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
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.
Available from: M. Christopher Newland
- "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.
Available from: Massimiliano De Paola
- "ng/g lipid (Gomara et al., 2007; Frederiksen et al., 2010)] or in the fetal brain for MeHg [4 ng/g (Lutz et al., 1996)], adjusted for the reported rates of accumulation of these contaminants in neurons (Lewandowski et al., 2003; Mundy et al., 2004; Huang et al., 2010; Schreiber et al., 2010; Verner et al., 2011). The doses for in vivo treatments of pregnant mice were derived from the estimated women daily intake of contaminants during pregnancy [WIP; decaBDE: about 1.6 ng/kg bw/day (Roosens et al., 2010; EFSA, 2011); MeHg: about 150 ng/kg bw/day (Mariani et al., 1980; Martorell et al., 2011)], after correction for the different tissue concentration rates in humans or mice [(McDonald, 2005; Castoldi et al., 2008b), see Supporting Information , Table S1 for details]. The lowest experimental concentrations were identified as 0.42 nM for DE-83R and 1.33 nM for MeHg in in vitro treatments (henceforth eFBC), and 0.03 mg/kg bw for DE-83R and 0.4 mg/kg bw for MeHg in in vivo administrations (eWIP). "
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ABSTRACT: The central nervous system (CNS) is extremely vulnerable to the toxic effects of environmental pollutants during development. Polybrominated diphenyl ethers (PBDEs) are persistent contaminants, increasingly present in the environment and in human tissues. Recent investigations identified a correlation between maternal exposure to PBDEs and impairment in fetal neurobehavioral development, suggesting that these contaminants pose a potential risk for children. We investigated on the potential effects of environmental decabrominated diphenyl ether (decaBDE, the fully brominated congener) on key neurodevelopmental molecules (e.g. synaptic proteins and immature neuron markers) in fetal mouse neurons. Methylmercury was used as reference neurotoxic contaminant, and to evaluate its possible synergism with decaBDE. The neurotoxic effects of decaBDE and methylmercury were determined in developing cultured neurons from mouse fetal hippocampus and cerebellum. Neuron death, dendritic branching, synaptic protein expression, markers of immature neurons and microglia activation were evaluated by immunocytochemistry. Brain samples from prenatally treated embryos were also examined for neurotoxicity signs by immunoblotting and histochemistry. DecaBDE significantly affected (down to 0.4 nM) the number of dendritic branches, and the levels of synaptic proteins and doublecortin in cultured neurons. Prenatal exposure to decaBDE decreased the synaptic proteins, and increased the expression of the immature neuron and microglial markers in mouse fetuses. In conclusion, prenatal exposure to realistic (relevant for human exposure) concentrations of decaBDE induces impairment of fetal CNS development in mice, suggesting a potential risk of fetotoxicity in humans. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014
Available from: Akira Naganuma
- "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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