MECHANISMS OF MEHG NEUROTOXICITY DURING DEVELOPMENT

Project Details

Description

Development of the brain procedes by a complex and regulated series
of morphogenetic steps, disturbance of which results in injury
ranging from retardation to gross malformations. The long-term
goal of these studies is to better understand the mechanisms by
which toxic compounds interfere with brain development. To study
these processes, advantage will be taken of the well-recognized
developmental neurotoxicity of methylmercury (MeHg). MeHg arrests
neuronal migration and inhibits maturation of post-migratory
neurons. The hypotheses to be tested are: 1) MeHg damages the
microtubular cytoskeleton of neurons and glia, thereby disturbing
neural-glial interactions required for neuronal migration and
maturation, and 2) MeHg independently perturbs the expression
and/or function of cell adhesion molecules (CAMs) essential for
cell migration, aggregation, and differentiation. These hypotheses
will be tested using an embryonal carcinoma (EC) cell culture model
of differentiating neuroectoderm, murine cerebellar slices in
culture, and mice treated with MeHg in vivo. The relative
sensitivities to MeHg of microtubules undergoing post-transnational
modifications will be studied using indirect immunofluorescence
microscopy. Data from the culture system will be compared with
MeHg-induced microtubule injury in murine cerebellar explants and
in cerebella of postnatally-exposed mice. The relationships
between microtubule disassembly, neuronal migration, and neurite
formation will be established. In parallel studies, the effects
of MeHg on the appearance and function of major CAMs will be
assessed in differentiating EC cells, cerebellar explants, and in
vivo. The dose-dependent effects of MeHg on cell migration in the
EC and cerebellar explant systems will be assessed by time-lapse
photomicroscopy, and correlated with microtubule and CAM staining.
CAMs will be identified in cultures and in cerebellum sections by
immunofluorescence microscopy and by SDS-PAGE. These studies will: 1) determine the relative sensitivities of
different classes of interphase microtubules in neurons and
astroglia to MeHg-induced disassembly, 2) correlate the pattern of
microtubule damage and reversibility with effects on neuron
migration and maturation, 3) determine whether function of neuronal
and/or glial CAMs is impaired by MeHg, and 4) determine whether CAM
involvement contributes to MeHg-induced brain injury.
StatusFinished
Effective start/end date1/1/8912/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $175,075.00
  • National Institutes of Health: $139,185.00
  • National Institutes of Health
  • National Institutes of Health: $171,522.00
  • National Institutes of Health

ASJC

  • Environmental Science(all)
  • Medicine(all)

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