Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways

Dam, Kristina; Garcia, Stéphanie; Seidler, Frederic J.; Slotkin, Theodore A.

doi:10.1016/s0165-3806(99)00067-x

Cited by 157 publications

(120 citation statements)

References 70 publications

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“…The major effect shared by both CPF and DZN was a suppression of the development of ACh systems and promotion of monoamine systems, results at the transcriptional level that confirm earlier work on the switching of neuronal phenotype as a final outcome [4][5][6]25,49]. A change in transmitter phenotype is likely to produce "miswiring" of major brain circuits, where presynaptic neurons of one phenotype are juxtaposed to postsynaptic cells containing the incorrect complement of receptors and signaling pathways, effects that have already been noted as a final outcome for both ACh and 5HT systems [3,4,48,59,60].…”

Section: General Conclusionsupporting

confidence: 82%

“…It is well-established that developmental exposure to CPF or DZN compromises the development of the ACh phenotype, as typified by choline acetyltransferase, the enzyme that manufactures acetylcholine, and the choline transporter which supplies the required choline precursor to the presynaptic terminal [25,49,80,91,116]. In the current study, we found significant reductions in chat, the gene encoding choline acetyltransferase, with either CPF or DZN treatment, accompanied by alterations in the expression of choline transporter genes.…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemssupporting

confidence: 56%

“…In any case, the most important comparison is that for the parallel gene families for the monoamine neurotransmitters, 5HT, dopamine and norepinephrine, we obtained significant upregulation, the opposite effect from that seen for chat. Earlier work both in vivo and in vitro suggests that one of the main adverse effects of CPF on brain development is to produce inappropriate switching of the neurotransmitter phenotype, away from ACh and toward the monoamines [4][5][6]25,49]. Thus, whereas neonatal CPF exposure produces a deficit in hippocampal ACh innervation and activity, 5HT systems then take over the corresponding neurobehavioral functions [3,60].…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 99%

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

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

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Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.

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Section: General Conclusionsupporting

confidence: 82%

Section: Cpf and Dzn Effects On Neurotransmitter Systemssupporting

confidence: 56%

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 99%

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

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

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“…There is limited information linking altered expression of specific members of the wnt and fzd families to adverse neurobehavioral outcomes, but it is notable that wnt5a and fzd3, which we found to be reduced by both chlorpyrifos and diazinon, are key determinants in establishing the dopaminergic phenotype [12] and development of dopamine projections [96]. Here again, our results provide strong evidence for parallel or interactive participation of the wnt and fzd pathways with the fgf family, since we previously identified suppression of fgf members associated with the ontogeny of dopamine systems [79], which are especially sensitive to chlorpyrifos [3,25,76,78,80], and which likely underlie the association of organophosphate exposure with the subsequent development of Parkinson's Disease [43,47]. However, the potential impact of combined or overlapping disruption of fgf, wnt and fzd pathways during critical developmental periods extends further, to include other neurodegenerative syndromes or psychiatric disorders [10,13,15,71], such as schizophrenia [23,29,45,46,96].…”

Section: Discussionsupporting

confidence: 69%

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

Slotkin¹,

Seidler²,

Fumagalli³

2008

Brain Research Bulletin

127

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Neurotrophic factors control neural cell differentiation and assembly of neural circuits. We previously showed that organophosphate pesticides differentially regulate members of the fibroblast growth factor (fgf) gene family. We administered chlorpyrifos and diazinon to neonatal rats on postnatal days 1-4 at doses devoid of systemic toxicity or growth impairment, and spanning the threshold for barely-detectable cholinesterase inhibition. We evaluated the impact on gene families for different classes of neurotrophic factors. Using microarrays, we examined the regional expression of mRNAs encoding the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families and the corresponding receptors. Chlorpyrifos and diazinon both had widespread effects on the fgf, ntf, wnt and fzd families but much less on the bdnf and ngf groups. However, the two organophosphates showed disparate effects on a number of key neurotrophic factors. To determine if the actions were mediated directly on differentiating neurons, we tested chlorpyrifos in PC12 cells, an in vitro model of neural cell development. Effects in PC12 cells mirrored many of those for members of the fgf, ntf and wnt families, as well as the receptors for the ntfs, especially during early differentiation, the stage known to be most susceptible to disruption by organophosphates. Our results suggest that actions on neurotrophic factors provide a mechanism for the developmental neurotoxicity of low doses of organophosphates, and, since effects on expression of the affected genes differed with test agent, may help explain regional disparities in effects and critical periods of vulnerability.

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“…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).…”

mentioning

confidence: 99%

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

Meyer

Seidler

Cousins

et al. 2003

Environ Health Perspect

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The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms over and above cholinesterase inhibition. In the present study, we evaluated the effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling cascade, which regulates the production of cyclic AMP, a major controller of cell replication and differentiation. In addition to basal AC activity, we assessed the AC response to direct enzymatic stimulants [forskolin, manganese (Mn 2+ )]; the response to isoproterenol, which activates signaling through β-adrenoceptors (βARs); and the concentration of βAR binding sites. CPF administered to pregnant rats on gestational days (GD) 9-12 elicited little or no change in any components of AC activity or βARs. However, shifting the treatment window to GD17-20 produced regionally selective augmentation of AC activity. In the brainstem, the response to forskolin or Mn 2+ was markedly stimulated by doses at or below the threshold for observable toxicity of CPF or for inhibition of fetal brain cholinesterase, whereas comparable effects were seen in the forebrain only at higher doses. In addition, low doses of CPF reduced βAR binding without impairing receptor-mediated stimulation of AC. These results indicate that signal transduction through the AC cascade is a target for CPF during a discrete developmental period in late gestation, an effect that is likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity. Key words: adenylyl cyclase, β-adrenoceptor, brain development, chlorpyrifos, organophosphate insecticides.

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Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways

Cited by 157 publications

References 70 publications

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

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

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

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

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