Organophosphate Insecticides Target the Serotonergic System in Developing Rat Brain Regions: Disparate Effects of Diazinon and Parathion at Doses Spanning the Threshold for Cholinesterase Inhibition
Slotkin, Theodore A., Tate, Charlotte A., Ryde, Ian T., Levin, Edward D., Seidler, Frederic J., Environmental Health Perspectives
BACKGROUND: In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates.
OBJECTIVES: We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion.
RESULTS: Diazinon evoked up-regulation of 5H[T.sub.1A] and 5H[T.sub.2] receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5H[T.sub.1A] receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects.
CONCLUSIONS: Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.
KEY WORDS: acetylcholine, brain development, chlorpyrifos, cholinesterase, diazinon, organophosphate insecticides, parathion, serotonin receptors, serotonin transporter. Environ Health Perspect 114:1542-1546 (2006). doi:10.1289/ehp.9337 available via http://dx.doi.org/ [Online 27 July 2006]
Organophosphates are undergoing increasing restrictions on their home use in the United States (U.S. Environmental Protection Agency 2000, 2002), but nonetheless they still account for > 50% of all insecticide use (Casida and Quistad 2004). One of the major concerns for human health is the propensity of these agents to produce developmental neurotoxicity, even when exposures are too low to elicit signs of systemic intoxication (Landrigan 2001; Landrigan et al. 1999; May 2000; Physicians for Social Responsibility 1995; Pope 1999; Slotkin 1999, 2004; Weiss et al. 2004). In that regard, chlorpyrifos has been the most studied organophosphate, and it is now clear that the original view of its mechanism of action--cholinesterase inhibition via its active metabolite, chlorpyrifos oxon--is insufficient to explain its ability to damage the developing brain. In fact, multiple mechanisms target neural cell replication and differentiation, axonogenesis and synaptogenesis, and the development and programming of synaptic activity, culminating in behavioral deficits (Barone et al. 2000; Casida and Quistad 2004; Gupta 2004; Pope 1999; Qiao et al. 2002, 2003; Yanai et al. 2002). There is an important corollary of the compound mechanisms for disruption of brain development: Whereas all organophosphates share actions directed toward cholinesterase, they may differ substantially in many of their noncholinesterase effects, such as actions directed toward oxidative stress, cell signaling, expression and function of nuclear transcription factors, and cell replication and differentiation (Gupta 2004; Pope 1999; Slotkin 1999, 2004, 2005), even if some of those additional mechanisms are shared by various organophosphates (Abu-Qare and Abou-Donia 2001; Morale et al. 1998; Pope 1999; Qiao et al. 2001; Slotkin 1999, 2004; Slotkin et al. 2006; Whyatt et al. 2002).
In a recent study (Slotkin et al. 2006), we compared the dose-effect relationships for systemic toxicity and developmental neurotoxicity for chlorpyrifos, diazinon, and parathion. Although parathion exhibited the highest systemic toxicity, it was actually less neurotoxic toward neurite formation and development of cholinergic projections, whereas diazinon and chlorpyrifos were less systemically toxic and more neurotoxic. …