Variability of brain lesions in rats administered methylmercury at various postnatal development phases

Wakabayashi, Keiji; Kakita, Akiyoshi; Sakamoto, Mineshi; Su, Mu; Iwanaga, Koichi; Ikuta, Fusahiro

doi:10.1016/0006-8993(95)01208-7

Cited by 58 publications

(27 citation statements)

References 33 publications

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“…While both hippocampus and cerebellum have been considered MeHg targets, differences we detect may reflect their distinct courses of neurogenesis during development (Wakabayashi et al, 1995;DiCicco-Bloom and Sondell, 2004). In neonatal rat brain, mercury accumulation (Sakamoto et al, 2002) and pathology (Wakabayashi et al, 1995) are regionally dependent on postnatal age.…”

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 85%

“…In neonatal rat brain, mercury accumulation (Sakamoto et al, 2002) and pathology (Wakabayashi et al, 1995) are regionally dependent on postnatal age. At P1, mercury distributes equally (Sakamoto et al, 2002) and produces histological disruption in hippocampus but not cerebellum (Wakabayashi et al, 1995). Our study defined similar differential effects on proliferation in hippocampus and cerebellum at P7.…”

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

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Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Burke

Cheng

et al. 2006

NeuroToxicology

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The developing brain is highly sensitive to methylmercury (MeHg). Still, the initial changes in cell proliferation that may contribute to long-term MeHg effects are largely undefined. Our previous studies with growth factors indicate that acute alterations of G1/S phase transition can permanently affect cell numbers and organ size. Therefore, we determined whether an environmental toxicant could also impact brain development with rapid (6-7h) effects on DNA synthesis and cell cycle machinery in neuronal precursors. In vivo studies in newborn rat hippocampus and cerebellum, two regions of postnatal neurogenesis, were followed by in vitro analysis of two precursor models, cortical and cerebellar cells, focusing on the proteins that regulate G1/S transition. In postnatal day 7 (P7) pups, a single subcutaneous injection of MeHg (3μg/g) acutely (7h) decreased DNA synthesis in the hippocampus by 40% and produced long-term (2 weeks) reductions in total cell number, estimated by DNA quantification. Surprisingly, cerebellar granule cells were resistant to MeHg effects in vivo at comparable tissue concentrations, suggesting region-specific differences in precursor populations. In vitro, MeHg altered proliferation and cell viability, with DNA synthesis selectively inhibited at an early timepoint (6h) corresponding to our in vivo observations. Considering that G1/ S regulators are targets of exogenous signals, we used a well-defined cortical cell model to examine MeHg effects on relevant cyclin dependent kinases (CDK) and CDK inhibitors. At 6h, MeHg decreased by 75% levels of cyclin E, a cell cycle regulator with roles in proliferation and apoptosis, without altering p57, p27, or CDK2 nor levels of activated caspase 3. In aggregate, our observations identify the G1/S transition as an early target of MeHg toxicity and raise the possibility that cyclin E degradation contributes to both decreased proliferation and eventual cell death.

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Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 85%

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Burke

Cheng

et al. 2006

NeuroToxicology

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“…Researchers of our group, as well as others, have reported that the cerebellum and dorsal root ganglion are the most severely injured sites in rat models of MeHg intoxication [9],[26]. The dorsal root ganglion is not covered by the BBB, and the BBB of the cerebellum is thought to be more vulnerable to MeHg-induced toxicity than that of the cerebrum [27].…”

Section: Discussionmentioning

confidence: 99%

Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression

et al. 2017

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Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

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“…Three groups of Wistar albino rats were treated for 10 days with oral doses of MeHg starting on PND 2, PND 15, or PND 60 (Wakabayashi et al, 1995). In newborn pups, no adverse clinical effects were observed and only minimal histological changes were noted in hippocampus and brainstem.…”

Section: Interspecies Differencesmentioning

confidence: 99%

Windows of sensitivity to toxic chemicals in the motor effects development

Ingber

Pohl

2016

Regulatory Toxicology and Pharmacology

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Many chemicals currently used are known to elicit nervous system effects. In addition, approximately 2000 new chemicals introduced annually have not yet undergone neurotoxicity testing. This review concentrated on motor development effects associated with exposure to environmental neurotoxicants to help identify critical windows of exposure and begin to assess data needs based on a subset of chemicals thoroughly reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR) in Toxicological Profiles and Addenda. Multiple windows of sensitivity were identified that differed based on the maturity level of the neurological system at the time of exposure, as well as dose and exposure duration. Similar but distinct windows were found for both motor activity (GD 8–17 [rats], GD 12–14 and PND 3–10 [mice]) and motor function performance (insufficient data for rats, GD 12–17 [mice]). Identifying specific windows of sensitivity in animal studies was hampered by study designs oriented towards detection of neurotoxicity that occurred at any time throughout the developmental process. In conclusion, while this investigation identified some critical exposure windows for motor development effects, it demonstrates a need for more acute duration exposure studies based on neurodevelopmental windows, particularly during the exposure periods identified in this review.

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Variability of brain lesions in rats administered methylmercury at various postnatal development phases

Cited by 58 publications

References 33 publications

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E

Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression

Windows of sensitivity to toxic chemicals in the motor effects development

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