Transcriptional Profiles for Chlorpyrifos, Diazinon, Dieldrin and Divalent
Nickel in PC12 Cells
http://www.ehponline.org/docs/2008/0800251/abstract.pdf
Theodore A. Slotkin and Frederic J. Seidler
doi: 10.1289/ehp.0800251 (available at http://dx.doi.org/)
Online 5 December 2008
ehponline.org
ABSTRACT
Background: Oxidative stress and excitotoxicity underlie the developmental
neurotoxicity of
numerous chemicals.
Objectives: We compared the effects of organophosphates (chlorpyrifos,
diazinon), an
organochlorine (dieldrin) and a metal (Ni2+) to determine how these
mechanisms contribute to
similar or dissimilar neurotoxic outcomes.
Methods: We used PC12 cells as a model of developing neurons and evaluated
transcriptional
profiles for genes for oxidative stress responses and glutamate receptors.
Results: Chlorpyrifos had a greater effect on oxidative stress-related genes
in differentiating
cells as compared to the undifferentiated state. Chlorpyrifos and diazinon
showed significant
concordance in their effects on glutathione-related genes but they were
negatively correlated for
effects on catalase and superoxide dismutase isoforms, and had no
concordance for effects on
ionotropic glutamate receptors. Surprisingly, the correlations were stronger
between diazinon
and dieldrin than between the two organophosphates. The effects of Ni2+ were
the least similar
for genes related to oxidative stress but there was a significant
concordance with dieldrin for
effects on glutamate receptors.
Conclusions: Our results point to underlying mechanisms by which different
organophosphates
produce disparate neurotoxic outcomes despite their shared property as
cholinesterase inhibitors
Further, apparently unrelated neurotoxicants may produce similar outcomes
because of
convergence on oxidative stress and excitotoxicity. The combined use of cell
cultures and
microarrays points to specific endpoints that can distinguish similarities
and disparities in the
effects of diverse developmental neurotoxicants.
