Persistent, differential alterations in developing cerebellar cortex of male and female mice after methylmercury exposure

Sager, Polly R.; Aschner, Michael; Rodier, Patricia M.

doi:10.1016/0165-3806(84)90170-6

Cited by 135 publications

(51 citation statements)

References 19 publications

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“…We assessed one such component, precursor proliferation, and found that MeHg rapidly alters DNA synthesis and cell production selectively in the hippocampus. While MeHg effects on mitosis, in particular, inducing metaphase arrest, are well-defined Sager et al, 1984), the knowledge that extracellular signals act during G1 to control cell division raised the possibility that toxicants also alter proliferation at the G1/S transition. Indeed, in cerebellar and cortical precursor cultures, MeHg decreased G1/S progression prior to alterations in cell number and elicited selective reductions in pro-mitogenic cyclin E, suggesting that MeHg may decrease proliferation by altering cell cycle regulators.…”

Section: Discussionmentioning

confidence: 99%

“…However, the long half-life of mercury in the brain (Magos and Butler, 1976;Burbacher et al, 2005) supports an alternative possibility that tissue levels remain high weeks after dosing and continually affect proliferation. While Sager et al (1984) found that P2 mice given 4 mg/kg MeHg had 1.8μg/g Hg after 24h but <0.1μg/g at P21, future studies need to address Hg levels, compartmentation and neurogenesis in the P21 rat following early postnatal exposure. Furthermore, while bFGF studies indicate a relatively permanent change in brain cell populations after newborn treatments, studies on adult rats after early MeHg exposures will be needed to explore this issue.…”

Section: Long-term Effects Of Mehg Suggests Alteration In Brain Regiomentioning

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: Discussionmentioning

confidence: 99%

Section: Long-term Effects Of Mehg Suggests Alteration In Brain Regiomentioning

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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“…Architectonic abnormalities are known to occur with mercury exposure during fetal development, which can result in abnormalities in neuronal and glial proliferation and neuronal migration [129,130,104]. Especially affected is the cerebellum.…”

Section: The Role Of Mercurymentioning

confidence: 99%

Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders

Blaylock

Strunecká

2009

CMC

123

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Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.

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“…MeHg in vitro inhibits microtubule formation and protein synthesis in nerve cells, alters neuronal membrane activity, and interferes with DNA synthesis (1); in vivo it impairs mitosis and disrupts neuronal migration (2,3). Its toxicity has been known for centuries (4) and multiple episodes of poisoning in children by both inorganic and organic mercury have been reported (5,6).…”

Section: Human Effects Of Methylmercurymentioning

confidence: 99%

Does Methylmercury Have a Role in Causing Developmental Disabilities in Children?

Myers¹,

Davidson²

2000

Environmental Health Perspectives

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Persistent, differential alterations in developing cerebellar cortex of male and female mice after methylmercury exposure

Cited by 135 publications

References 19 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

Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders

Does Methylmercury Have a Role in Causing Developmental Disabilities in Children?

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