Fetal Chlorpyrifos Exposure: Adverse Effects on Brain Cell Development and Cholinergic Biomarkers Emerge Postnatally and Continue into Adolescence and Adulthood. (Research)

By Qiao, Dan; Seidler, Frederic J. et al. | Environmental Health Perspectives, April 2003 | Go to article overview

Fetal Chlorpyrifos Exposure: Adverse Effects on Brain Cell Development and Cholinergic Biomarkers Emerge Postnatally and Continue into Adolescence and Adulthood. (Research)


Qiao, Dan, Seidler, Frederic J., Tate, Charlotte A., Cousins, Mandy M., Slotkin, Theodore A., Environmental Health Perspectives


Fetal and childhood exposures to widely used organophosphate pesticides, especially chlorpyrifos (CPF), have raised concerns about developmental neurotoxicity. Previously, biomarkers for brain cell number, cell packing density, and cell size indicated that neonatal rats were more sensitive to CPF than were fetal rats, yet animals exposed prenatally still developed behavioral deficits in adolescence and adulthood. In the present study, we administered CPF to pregnant rats on gestational days 17-20, using regimens devoid of overt fetal toxicity. We then examined subsequent development of acetylcholine systems in forebrain regions involved in cognitive function and compared the effects with those on general biomarkers of cell development. Choline acetyltransferase, a constitutive marker for cholinergic nerve terminals, showed only minor CPF-induced changes during the period of rapid synaptogenesis. In contrast, hemicholinium-3 binding to the presynaptic choline transporter, which is responsive to nerve impulse activity, displayed marked suppression in the animals exposed to CPF; despite a return to nearly normal values by weaning, deficits were again apparent in adolescence and adulthood. There was no compensatory up-regulation of cholinergic receptors, as [m.sub.2]-muscarinic cholinergic receptor binding was unchanged. CPF also elicited delayed-onset alterations in biomarkers for general aspects of cell integrity, with reductions in cell packing density, increases in relative cell size, and contraction of neuritic extensions; however, neither the magnitude nor timing of these changes was predictive of the cholinergic defects. The present findings indicate a wide window of vulnerability of cholinergic systems to CPF, extending from prenatal through postnatal periods, occurring independently of adverse effects on general cellular neurotoxicity. Key words: brain development, chlorpyrifos, choline acetyltransferase, cholinesterase, development, DNA, hemicholinium-3 binding, muscarinic [m.sub.2]-acetylcholine receptor.

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Although some uses of the organophosphate insecticide chlorpyrifos (CPF)'s were recently curtailed in the United States (U.S. EPA 2000), CPF and other organophosphates continue to be applied worldwide on a major scale. Studies with animal and cell culture models of CPF exposure indicate that CPF is especially damaging to the developing brain, targeting diverse events in neural development, including cell proliferation and differentiation, axonogenesis and synaptogenesis, and synaptic function (see reviews in Barone et al. 2000; Pope 1999; Rice and Barone 2000; Slotkin 1999); although some developmental toxicant effects may be unique to CPF, major features of its actions are shared by related organophosphates as well as carbamates (Mileson et al. 1998; Pope 1999; Qiao et al. 2001). The mixture of mechanisms underlying CPF's actions renders the developing brain vulnerable to adverse effects over a broad period, spanning prenatal and postnatal stages (Barone et al. 2000; Lassiter et al. 1998, 2002; Moser and Padilla 1998; Pope 1999; Qiao et al. 2002; Rice and Barone 2000; Slotkin 1999). Indeed, interference with cell proliferation and differentiation extends to glia, which continue to proliferate into adolescence (Barone et al. 2000; Garcia et al. 2001, 2002; Monnet-Tschudi et al. 2000; Qiao et al. 2001).

We recently compared biochemical indices of brain cell damage in developing rats exposed to CPF prenatally or postnatally (Garcia et al. 2002; Qiao et al. 2002; Slotkin 1999) and found that postnatal exposure had a greater, immediate effect on the number of brain cells and on indices of synaptic development. On the surface, this seemed somewhat surprising, given that CPF readily crosses the placenta to enter the fetal brain and actually achieves higher concentrations than in the maternal brain (Hunter et al. 1999; Lassiter et al. 1998). Indeed, when we examined more selective indices of neuronal development, there was some evidence for specific disruption of acetylcholine systems after prenatal exposure, even at CPF doses below the threshold for fetal growth impairment or for inhibition of fetal brain cholinesterase (Qiao et al. …

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