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.

Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.

No abstract

Manganese (Mn) is an essential metal that is responsible for several physiological functions, including proper immune function, bone growth, digestion, reproduction, energy metabolism and antioxidant defences. However, excessive exposure to this metal can result in an irreversible condition known as “manganism”, a disease that primarily results in Parkinsonian-like symptomatology. Although the mechanisms by which Mn is absorbed into the digestive tract are not completely clear, a number of uptake mechanisms have been identified on the surface of enterocytes. These include import of Mn2+ via the divalent metal transporter 1 (DMT1) and uptake of Mn3+ via complexation with the protein transferrin (Tf). Upon entering the blood, Mn is distributed diffusely throughout the body, with the brain, bone, kidneys and liver acquiring the highest accumulation. A variety of transporters regulate Mn import, including DMT1 or Tf-Tf receptor internalization, choline transporter, citrate transporter, voltage-gated and store-operated calcium channels, and the zinc transporters ZIP8/14. Recent findings suggest a role for the magnesium transporter HIP14 and the P-type transmembrane ATPase ATP13A2 in Mn uptake across cellular membranes. Mn serves as an important cofactor for many enzymes that are key in regulating general cellular function. Intracellular buffering mechanisms also include preferential sequestration within mitochondria. Finally, Mn export has yet to be fully understood, but new evidence points to the iron exporter ferroportin as a potential exporter. This chapter will address the various processes associated with maintenance of optimal Mn levels and the consequences of improper Mn homeostasis.