Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos.
Considering the wide variety of effects that have been reported to occur in the developmental neurotoxicity of chlorpyrifos (CP) and the lack of consensus on their dependence of brain acetylcholinesterase (AChE) activity inhibition, we applied microarray technology to explore dose-dependent alterations in transcriptional response in the fetal and maternal C57BL/6 mouse brain after daily gestational exposure (days 6 to 17) to CP (2, 4, 10, 12 or 15 mg/kg, sc). We identified significantly altered genes across doses and assessed for overrepresentation of Gene Ontology (GO) biological processes and KEGG pathways. We further clustered genes based on their expression profiles across doses and repeated the GO/pathways analysis for each cluster. The dose-effect relationship of CP on gene expression, both at the gene and pathway levels was non-monotonic and not necessarily related to brain AChE inhibition. The largest impact was observed in the 10mg/kg dose group which was also the LOAEL for brain AChE inhibition. In the maternal brain, lower doses (4 mg/kg) influenced GO categories and pathways such as cell adhesion, behavior, lipid metabolism, long-term potentiation, nervous system development, neurogenesis, synaptic transmission. In the fetal brain, lower doses (2 and/or 4 mg/kg) significantly altered cell division, translation, transmission of nerve impulse, chromatin modification, long-term potentiation. In addition, some genes involved in nervous system development and signaling were shown to be specifically influenced by these lower CP doses. Our approach was sensitive and reflected the diversity of responses known to be disrupted by CP and highlighted possible additional consequences of CP neurotoxicity, such as disturbance of the ubiquitin proteasome system.
Moreira
Estefania G
EG
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.
Yu
Xiaozhong
X
Robinson
Joshua F
JF
Griffith
Willian
W
Hong
Sung Woo
SW
Beyer
Richard P
RP
Bammler
Theo K
TK
Faustman
Elaine M
EM
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D053263:Gene Regulatory Networks; D005865:Gestational Age; D007279:Injections, Subcutaneous; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D015203:Reproducibility of Results; D018570:Risk Assessment; D043922:Toxicogenetics / Q000379:methods*; D014158:Transcription, Genetic / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D004390:Chlorpyrifos