Morphologic effects of subtoxic neonatal chlorpyrifos exposure in developing rat brain: regionally selective alterations in neurons and glia.
The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral teratogenesis with exposure windows ranging from the embryonic neural tube stage through postnatal development. To explore the morphologic changes occurring in late-stage exposure, newborn rats were given 5 mg/kg of CPF s.c. daily on postnatal days (PN) 11-14, a regimen that is devoid of systemic toxicity, but that elicits long-term cognitive impairment. On PN15 and 20, we examined the septal nucleus, striatum and somatosensory cortex. Across all three regions, CPF elicited a significant decrease in the number of glial cells. Superimposed on this basic pattern, there were region-specific alterations in the number and type of neurons, and neuronal perikaryal dimensions. In the septal nucleus, the CPF group exhibited an increase in the number of neurons on PN20, representing a delay in the normal maturational decline; there was a parallel decrease in the glial/neuronal ratio. In the striatum, the number of neurons per unit area was reduced in the CPF group, accompanied by perikaryal hypertrophy, as evidenced by an increase in the average neuronal cell diameter. In the somatosensory cortex, the distribution of cell sizes indicated a decrease in the proportion of small, nonpyramidal cells. Thus, there are subtle morphological changes in the juvenile rat brain after neonatal CPF exposure that are detectable with quantitative analysis and that correlate with later emergence of behavioral alterations. Furthermore, the current findings support the hypothesis that CPF interferes with gliogenesis, a relatively late event in brain development; accordingly, the vulnerable period for adverse effects of CPF is likely to extend into childhood or adolescence.
Roy
Tara Sankar
TS
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D016009:Chi-Square Distribution; D004390:Chlorpyrifos / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D004390:Chlorpyrifos