Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

Abstract

Previously, we found that exposure of neonatal rats to chlorpyrifos (CPF) produced brain cell damage and loss, with resultant abnormalities of synaptic development. We used the same biomarkers to examine prenatal CPF treatment so as to define the critical period of vulnerability. One group of pregnant rats received CPF (subcutaneous injections in dimethyl sulfoxide vehicle) on gestational days (GD) 17-20, a peak period of neurogenesis; a second group was treated on GD9-12, the period of neural tube formation. In the GD17-20 group, the threshold for a reduction in maternal weight gain was 5 mg/kg/day; at or below that dose, there was no evidence (GD21) of general fetotoxicity as assessed by the number of fetuses or fetal body and tissue weights. Above the threshold, there was brain sparing (reduced body weight with an increase in brain/body weight ratio) and a targeting of the liver (reduced liver/body weight). Indices of cell packing density (DNA per gram of tissue) and cell number (DNA content) similarly showed effects only on the liver; however, there were significant changes in the protein/DNA ratio, an index of cell size, in fetal brain regions at doses as low as 1 mg/kg, below the threshold for inhibition of fetal brain cholinesterase (2 mg/kg). Indices of cholinergic synaptic development showed significant CPF-induced defects but only at doses above the threshold for cholinesterase inhibition. With earlier CPF treatment (GD9-12), there was no evidence of general fetotoxicity or alterations of brain cell development at doses up to the threshold for maternal toxicity (5 mg/kg), assessed on GD17 and GD21; however, augmentation of cholinergic synaptic markers was detected at doses as low as 1 mg/kg. Compared with previous work on postnatal CPF exposure, the effects seen here required doses closer to the threshold for fetal weight loss; this implies a lower vulnerability in the fetal compared with the neonatal brain. Although delayed neurotoxic effects of prenatal CPF may emerge subsequently in development, our results are consistent with the preferential targeting of late developmental events such as gliogenesis, axonogenesis, and synaptogenesis.

Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

“…Systemic toxicity of CPF. As reported previously (Garcia et al 2002;Qiao et al 2002), the threshold for CPF-induced impairment of maternal growth was 5 mg/kg with treatment on either GD9-12 or GD17-20, but fetal brain growth was unaffected even at the highest doses (data not shown). Neither the early nor the late treatment paradigm affected the number of fetuses or fetal viability.…”

“…In both periods, CPF elicits mitotic abnormalities, apoptosis, and architectural anomalies in the developing brain at exposures that are not otherwise embryotoxic Roy et al 1998;White et al 2002). At lower exposure levels, CPF-induced damage is not immediately apparent, but synaptic and functional abnormalities appear later, in adolescence and adulthood (Levin et al 2002;Qiao et al 2002Qiao et al , 2003. Thus, if the production of cAMP is involved in the adverse effects of CPF on brain development, effects on the AC signaling pathway should be evident immediately upon exposure to these lower exposures, preceding the delayed-onset anomalies.…”

“…Because the treatments were given to the dams, only one fetus was used from each dam, so the number of determinations represents the number of dams. The fetuses were derived from the same litters as those used in two previous studies on cell damage and cholinergic biomarkers; therefore effects on cholinesterase activity, maternal and fetal body weights, and other litter characteristics have been published elsewhere (Garcia et al 2002;Qiao et al 2002).…”

Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner-City Children

“…39 Given the diversity of possible mechanisms and target tissues, the developing brain could be vulnerable to organophosphate pesticide exposure from early embryonic life into childhood. 16,[80][81][82][83][84][85] According to Slotkin, 22 the period of vulnerability to chlorpyrifos extends through the period of synaptic modeling, and this continues well into childhood and even adolescence. In the present report, both chlorpyrifos and lead exposures were assessed during the prenatal period only, which is a limitation.…”

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

“…Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112]. Accordingly, whereas all the organophosphates share cholinesterase as a target, they are likely to differ to a greater or lesser extent in their effects unrelated to that particular mechanism.…”