Biomarkers of mercury toxicity: Past, present, and future trends

Abstract

Mercury (Hg) toxicity continues to represent a global health concern. Given that human populations are mostly exposed to low chronic levels of mercurial compounds (methylmercury through fish, mercury vapor from dental amalgams, and ethylmercury from vaccines), the need for more sensitive and refined tools to assess the effects and/or susceptibility to adverse metal-mediated health risks remains. Traditional biomarkers, such as hair or blood Hg levels, are practical and provide a reliable measure of exposure, but given intra-population variability, it is difficult to establish accurate cause-effect relationships. It is therefore important to identify and validate biomarkers that are predictive of early adverse effects prior to adverse health outcomes becoming irreversible. This review describes the predominant biomarkers used by toxicologists and epidemiologists to evaluate exposure, effect and susceptibility to Hg compounds, weighing on their advantages and disadvantages. Most importantly, and in light of recent findings on the molecular mechanisms underlying Hg-mediated toxicity, potential novel biomarkers that might be predictive of toxic effect are presented, and the applicability of these parameters in risk assessment is examined.

Figures

Figure 1.. Applications of biomarkers in different areas of Toxicology and Medicine.

Biomarkers can be used to evaluate exposure and predict the toxicity (A) of a xenobiotic by measuring the internal dose, the dose interacting with molecular targets or molecular effects that reflect early changes or that represent an established toxic response. If toxicity persists, disease ensues (B) and it may be diagnosed by standard clinical markers. New approaches make use of biomarkers for the development of new medicines and moreover the identification of biomarkers that follow disease progression will become a key element for personalized medicine.

Figure 2.

Pathway leading from exposure to a xenobiotic to toxic manifestations, and the relative position of exposure and effect biomarkers.

Figure 3.. Main pathways of exposure to mercury compounds, exposure biomarkers and relative concentrations of MeHg in hair, brain and blood.

Humans are exposed to different mercury compounds by different routes, such as MeHg (fish consumption), Hg0 (dental amalgams), and EtHg (TCV). The major target organs include the brain, kidney and the developing fetus, and exposure levels are normally assessed by measuring mercury levels in hair, blood and urine. In the case of MeHg levels in hair and blood correlate well with the values found in the brain in the proportion 250:5:1. (adapted from Clarkson et al., 2007)

Figure 4.. The Heme Biosynthetic Pathway.

The enzymes involved in heme biosynthesis include: 1- δ-aminolevulinic acid (ALA) synthetase; 2- ALA dehydratase; 3- uroporphyrinogen I synthetase; 4- uroporphyrinogen III cosynthetase; 5- uroporphyrinogen decarboxylase; 6- coproporphyrinogen oxidase; 7- protoporphyrinogen oxidase; 8- ferrochelatase. Mercury targets the enzymes uroporphyrinogen decarboxylase (UROD; 5), and especially coproporphyrinogen oxidase (CPOX; 6), thus leading to the accumulation and excretion of 4 and 5 carboxylporphyrinogens which afterwards are oxidized to porphyrins and excreted in urine (adapted from Pingree et al., 2001).

Figure 5.. Potential mechanisms by which MeHg decreases selenoproteins’ homeostasis.

(A) MeHg directly interacts with the selenol group of selenocysteine. Due to its high electrophilicity, MeHg directly interacts with the selenol group (–SeH) of selenoccysteine (red arrow). Because this group is classically responsible for catalytic activity in several selenoproteins, loss of protein function is observed. (B) MeHg may impair the biosynthesis of selenocysteine. Selenocysteine (Sec) is crucial for the proper synthesis and functioning of selenoproteins. The biosynthesis of Sec occurs on its tRNA, and the pathway begins with the attachment of serine to Sec tRNA[Ser]Sec (event 1; catalyzed by seryl-tRNAsynthetase) in the presence of ATP. Phosphoseryl-tRNA kinase (event 2) phosphorylates the serine moiety to form an intermediate, phosphoseryl-tRNA[Ser]Sec (PSer-tRNA[Ser]Sec). Sec synthase (event 3) catalyzes the formation of Sec-tRNA[Ser]Sec, which is subsequently incorporated into selenoproteins during protein synthesis. This metabolic step requires the presence of selenophosphate (H2SePO3–), whose precursor is selenide (HSe-) (event 4). MeHg (CH3Hg+) directly interacts with selenide (red arrow), leading to a “selenium-deficient-like” condition, which lead to inappropriate selenoprotein synthesis (Usuki et al., 2011). For additional details on Sec biosynthesis, see Hatfield et al., 2014. Abbreviations: Pi, inorganic phosphate; PPi, inorganic pyrophosphate.

Figure 6.. Interaction between mercury compounds and TrxR1 and TrxR2 at the cytosol and mitochondria.

Mercury compounds enter liver cells and target TrxR1 and 2 at the cytosol and mitochondria, respectively (1A and 1B), leading to a decrease in activity. Loss of TrxR1 promotes Nrf-2 release from Keap-1 (2 and 3) and its subsequent translocation to the nucleus of the cell (4) where it binds the ARE element in the promoter region of the TXNRD1 gene (5). This process is faster upon exposure to Hg2+ than to MeHg (see Branco et al., 2014 for detailed explanation). Transcription of the gene is enhanced and TrxR1 mRNA builds up in the cytosol (6) and TrxR1 is de novo synthetized (7)