The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: mercury and lead

Abstract

The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized.