Transcriptional biomarkers distinguish between vulnerable periods for developmental neurotoxicity of chlorpyrifos: Implications for toxicogenomics.
The widespread use of organophosphate insecticides has raised concern about neurotoxic effects of fetal and childhood exposures. Studies in rats show that chlorpyrifos (CPF) elicits CNS cell damage, in part, through noncholinergic mechanisms that involve alterations in the expression and function of nuclear transcription factors that control cell replication, differentiation, and apoptosis. In the current study, we examined mRNAs encoding c-fos and p53, in order to determine if changes in these factors correspond to the differential susceptibility of forebrain neurons and glia, when exposure is shifted from the early neonatal period (postnatal days 1-4) to a later period (days 11-14). The early treatment paradigm elicited a significant elevation of c-fos whereas the later treatment suppressed c-fos. Neither regimen altered forebrain p53 expression, but values were elevated in the cerebellum following the later treatment; the cerebellum develops later than the forebrain and has its peak of neurogenesis postnatally. Our results suggest that a wider profiling of mRNAs using genomic arrays would enable screening for developmental neurotoxicants, but that regional and temporal profiles will be required in order to draw mechanistic conclusions or to identify critical periods of vulnerability.
Dam
Kristina
K
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D004390:Chlorpyrifos / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016548:Prosencephalon / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*
D015415:Biomarkers; D007306:Insecticides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004390:Chlorpyrifos