Prenatal exposure to the acetylcholinesterase inhibitor methanesulfonyl fluoride alters forebrain morphology and gene expression

Abstract

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.