TY - JOUR
T1 - Prenatal exposure to the acetylcholinesterase inhibitor methanesulfonyl fluoride alters forebrain morphology and gene expression
AU - Byers, Donna M.
AU - Irwin, Louis N.
AU - Moss, Donald E.
AU - Sumaya, Isabel C.
AU - Hohmann, Christine F.
N1 - Funding Information:
Support was provided by grants to L. Irwin (NIH-NICD, #R15 DC005179-01), to D. Moss (Coldwell Foundation), to C. Hohmann (NIH #SO6-GM51971), and a fellowship to I. Sumaya (NRSA #IF31 NS10811). The RCMI program of NIH-NCRR also provided research infrastructure support at the University of Texas at El Paso (#G12 RRO8124) and at Morgan State University (#5G12 RR017581). The authors also thank Carmen Redding for technical assistance with histology and morphometry, and Jennifer Taylor for assistance with microarray assays.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/8/8
Y1 - 2005/8/8
N2 - 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] [43]. 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.
AB - 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] [43]. 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.
KW - Acetylcholinesterase
KW - Cortical morphogenesis
KW - Gene expression
KW - Methanesulfonyl fluoride
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U2 - 10.1016/j.devbrainres.2005.05.003
DO - 10.1016/j.devbrainres.2005.05.003
M3 - Article
C2 - 15964079
AN - SCOPUS:23644439568
SN - 0165-3806
VL - 158
SP - 13
EP - 22
JO - Developmental Brain Research
JF - Developmental Brain Research
IS - 1-2
ER -