Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells

Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

“…Differences in the rate of resynthesis of cholinesterase may also account for the smaller effects on enzyme activity in the brainstem compared with forebrain; certainly, pharmacokinetic disparities between these two regions would seem extremely unlikely. Second, recent data suggest that CPF targets development of glial cells to a greater extent than it does neuronal cell development (Aschner 2000;Garcia et al 2001Garcia et al , 2002Monnet-Tschudi et al 2000;Qiao et al 2001); glial development peaks during the postnatal period Valles et al 1997;Zawia and Harry 1996), whereas neurogenesis occurs much earlier (Rodier 1988), so the neonatal brain may be inherently more sensitive to CPF than is the fetal brain. Third, in light of the recent recognition that CPF itself is a developmental neurotoxicant Pope 1999;Rice and Barone 2000;Slotkin 1999), over and above inhibition of cholinesterase by its metabolite, chlorpyrifos oxon, there are likely to be substantial differences of effects reflecting the dissimilarities in fetal versus neonatal pharmacokinetics (Hunter et al , 1999Padilla et al 2000); it is highly likely that more unchanged CPF reaches the neonatal brain after direct administration to pups than is achieved with fetal exposure paradigms that involve maternal administration .…”

“…Nevertheless, it is increasingly clear that the developmental neurotoxicity of CPF involves mechanisms other than the inhibition of cholinesterase, with specific targeting of neural cell replication and differentiation, axonogenesis, and synaptogenesis Pope 1999;Slotkin 1999). Several recent studies suggest that CPF affects relatively late events in brain development, centered around the proliferation, differentiation, and functioning of glial cells (Garcia et al 2001(Garcia et al , 2002Qiao et al 2001), the cells that provide metabolic support for neurons and that guide axons to their proper targets within the developing central nervous system. In turn, these findings raise the issue of identifying the critical window for adverse effects of CPF on neurodevelopment.…”

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

“…The adverse effects of CPF on brain development prominently feature mechanisms centered around cell signaling cascades that control the expression and function of nuclear transcription factors required for neural cell differentiation [17,22,36,47,64,65,83,100,106]. Among the best studied is the pathway connecting GPCRs to the generation of cAMP and the downstream effectors controlled by cAMP, such as PKA and the transcription factors AP-1, Sp1 and CREB.…”

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

“…Although originally all organophosphates were thought to elicit neurodevelopmental damage through inhibition of cholinesterase (Mileson et al 1998;Pope 1999), it is now apparent that other mechanisms play an important, perhaps predominating role, involving concentrations below the threshold for the systemic toxicity associated with cholinergic hyperstimulation Das and Barone 1999;Pope 1999;Schuh et al 2002;Slotkin 1999, In press). CPF itself, as distinct from CPF oxon, the active metabolite that inhibits cholinesterase, disrupts the fundamental processes of brain development, such as DNA synthesis (Dam et al 1998;Whitney et al 1995), expression and function of macromolecular constituents and transcription factors that control cell differentiation (Crumpton et al 2000;Garcia et al 2001;Johnson et al 1998;Schuh et al 2002), and expression and function of neurotransmitters and their receptors that act as neurotrophins in the developing brain (Buznikov et al 2001;Dam et al 1999aDam et al , 1999bHoward and Pope 2002;Huff et al 2001;Liu et al 2002;Yanai et al 2002;Zhang et al 2002).…”

“…Third, we probed the AC response to specific receptor-mediated activation with isoproterenol, a β-adrenoceptor (βAR) agonist that links to AC by activating the stimulatory G-protein, G s . This receptor has defined neurotrophic roles in brain cell development and is a postulated target for CPF (Auman et al 2000;Dreyfus 1998;Garcia et al 2001;Kasamatsu 1985 (Polytron) in homogenization buffer, followed by resedimentation, and were then dispersed with a homogenizer (smooth glass fitted with Teflon pestle) in a buffer consisting of 250 mM sucrose, 2 mM MgCl 2 , and 50 mM Tris (pH 7.5).…”