Effects of Methyl Mercury on the Cell Cycle of Primary Rat CNS Cells in Vitro

Ponce, Rafael; Kavanagh, Terrance J.; Mottet, N. Karle; Whittaker, Stephen G.; Faustman, Elaine M.

doi:10.1006/taap.1994.1142

Cited by 80 publications

(57 citation statements)

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“…Studies in other systems have reported MeHg effects on G1/S transition and regulatory molecules. In primary embryonic midbrain cultures, MeHg affected G1/S only at 4 μM, when all cycling had ceased (Ponce et al, 1994). However, in fibroblasts and splenocytes, MeHg apparently decreased the rate of the G1/S transition, with the underlying mechanism undefined (Vogel et al, 1986;Roy et al, 1991).…”

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

confidence: 95%

“…Similarly, while midbrain cells are resistant to MeHg exposure in vivo (Lewandowski et al, 2003), they show cell cycle alterations in culture (Ponce et al, 1994). The inconsistency between in vitro and in vivo responses may represent a deficiency in cell culture models, differences on Hg levels to which cells are exposed, or the presence of protective factors in vivo.…”

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

“…In contrast, changes observed at 24h may represent more general cell damage to proliferating precursors. MeHg is known to reduce cell viability at 24h in PC12 cells (Parran et al, 2001), neuroepithelial cells (Ponce et al, 1994;Faustman et al, 2002) and dorsal root ganglion neurons (Wilke et al, 2003) through mechanisms including glutathione depletion, reactive oxygen species production, microtubule damage, and apoptosis. MeHg-induced cell death is highly dependent on p53, a protein commonly associated with apoptosis but also involved in the G2/M and G1/S transitions (Gribble et al, 2005), raising the possible connection between G1/S regulation and cell death following MeHg exposure.…”

Section: Decreased Precursor Proliferation May Reflect Mehg Effects Omentioning

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

confidence: 95%

Section: Mehg Has Rapid Differential Effects On Proliferation In Devmentioning

confidence: 99%

Section: Decreased Precursor Proliferation May Reflect Mehg Effects Omentioning

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 historic use of organomercury-based fungicides and the present-day use of the benomyl and other benzimidazole analogues as anthelmintics are examples of cell-cycle inhibitors that have been investigated with regard to their influence on the developing CNS (13)(14)(15)(16)(17). Recent reports suggesting that chlorpyrifos (a pesticide used on many fruit crops such as apples, cherries, and pears)…”

Section: Why Study Mechanisms Ofsusceptibility?mentioning

confidence: 99%

Mechanisms underlying Children's susceptibility to environmental toxicants.

Faustman

Silbernagel

Fenske

et al. 2000

Environ Health Perspect

247

163

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An important public health challenge has been the need to protect children's health. To accomplish this goal, the scientific community needs scientifically based child-specific risk assessment methods. Critical to their development is the need to understand mechanisms underlying children's sensitivity to environmental toxicants. Risk is defined as the probability of adverse outcome and when applied to environmental risk assessment is usually defined as a function of both toxicity and exposure. To adequately evaluate the potential for enhanced health risks during development, both child-specific factors affecting toxicity and exposure need to be considered. In the first section of this article, example mechanisms of susceptibility relevant for toxicity assessment are identified and discussed. In the second section, examples of exposure factors that help define children's susceptibility are presented. Examples of pesticide research from the newly funded Child Health Center at the University of Washington will be given for illustration. The final section discusses the importance of putting these considerations of children's susceptibility into an overall framework for ascertaining relevancy for human risk assessment. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6

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“…Third, examination of the cell cycle effects elicited by MeHg demonstrates mitotic inhibition both in vivo and in vitro (Miura et al 1978;Ponce et al 1994;Rodier et al 1984;Sager 1988).…”

mentioning

confidence: 99%

Investigations of methylmercury-induced alterations in neurogenesis.

Faustman

Ponce

et al. 2002

Environ Health Perspect

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Methylmercury (MeHg) has been an environmental concern to public health and regulatory agencies for over 50 years because of its toxicity to the human nervous system. Its association with nervous system toxicity in adults and infants near Minamata Bay, Japan, in the 1950s initiated environmental health research inquiries that continue to this day. Observations of greater neurotoxicity with gestational compared with adult exposure suggest a unique susceptibility of the developing nervous system to MeHg. Despite extensive research conducted over the last half century, determination of definitive molecular mechanisms underlying the observed neurotoxic effects of MeHg have not been identified. This paper summarizes results of a series of experiments conducted to examine the effects of MeHg on neuroepithelial cell proliferation, a hypothesized mode of action for its selective effects on neurogenesis. Observed effects of MeHg on cell cycle entry and progression were associated with alterations in a variety of cell cycle regulatory molecules, including p21 signaling pathways. We place these studies in the context of other cellular responses involved in signal transduction, including oxidative stress, altered protein phosphorylation, and altered intracellular calcium homeostasis. Although existing information suggests that no single mechanism underlies the diverse array of effects associated with MeHg-induced developmental neurotoxicity, we demonstrate characteristic effects of MeHg on cell signaling that contribute to observed effects on cell proliferation. Experimentally derived cell cycle kinetic and cytotoxicity data allowed development of a biologically based dose-response model of MeHg-induced alterations in neurodevelopment, which can form the basis for information synthesis and hypothesis testing and for use in assessing risks from environmental exposures.

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Effects of Methyl Mercury on the Cell Cycle of Primary Rat CNS Cells in Vitro

Cited by 80 publications

References 0 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

Mechanisms underlying Children's susceptibility to environmental toxicants.

Investigations of methylmercury-induced alterations in neurogenesis.

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