N-Acetylcysteine as a Biomonitoring Agent of Methylmercury Exposure

Aremu, David

Abstract

A recent report claims that 60,000 fetuses are at risk of methylmercury (MeHg)-induced brain damage in the USA, to such a degree that it may affect their school performance. An early detection and accelerated elimination of MeHg from the body, particularly in pregnant mothers, can prevent or ameliorate its toxic effects and reduce costs associated with decreased IQ in MeHg-poisoned children that has been estimated to be over $8 billion annually. Once neurological effects of MeHg start, they are irreversible. The proposed studies are designed to devise a MeHg monitoring protocol in experimental animals that is effective under conditions that closely mimic human environmental MeHg exposure with the hope that the protocol may eventually be tested in humans. The studies shall provide answers to the following specific questions: (1) What dose of N-Acetylcysteine (NAC) challenge is optimally effective for monitoring various levels of MeHg exposure and body burden? (2) How do various routes of MeHg exposure influence the efficacy of the NAC challenge? (3) Is NAC challenge effective at estimating body burden after chronic MeHg poisoning? and (4) Does the selected biomonitoring dose of NAC works equally well for all ages and both genders including pregnant dams? The proposed studies are also designed to identify the mechanism by which NAC enhances urinary excretion of MeHg with the hope that if the putative transporters of the MeHg-NAC complex are known, it will help in the design of drugs to further increase the efficacy of NAC as biomonitoring agent and antidote for MeHg poisoning. The rationale of the proposed work is that if a person has an elevated body burden of MeHg, then administration of a standardized dose of NAC should cause a transient increase in the urinary excretion of MeHg that is proportional to the body burden. In contrast to other chelators hitherto employed, NAC does not affect the distribution of essential metals and it is widely available in clinical settings. In vivo techniques using Wistar Rats exposed to [14C]MeHg prior to NAC challenge, shall be employed for the biomonitoring of MeHg in urine samples. Transcellular transport techniques, using MDCK cells doubly transfected with selected basolateral and apical transporters shall be employed in the mechanistic studies. The cells will be grown as a well-polarized monolayer using Transwell membrane units. Transport deficient TR- rats will also be used for in vivo mechanistic studies. Public Health Importance: Many people are exposed to levels of MeHg that are generally considered to be quite low, but that may nevertheless produce brain damage, particularly in infants and children. The proposed studies will device a monitoring protocol for early detection of relatively low MeHg levels that may nevertheless put an individual or unborn baby at risk of brain damage. When detected early enough, source(s) of MeHg can be removed and its excretion can be accelerated before the unset of irreversible brain damage. ? ? ?