Project title

(MERTOX-TRX) Molecular Mechanisms of Mercury Toxicity: Study of the inhibition of human thioredoxin system

Scientific Coordinator's name:

Cristina Maria Leitão de Carvalho

Scientific Coordinator's e-mail:

cristina.carvalho@ff.ul.pt

Principal R&D Unit:

iMed.UL/FFUL

Other R&D Units involved in the project:

Karolinska Institutet (KI)

Project keyword(s)

Mercury; Thioredoxin system; Molecular mechanisms of toxicity; Health risk assessment

Short abstract and comments

Over centuries, human populations have been exposed to different chemical and physical forms of mercury, all of which have deleterious effects. Past medical applications of mercury included the treatment of syphilis and skin infections and presently its use in amalgams and as a preservative in vaccines and topic preparations is very controversial (1). Methylmercury (MeHg), being a strong neurotoxicant, affects mainly the central nervous system (CNS). Other health risks arising from exposure to MeHg include developmental, cardiotoxic, renal and immunotoxic effects (2,3). Fish constitutes the major source of this xenobiotic to humans and its contamination by MeHg is a major public health problem since MeHg bioaccumulation and bioconcentration through the aquatic food chain puts at risk human populations, with high fish consumption such as the Portuguese population (4,5, Carvalho et al.,JBC,2008b). The Trx system is critical for cellular stress response, protein repair and protection against oxidative damage (13-15)and additionally, selenium-compromised forms of TrxR induce apoptosis (16.) Therefore, the Trx system attracted our attention a few years ago when we started the study of its involvement in the development of mercury endpoints of toxicity. We investigated the effects of HgCl2 and MeHg on the components of the Trx system, TrxR and Trx, and their related components in the glutaredoxin system, glutathione reductase and glutaredoxin (Carvalho et al.,JBC,2008a). The results showed for the first time a clear inhibition of the thioredoxin system by mercurials and indicated that this system is a fast target of mercury toxicity . Later on, we investigated exogenous and endogenous antioxidants and again we collected proofs that selenium (in the form of selenite) regenerated TrxR activity after full inhibition with mercury (Carvalho et al, FASEB J. 2011). In this project our main goal is the epidemiological survey for verification of thioredoxin reductase inhibition in blood samples of human population to relate our previous observations of the molecular mechanisms accounting for mercury toxicity in toxicological studies with epidemiological (human) studies. Additionally, there will be a study in human cells to correlate the manifestations of cellular toxicity with the thioredoxin system.

Potential uses/indications

Possible applications of the project results include the identification and characterization of Portuguese subsets of population that we demonstrated before are at-risk concerning the MeHg exposure and especially the development of a method for monitoring adverse effects arising from its exposure.