Developmental neurotoxicity of parathion: Progressive effects on serotonergic systems in adolescence and adulthood
Introduction
It is increasingly evident that organophosphate pesticides damage the developing brain at exposures below the threshold for overt signs of intoxication and even below that required for cholinesterase inhibition, the biomarker used for risk assessment [12], [14], [22], [23], [30], [36], [37], [38], [46], [47], [48], [63]. Numerous studies have detailed how organophosphates disrupt the basic patterns of neural cell replication and differentiation, alter axonogenesis and synaptogenesis, and discoordinate the development of neural circuits, ultimately producing widespread behavioral deficits [7], [9], [10], [12], [18], [38], [39], [40], [46], [47], [48], [56], [65]. Because of the initial focus on cholinergic actions, many reports of the effects of organophosphate exposure have concerned the targeting of acetylcholine systems and cognitive/learning deficits related to these pathways [15], [16], [19], [21], [22], [26], [27], [41], [46], [47], [48], [63]. However, recent research indicates that organophosphates target serotonin (5HT) systems to an even greater extent, contributing to adverse outcomes related to emotional and social behaviors [1], [2], [3], [4], [5], [33], [42], [43], [51], [53], [54], [55], [57], [58], [62]. Indeed, evidence is now accumulating that relate organophosphate exposures to depression and suicide [8], [20], [25], [28].
Because organophosphates cause developmental neurotoxicity through mechanisms beyond their shared property as cholinesterase inhibitors, the various members of this pesticide class could differ in their impact on 5HT systems. In recent studies, we showed that exposures of neonatal rats on postnatal days (PN) 1–4 to three different organophosphates, chlorpyrifos, diazinon and parathion, at doses spanning the threshold for detectable but nonsymptomatic cholinesterase inhibition, produced dissimilar initial effects on 5HT systems, as monitored on PN5 [4], [52], [58]. Notably, parathion was entirely distinct, eliciting deficits in 5HT1A receptor expression, whereas the other two organophosphates produced increases. In subsequent work, we showed some basic similarities in the long-term effects of chlorpyrifos and diazinon on 5HT systems, but also some significant disparities that emerged between adolescence and adulthood [3], [5], [51], [55], contributing to divergent effects on emotional behaviors [1], [45]. Accordingly, in the present study, we evaluated the long-term effects of neonatal parathion exposure, again conducting studies from adolescent through adult stages. We gave parathion on PN1–4, an exposure window identified in our earlier work with chlorpyrifos as a peak of sensitivity for disrupting 5HT systems [2], [4], [5], [54]. We focused on two parathion treatments spanning the maximum tolerated dose, 0.1 mg/kg/day, which produces 10% cholinesterase inhibition [58], well below the 70% inhibition required for the symptoms of cholinergic hyperstimulation [13], and 0.2 mg/kg/day, just past the threshold for the first signs of systemic toxicity in neonates [50]. Our measurements focused on three 5HT synaptic proteins known to be highly affected by developmental exposure to chlorpyrifos [3], [4], [5], [55] or diazinon [51], [58], the 5HT1A and 5HT2 receptors, and the presynaptic 5HT transporter (5HTT). The two receptors play major roles in 5HT-related mental disorders, particularly depression [6], [17], [66], [67], and the transporter, which regulates the synaptic concentration of 5HT, is the primary target for antidepressant drugs [29], [34], [35]. We evaluated effects in all the brain regions comprising the major 5HT projections (frontal/parietal cortex, temporal/occipital cortex, hippocampus, striatum) as well as those containing 5HT cell bodies (midbrain, brainstem). The study design and assays were all identical to those in our previous work on chlorpyrifos and diazinon [1], [5], [51], [55], [58], so as to foster comparison of the outcomes of exposure to the three different organophosphates.
Section snippets
Animal treatments
All experiments were carried out humanely and with regard for alleviation of suffering, with protocols approved by the Duke University Institutional Animal Care and Use Committee and in accordance with all federal and state guidelines. Timed-pregnant Sprague–Dawley rats were housed in breeding cages, with a 12 h light–dark cycle and free access to food and water. On the day after birth, all pups were randomized and redistributed to the dams with a litter size of 10 (5 males, 5 females) to
Results
Because only three of the six regions were analyzed at all three ages, there were two global ANOVAs conducted on the data set. The first evaluated all measurements at all ages for the frontal/parietal cortex, temporal/occipital cortex and brainstem and the second evaluated the two ages (PN60, PN100) for which we had all six regions. The ANOVAs indicated interactions of treatment × region (p < 0.006), treatment × protein measure (p < 0.003), treatment × age × sex (p < 0.003), treatment × age × region (p < 0.0001),
Discussion
In our earlier work with neonatal chlorpyrifos exposure, we noted immediate upregulation of forebrain and brainstem 5HT receptors in association with the initial neural cell damage [4], [11]. Afterwards, there was a period of transition in which different regional patterns and sex-selectivity emerged [2], [5], [55], indicating that the net effect on 5HT systems represents not only the primary injury but also the adaptive changes and plasticity in response to that damage. Accordingly, although
Conflict of interest
The authors declare they have no competing financial interests.
Acknowledgments
This research was supported by NIH ES10356. We thank Bethany Bodwell for technical assistance. Theodore Slotkin and Frederic Seidler have provided expert witness testimony on behalf of government agencies, corporations and individuals.
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