PFPC Daily - June 22, 2005

SEE also: Hazardous Substances Fact Sheet
http://www.state.nj.us/health/eoh/rtkweb/2553.pdf

Byers DM, Irwin LN, Moss DE, Sumaya IC, Hohmann CF - "Prenatal
exposure to the acetylcholinesterase inhibitor methanesulfonyl
fluoride alters forebrain morphology and gene expression" Brain Res
Dev Brain Res. 2005 Jun 15; [Epub ahead of print]

Methanesulfonyl fluoride (MSF) is a CNS-selective
acetylcholinesterase (AChE)inhibitor, currently being developed and
tested for the treatment of symptoms of Alzheimer's disease [D.E.
Moss, P. Berlanga, M.M. Hagan, H. Sandoval, and C. Ishida,
Methanesulfonyl fluoride (MSF): a double-blind, placebo-controlled
study of safety and efficacy in the treatment of senile dementia of
the Alzheimer type, Alzheimer Dis. Assoc. Disord., 13 (1999) 20-25] .
We have previously confirmed that a single in utero exposure to MSF
at clinically appropriate doses inhibits AChE activity in fetal rat
brain by 20%, and when administered throughout gestation, MSF
achieves a 40% level of inhibition. Here, we show that rats
chronically exposed in utero to MSF display marked sex-specific
differences in morphological development of the cerebral cortical
layers compared with controls at 7 days of age. Forebrain size and
cortical thickness were increased in females and decreased in males.
An analysis of gene expression in neonate brain on the day of birth
revealed sex-specific differential expression of over 25 genes,
including choline acetyltransferase (ChAT), which were affected by
prenatal MSF exposure. Many of these genes are associated with sexual
differentiation and brain development, while others are involved in
more generalized cellular and metabolic processes. The changes
observed in cortical morphology and gene expression suggest a
critical developmental role for AChE in the fetal nervous system,
most likely through its effect on cholinergic neurotransmission.