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Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system.

ABSTRACT: Dimethyl sulfoxide (DMSO) is a solvent that is routinely used as a cryopreservative in allogous bone marrow and organ transplantation. We exposed C57Bl/6 mice of varying postnatal ages (P0-P30) to DMSO in order to study whether DMSO could produce apoptotic degeneration in the developing CNS. DMSO produced widespread apoptosis in the developing mouse brain at all ages tested. Damage was greatest at P7. Significant elevations above the background rate of apoptosis occurred at the lowest dose tested, 0.3 ml/kg. In an in vitro rat hippocampal culture preparation, DMSO produced neuronal loss at concentrations of 0.5% and 1.0%. The ability of DMSO to damage neurons in dissociated cultures indicates that the toxicity likely results from a direct cellular effect. Because children, who undergo bone marrow transplantation, are routinely exposed to DMSO at doses higher than 0.3 ml/kg, there is concern that DMSO might be producing similar damage in human children.

SUBMITTER: Hanslick JL

PROVIDER: S-EPMC2682536 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system.

Hanslick Jennifer L JL Lau Karen K Noguchi Kevin K KK Olney John W JW Zorumski Charles F CF Mennerick Steven S Farber Nuri B NB

Neurobiology of disease 20081203 1

Dimethyl sulfoxide (DMSO) is a solvent that is routinely used as a cryopreservative in allogous bone marrow and organ transplantation. We exposed C57Bl/6 mice of varying postnatal ages (P0-P30) to DMSO in order to study whether DMSO could produce apoptotic degeneration in the developing CNS. DMSO produced widespread apoptosis in the developing mouse brain at all ages tested. Damage was greatest at P7. Significant elevations above the background rate of apoptosis occurred at the lowest dose teste ...[more]

PMID: 19100327

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Project description:Prenatal Human Cytomegalovirus (HCMV) infection often causes CNS maldevelopment. In a murine model, we detect Murine Cytomegalovirus (MCMV) in brain following intra-peritoneal inoculation at birth. Infected mice show impaired cerebellar development and impaired neurologic function on a beam balance test as adults. Among developmental genes differentially regulated, hindbrain expression of the homeodomain transcription factor HOXa5 was reduced with infection, and fewer HOXa5 expressing neurons were found in vestibular nuclei. Based on the hypothesis that immune activation connects focal viral infection and global CNS maldevelopment, we defined the components of CNS immune response. Flow cytometry showed a large increase in both number and activation of CNS monocytes. Monocytes were found in close association with infected cells by immunohistochemistry (IHC). Oligonucleotide microarrays contained herein identified many differentially expressed genes related to innate immune response. Chemokines, cytokines, cell surface receptors, and proteases are some of the many immunological genes shown to be differentially regulated by MCMV infection. These results together show that MCMV infection induces a complex immune response associated with changes in developmental gene expression and lasting neurologic defecit. Keywords: disease state comparison (virus infection) and competetive hybridization for expression analysis Previous work empirically determined the kinetics of viral spread to and replication in the Balb-C murine CNS. Balb-C mice were inoculated intra-peritoneally at birth, and harvested at 5, 8, 12, and 21 days post inoculation for cerebellar experiments. Controls were mock infected with vehicle (DMEM cell growth media) and harvested at the same timepoints. Each microarray was a two channel MEEBO array, upon which labeled and reverse transcribed cDNA from 3 pooled infected cerebella and three pooled uninfected cerebella competetively hybridized. Three unique biological replicates were performed with day 5 cDNA, 5 unique biological replicates at day 8, 5 unique biological replicates at day 12, and 4 unique biological replicates at day 21. For the analysis, colors channels were seperated and treated as independent hybridizations. However, since the experiments were dual channel, the primary data may be employed to generate ratio based measurements, and each sample is provided a corresponding number that can be used to pair the processed data and derive ratios (mock 3, infected 3). Mice were similarly inoculated and harvested at 5, 15, and 21 days post natal for liver tissue analysis. Inoculation was performed by injection with a microsyringe of 50ul titered virus delivering 500-1000 PFU per animal.

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Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system.

Publications

Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system.

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