gene and the co-occurrence of polymorphisms in other genes—add layers of complexity that contribute to inconsistent findings also in the literature.
In the investigated population of pregnant women, maternal APOE ε2 allele carriers exhibited higher (cord)blood Pb levels and blood Hg levels, but only when the fetus/newborn was female. Conversely, the APOE ε4 allele was linked to lower levels of Pb regardless of the fetal sex. These findings align with the possible theory that the ε2 has the least protective effect on maintaining bone mass, which could influence bone mineral changes during pregnancy, while the ε4 allele demonstrates antagonistic pleiotropy, providing protective benefits during reproductive years but potentially having adverse effects later in life.
An insight from this research highlights the importance of considering sex-based differences in future studies on Pb and Hg toxicokinetics. Also, we have shown that parity should be taken into considerations in these types of studies, as genetic influences were more pronounced in nulliparous women.
The observed associations indicate the possible modification effects of ALAD SNPs on Pb and APOE SNPs on Pb and Hg toxicokinetics even at low exposure levels, while VDR SNPs appear to be overwhelmed by other factors at these low exposure levels.