Demethylation of methylmercury and the enhanced production of formaldehyde in mouse liver

Abstract

-Methylmercury (MeHg) is gradually changed to inorganic Hg after demethylation in animal tissues, and a selective quantification of inorganic Hg in the tissues is necessary to detect the reaction. We detected inorganic Hg formation in liver and kidney of mouse as early as 24 hr after MeHg injection. As an example of biological demethylation, the cytochrome P450 (P450)-mediated N-demethylation of drugs has been well documented, and formaldehyde was detected as a reaction product. Here we incubated mouse liver homogenate with added MeHg and observed a dose-dependent production of formaldehyde, as well as inorganic Hg formation. Since the amount of formaldehyde was approx. 500 times higher than that of the inorganic Hg that formed, the formaldehyde production would be stimulated by inorganic Hg formed from MeHg. We observed that inorganic Hg caused formaldehyde production, and it was enhanced by L-methionine and sarcosine. Thus, some biomolecules with S-methyl and N-methyl groups may function as methyl donors in the reaction. Using subcellular fractions of mouse liver, we observed that microsomal P450 did not participate in the demethylation of MeHg, but the greatest activity was located in the mitochondria-rich fraction. The addition of superoxide anion in the reaction mixture significantly enhanced the formaldehyde production, whereas Mn-superoxide dismutase depressed the reaction. Our present findings demonstrated that inorganic Hg formed by MeHg demethylation in mouse liver stimulated the endogenous formaldehyde production, and we observed that MeHg demethylation could be estimated by a formaldehyde analysis. Our results also suggested that superoxide anion is involved in the reaction.

Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation

“…These results suggest that a slow rate demethylation occurs in brain [71]. Toxicokinetic studies in human subjects suggest a positive correlation between the rate of MeHg demethylation into inorganic Hg and MeHg elimination rate [68]. Regarding excretion pathways, inorganic Hg can be excreted via bile discharges or via urine, while excretion of MeHg occurs predominantly via feces.…”

“…In several organs, a small fraction of MeHg is gradually demethylated to inorganic mercury. In vitro studies have reported a dose-response relationship between MeHg administration and inorganic mercury accumulation [67,68]. Thus, even though MeHg-contaminated food constitutes the source of exposure, it is frequent to find both organic and inorganic mercurial species within the organism.…”

“…In fact, hepatic HgSe granules were detected in mammals fed with MeHg-contaminated aliments. This suggests that MeHg is possibly demethylated in the liver [68]. Cohort studies from humans exposed to MeHg for a long period have shown a high concentration of inorganic mercury in brain.…”

Formaldehyde‐Crosslinked Nontoxic Aβ Monomers to Form Toxic Aβ Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives

“…Numerous studies have shown that FA can rapidly accumulate in organism, and is primarily associated with FA pollutants, [104,209] diets (deep‐sea fish polluted with methyl mercury [210,211] ), viral infect, [212–216] external stimuli, [19] stress, [20,36] and trauma, as well as with endogenous factors, such as: age, [11,32] stroke, [36] diabetes, [217] postoperative cognitive dysfunction (POCD), [218] and ALDH2 polymorphisms [217,219,210] (Figure 5a). The most direct evidence is that injection of 0.45 mM FA (a concentration detected in aged rats with cognitive deficits) can mimic memory disorders in healthy adult male mice and rats [10] …”

Use of Zebrafish ( Danio rerio ) Embryos as a Model to Assess Effects of Mercury on Developing Skeletal Muscle: A Morphometric and Immunohistochemical Study

“…Early embryogenesis is one of the most sensitive life stages to environmental toxicants, and while the developing brain is particularly sensitive to mercury toxicity (Hassan et al, 2012;Chan et al, 2017), other developing organ systems and tissues also are highly susceptible to mercury toxicity. Mechanisms through which mercury affects cellular functions include induction of apoptosis, increased cellular oxidative stress, reduced function of ion channels and neurotransmitter receptors, and perturbations in energy metabolism and calcium balance, primarily through effects on mitochondrial function and integrity are adversely affected when exposed to mercury (Reis et al, 2007;Uchikawa et al, 2016). Mercury also has a pronounced affinity for protein sulfhydryl (SH) groups that, when bound to mercury, will diminish or completely inhibit normal protein function, including enzyme functions (Reis et al).…”