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.

15 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "In adults, both humans and rats, cerebellar MeHg poisoning is characterized by a loss of neurons accompanied by astrocytosis, a replacement scartype tissue generated by injury in the nervous system (Choi et al. 1978). However, in the fetal cerebellum, pathologies generated by maternal ingestion of MeHg are presented quite differently, as a more consistent constellation of abnormalities, varying only slightly by developmental age, dose and duration of exposure (Choi et al.1978; Castoldi et al. 2008; Burbacher et al. 1990). Indeed, the fetal The saltmarsh sparrow was collected observing all permits issued by the United States Fish and Wildlife Service and the State "
    [Show abstract] [Hide abstract]
    ABSTRACT: A fledged, 12-15 day-old saltmarsh sparrow, Ammodramus caudacutus, was collected from an accidental kill on Cinder Island, Long Island, NY, USA. The sparrow was assessed for feather mercury levels and the brain analyzed for cerebellar abnormalities by microscopic examination. In humans, fetal Minamata disease is caused by maternal ingestion of mercury. It is characterized by disrupted and disordered cerebellar neuronal migration in the fetus or infant. Results from this sparrow show cerebellar abnormalities typical of Minamata disease. It is the first known avian or mammalian specimen taken from the wild to show the abnormalities typical of the human fetal syndrome.
    Bulletin of Environmental Contamination and Toxicology 03/2013; 90(5). DOI:10.1007/s00128-013-0974-y · 1.26 Impact Factor
Show more