Release and Metabolism of Dopamine in a Clonal Line of Pheochromocytoma (PC12) Cells Exposed to Fenthion

Tuler, S. M.; HAZEN, ALLISON; Bowen, John M.

doi:10.1093/toxsci/13.3.484

Cited by 21 publications

(27 citation statements)

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“…In the case of the organophosphates, this is approximately an order of magnitude higher than the levels in newborn babies after nonsymptomatic environmental exposures in agricultural communities [32] but it should be noted that the cultures contain high concentrations of serum proteins; accordingly, less than 10% of the nominal concentration is actually available to diffuse into the cells [33]. Nevertheless, to offset some of these problems, two different organophosphates, chlorpyrifos and diazinon, have been thoroughly evaluated and found to elicit parallel outcomes in the PC12 model and in developing rat brain [2,3,11-13,17,23,24,27,31,33,34,48,49,52,53,58]. …”

Section: Discussionmentioning

confidence: 99%

Unrelated developmental neurotoxicants elicit similar transcriptional profiles for effects on neurotrophic factors and their receptors in an in vitro model

Slotkin

Seidler

Fumagalli

2010

Neurotoxicology and Teratology

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Diverse developmental neurotoxicants can often produce similar functional and behavioral outcomes. We examined an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni 2+ ) for effects on the expression of neurotrophic factors and their receptors and modulators in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30 μM for 24 or 72 hr, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding members of the fibroblast growth factor (fgf) family, the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families, and the receptors and modulators for each class. All three agents evoked highly concordant patterns of effects on genes encoding the fgf family, whereas the correlations were poor for the group comprising bdnf, ngf and their respective receptors. For wnt, fzd and their receptors/ modulators, the relationships between diazinon and dieldrin were highly concordant, whereas the effect of Ni 2+ was less similar, albeit still significantly correlated with the others. Our results show that otherwise disparate developmental neurotoxicants converge on common sets of neurotrophic pathways known to control neuronal differentiation, likely contributing to similarities in functional outcomes. Further, cell culture models can provide a useful initial screen to identify members of a given class of compounds that may be greater or lesser risks for developmental neurotoxicity, or to provide an indication of agents in different classes that might produce similar effects.

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Section: Discussionmentioning

confidence: 99%

Unrelated developmental neurotoxicants elicit similar transcriptional profiles for effects on neurotrophic factors and their receptors in an in vitro model

Slotkin

Seidler

Fumagalli

2010

Neurotoxicology and Teratology

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“…For our evaluations, we used PC12 cells, a classical in vitro model for neuronal development (Teng and Greene, 1994) that has already been validated to reproduce the mechanisms and outcomes found after in vivo OP exposures (Bagchi et al, 1995, 1996; Crumpton et al, 2000a, b; Das and Barone, 1999; Flaskos et al, 1994; Jameson et al, 2006, 2007; Li and Casida, 1998; Nagata et al, 1997; Qiao et al, 2001, 2005; Slotkin et al, 2007a, b, 2008d, 2009; Song et al, 1998; Tuler et al, 1989). With the addition of nerve growth factor, PC12 cells begin to differentiate, forming neuritic projections and acquiring electrical excitability and neuronal phenotypes (Fujita et al, 1989; Song et al, 1998; Teng and Greene, 1994).…”

Section: Introductionmentioning

confidence: 99%

Disparate developmental neurotoxicants converge on the cyclic AMP signaling cascade, revealed by transcriptional profiles in vitro and in vivo

2010

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Cell-signaling cascades are convergent targets for developmental neurotoxicity of otherwise unrelated agents. We compared organophosphates (chlorpyrifos, diazinon), an organochlorine (dieldrin) and a metal (Ni 2+ ) for their effects on neuronotypic PC12 cells, assessing gene transcription involved in the cyclic AMP pathway. Each agent was introduced during neurodifferentiation at a concentration of 30 μM for 24 or 72 hr and we assessed 69 genes encoding adenylyl cyclase isoforms and regulators, G-protein α-and β,γ-subunits, protein kinase A subtypes and the phosphodiesterase family. We found strong concordance among the four agents across all the gene families, with the strongest relationships for the G-proteins, followed by adenylyl cyclase, and lesser concordance for protein kinase A and phosphodiesterase. Superimposed on this pattern, chlorpyrifos and diazinon were surprisingly the least alike, whereas there was strong concordance of dieldrin and Ni 2+ with each other and with each individual organophosphate. Further, the effects of chlorpyrifos differed substantially depending on whether cells were undifferentiated or differentiating. To resolve the disparities between chlorpyrifos and diazinon, we performed analyses in rat brain regions after in vivo neonatal exposures; unlike the in vitro results, there was strong concordance. Our results show that unrelated developmental neurotoxicants can nevertheless produce similar outcomes by targeting cell signaling pathways involved in neurodifferentiation during a critical developmental period of vulnerability. Nevertheless, a full evaluation of concordance between different toxicants requires evaluations of in vitro systems that detect direct effects, as well as in vivo systems that allow for more complex interactions that converge on the same pathway.

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“…We had three specific objectives: first, to determine if OPs affect AC signaling during a discrete stage of cell development; second, to establish whether the effects persist so long as OP exposure continues or rather whether effects emerge beyond the exposure period; and third, to evaluate whether the effects on AC signaling are separable from effects on general aspects of cell growth. We conducted our evaluations in PC12 cells, a well-characterized neurodevelopmental model (Teng and Greene, 1994) that reproduces many of the key mechanisms and features of the adverse effects of OPs in vivo (Bagchi et al, 1995, 1996; Crumpton et al, 2000a, b; Das and Barone, 1999; Flaskos et al, 1994; Jameson et al, 2006a; Li and Casida, 1998; Nagata et al, 1997; Qiao et al, 2001, 2005; Slotkin, 1999, 2004, 2005; Song et al, 1998; Tuler et al, 1989; Yanai et al, 2002). When nerve growth factor (NGF) is introduced, PC12 cells exit the mitotic cycle and undergo neurodifferentiation (Fujita et al, 1989; Song et al, 1998; Teng and Greene, 1994).…”

Section: Introductionmentioning

confidence: 99%

Organophosphate exposure during a critical developmental stage reprograms adenylyl cyclase signaling in PC12 cells

Adigun¹,

Ryde²,

Seidler³

et al. 2010

Brain Research

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Early-life organophosphate (OP) exposures elicit neurobehavioral deficits through mechanisms other than inhibiting cholinesterase. Cell signaling cascades are postulated as critical noncholinesterase targets that mediate both the initial alterations in neurodevelopment as well as subsequent abnormalities of synaptic function. We exposed PC12 cells to chlorpyrifos, diazinon or parathion in the undifferentiated state and during neurodifferentiation; we then assessed the function of the adenylyl cyclase (AC) signaling cascade, measuring basal AC activity as well as responses to stimulants acting at G-proteins or on the AC molecule itself. In undifferentiated cells, a 2 day exposure to the OPs had no significant effect on AC signaling but the same treatment in differentiating cells produced deficits in all AC measures when exposure commenced at the initiation of differentiation. However, when exposure of the differentiating cells was continued for 6 days, AC activities then became supranormal. The same increase was obtained if cells were exposed only for the first two days of differentiation, followed by four subsequent days without the OPs. Further, the OP effects on cell signaling were entirely distinct from those on indices of cell number and neurite outgrowth. These results indicate that OP exposure reprograms the AC pathway during a discrete developmental stage at the commencement of neurodifferentiation, with effects that continue to emerge after OP exposure is discontinued. Importantly, the same sequence is seen with OP exposures in neonatal rats, indicating that direct effects of these agents to reprogram cell signaling provide a major mechanism for functional effects unrelated to cholinesterase inhibition.

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Release and Metabolism of Dopamine in a Clonal Line of Pheochromocytoma (PC12) Cells Exposed to Fenthion

Cited by 21 publications

References 0 publications

Unrelated developmental neurotoxicants elicit similar transcriptional profiles for effects on neurotrophic factors and their receptors in an in vitro model

Unrelated developmental neurotoxicants elicit similar transcriptional profiles for effects on neurotrophic factors and their receptors in an in vitro model

Disparate developmental neurotoxicants converge on the cyclic AMP signaling cascade, revealed by transcriptional profiles in vitro and in vivo

Organophosphate exposure during a critical developmental stage reprograms adenylyl cyclase signaling in PC12 cells

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