Neurodevelopmental toxicity of methylmercury: Laboratory animal data and their contribution to human risk assessment

Toxicology Division, University of Pavia, Via Palestro 26, 27100 Pavia, Italy.
Regulatory Toxicology and Pharmacology (Impact Factor: 2.03). 08/2008; 51(2):215-29. DOI: 10.1016/j.yrtph.2008.03.005
Source: PubMed


Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.

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    • "That is, exposed animals showed no neurological signs, weight loss, reproductive toxicity, or changes in physical appearance even as they showed significant, if subtle, neurotoxicity as adults (Newland, 2012; Newland et al., 2008). Such sensitivity has been reported with auditory, visual, and somatosensory deficits in monkeys (Rice, 1996b) and in behavioral studies with rodents (Bourdineaud et al., 2008; Bourdineaud et al., 2011; Castoldi et al., 2008; Liang et al., 2009; Montgomery et al., 2008; Newland et al., 2008; Onishchenko et al., 2008; Weiss et al., 2005) and are linked to disturbances in the development of the dopamine systems (Rasmussen and Newland, 2001; Reed and Newland, 2009). Some of the behavioral effects of gestational exposure that we have reported, such as response perseveration, were affected at the lowest exposure level examined, 0.5 ppm in drinking water, yielding about 40 ␮g/kg/day of Hg as MeHg. "
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    ABSTRACT: Events that disrupt the early development of the nervous system have lifelong, irreversible behavioral consequences. The environmental contaminant, methylmercury (MeHg), impairs neural development with effects that are manifested well into adulthood and even into aging. Noting the sensitivity of the developing brain to MeHg, the current review advances an argument that one outcome of early MeHg exposure is a distortion in the processing of reinforcing consequences that results in impaired choice, poor inhibition of prepotent responding, and perseveration on discrimination reversals (in the absence of alteration of extradimensional shifts). Neurochemical correlates include increased sensitivity to dopamine agonists and decreased sensitivity to gamma-aminobutyric acid (GABA) agonists. This leads to a hypothesis that the prefrontal cortex or dopamine neurotransmission is especially sensitive to even subtle gestational MeHg exposure and suggests that public health assessments of MeHg based on intellectual performance may underestimate the impact of MeHg in public health. Finally, those interested in modeling neural development may benefit from MeHg as an experimental model. Copyright © 2015. Published by Elsevier B.V.
    Behavioural processes 03/2015; 114(1). DOI:10.1016/j.beproc.2015.03.007 · 1.57 Impact Factor
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    • "Methylmercury is an environmental pollutant that affects the central nervous system (Castoldi et al., 2008; Grandjean and Herz, 2011). However, the mechanism of development of methylmercury toxicity or development of a defense mechanism against this toxicity is remain poorly understood. "
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    ABSTRACT: The ubiquitin-proteasome system is believed to play an important role in the determination of cell sensitivity to methylmercury. The ubiquitin ligase enzyme is involved in the recognition of substrate proteins that are degraded by the ubiquitin-proteasome system. In this study, the ubiquitin ligase species affecting methylmercury sensitivity was investigated by the gene interference method. We found that the inhibition of expression of the gene for Cell division cycle 23 (CDC23), a constitutional component of the ubiquitin ligase anaphase promoting complex/cyclosome, sensitized HEK 293 cells to methylmercury.
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    • "The concentration of Hg in blood and brain can be used as a biomarker of exposure and allows comparison of adverse effects across studies and different species [28]. In vivo rodent studies demonstrated at birth neuropathologic damage and neurobehavioral alterations at brain [Hg] of 4.5 and 0.5 mg/kg, respectively [44]. Perinatal MeHg treatment resulted in neonatal rat brain [Hg] of 3–11 mg/kg [45]. "
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    ABSTRACT: Early methylmercury (MeHg) exposure can have long-lasting consequences likely arising from impaired developmental processes, the outcome of which has been exposed in several longitudinal studies of affected populations. Given the large number of newborns at an increased risk of learning disabilities associated with in utero MeHg exposure, it is important to study neurobehavioral alterations using ecologically valid and physiologically relevant models. This review highlights the benefits of using the MeHg drinking water exposure paradigm and outlines behavioral outcomes arising from this procedure in rodents. Combination treatments that exacerbate or ameliorate MeHg-induced effects, and possible molecular mechanisms underlying behavioral impairment are also discussed.
    Journal of Trace Elements in Medicine and Biology 10/2013; 28(2). DOI:10.1016/j.jtemb.2013.09.008 · 2.37 Impact Factor
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