Academic journal article Environmental Health Perspectives

Alterations in Central Nervous System Serotonergic and Dopaminergic Synaptic Activity in Adulthood after Prenatal or Neonatal Chlorpyrifos Exposure

Academic journal article Environmental Health Perspectives

Alterations in Central Nervous System Serotonergic and Dopaminergic Synaptic Activity in Adulthood after Prenatal or Neonatal Chlorpyrifos Exposure

Article excerpt

Exposure to chlorpyrifos (CPF) alters neuronal development of serotonin (5HT) and dopamine systems, and we recently found long-term alterations in behaviors related to 5HT function. To characterize the synaptic mechanisms underlying these effects, we exposed developing rats to CPF regimens below the threshold for systemic toxicity, in three treatment windows: gestational days (GD) 17-20, postnatal days (PN) 1-4, or PN11-14. In early adulthood (PN60), we assessed basal neurotransmitter content and synaptic activity (turnover) in brain regions containing the major 5HT and dopamine projections. CPF exposure on GD17-20 or PN 1-4 evoked long-term increases in 5HT turnover across multiple regions; the effects were not secondary to changes in neurotransmitter content, which was unaffected or even decreased. When the treatment window was shifted to PN11-14, there were no long-term effects. Dopamine turnover also showed significant increases after CPF exposure on GD17-20, but only when the dose was raised above the threshold for overt toxicity; however, hippocampal dopamine content was profoundly subnormal after exposures below or above the acute, toxic threshold, suggesting outright neurotoxicity. These results indicate that, in a critical developmental period, apparently nontoxic exposures to CPF produce lasting activation of 5HT systems in association with 5HT-associated behavioral anomalies. Key words: brain development, chlorpyrifos, dopamine, organophosphate pesticides, serotonin. doi:10.1289/ehp.7968 available via http://dx.doi.org/[Online 28 April 2005]

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The organophosphorus pesticide chlorpyrifos (CPF) remains in use throughout the world despite its recent curtailment in the United States [U.S. Environmental Protection Agency (EPA) 2000, 2002]. The major concern for CPF is its propensity to elicit developmental neurotoxicity at exposure levels below the threshold for systemic toxicity, such that damaging exposures of pregnant women and children may go undetected because of the lack of symptoms (Landrigan 2001; Landrigan et al. 1999; May 2000; Physicians for Social Responsibility 1995; Pope 1999; Slotkin 1999, 2004; Weiss et al. 2004). CPF was originally thought to exert adverse effects on brain development through the same mechanism by which it elicits systemic toxicity, namely, inhibition of cholinesterase through its active metabolite, CPF oxon, but it is now evident that other, noncholinergic mechanisms participate in its developmental neurotoxicity (Barone et al. 2000; Clegg and van Gemert 1999a, 1999b; Gupta 2004; Mileson et al. 1998; Pope 1999; Slotkin 1999, 2004). Even at exposures below the threshold for cholinesterase inhibition, CPF itself disrupts the patterns of neural cell replication and differentiation, axonogenesis and synaptogenesis, and the functional development of neurotransmitter and neurotrophin systems, culminating in aberrant behavioral performance (Barone et al. 2000; Casida and Quistad 2004; Gupta 2004; Pope 1999; Qiao et al. 2002, 2003; Yanai et al. 2002). Consequently, CPF-induced damage extends beyond cholinergic pathways to include other neurotransmitter systems, notably the monoamines, norepinephrine, dopamine (DA), and serotonin (5HT), and recent studies show that 5HT systems are especially sensitive (Aldridge et al. 2003, 2004, 2005a, 2005b; Raines et al. 2001; Sachana et al. 2001).

In recent work we found that, during a critical developmental window centered around the immediate perinatal period, CPF elicits immediate and persistent effects on expression of 5HT receptors and the 5HT transporter, biomarkers for 5HT synaptic development and integrity (Aldridge et al. 2003, 2004, 2005a; Raines et al. 2001). Additionally, we found that the same exposures elicited lasting changes in 5HT-related behaviors, resembling animal models of depression (Aldridge et al. 2005a). Notably, these studies were conducted spanning CPF exposures below the threshold for observable toxicity and, more important, could be detected at doses devoid of cholinesterase inhibition in the developing brain (Qiao et al. …

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