Academic journal article Environmental Health Perspectives

Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel

Academic journal article Environmental Health Perspectives

Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel

Article excerpt

BACKGROUND: In light of the large number of chemicals that are potential developmental neurotoxicants, there is a need to develop rapid screening techniques.

OBJECTIVES: We exposed undifferentiated and differentiating neuronotypic PC12 cells to different organophosphates (chlorpyrifos, diazinon, parathion), a carbamate (physostigmine), an organochlorine (dieldrin), and a metal (divalent nickel; [Ni.sup.2+]) and examined indices of cell replication and differentiation for both short- and long-term exposures.

RESULTS: In undifferentiated cells, all the agents inhibited DNA synthesis, with the greatest effect for diazinon, but physostigmine eventually produced the largest deficits in the total number of cells after prolonged exposure. The onset of differentiation intensified the adverse effects on DNA synthesis and changed the rank order in keeping with a shift away from noncholinergic mechanisms and toward cholinergic mechanisms. Differentiation also worsened the effects of each agent on cell number after prolonged exposure, whereas cell growth was not suppressed, nor were there any effects on viability as assessed with trypan blue. Nevertheless, differentiating cells displayed signs of oxidative stress from all of the test compounds except [Ni.sup.2+], as evidenced by measurements of lipid peroxidation. Finally, all of the toxicants shifted the transmitter fate of the cells away from the cholinergic phenotype and toward the catecholaminergic phenotype.

CONCLUSIONS: These studies point out the feasibility of developing cell-based screening methods that enable the detection of multiple end points that may relate to mechanisms associated with developmental neurotoxicity, revealing some common targets for disparate agents.

KEY WORDS: acetylcholine systems, carbamates, catecholamine systems, chlorpyrifos, developmental neurotoxicity, diazinon, dieldrin, nickel, organochlorines, organophosphates. Environ Health Perspect 115:93-101 (2007). doi:10.1289/ehp.9527 available via http://dx.doi.org/ [Online 6 September 2006]

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Recent evidence points to important contributions of exposure to environmental neurotoxicant chemicals in the marked increase in neurodevelopmental disorders, including learning disabilities, attention deficit and hyperactivity disorder, and autism spectrum disorders (Szpir 2006). Despite the increasing recognition of the importance of evaluating developmental neurotoxicity in safety assessment (Claudio et al. 2000; Eriksson 1997; Tilson 1995, 2000), the fact remains that, of > 70,000 commercial chemicals in current use, neurotoxicity of any kind has been evaluated in < 10% (Landrigan et al. 1994), and obviously, developmental neurotoxicity in a substantially smaller fraction. Even now, of the 2,000-3,000 new chemicals released each year, two-thirds never get tested for neurotoxicity, let alone developmental effects (Claudio et al. 2000), whereas between 25-40% will eventually prove to be neurotoxic (Boyes 2001). Among the many potential developmental neurotoxicants, the greatest attention has been paid to pesticides, in light of their widespread use in the home and in agriculture [U.S. Environmental Protection Agency (EPA) 2006]. Here, too, despite the institution of a standardized protocol for developmental neurotoxicity, few compounds have actually been tested relative to the total number of concern, even after mandated call-ins for data by the U.S. EPA (Makris 2006; U.S. EPA 2006).

A number of factors contribute to the dearth of information on developmental neurotoxicity relative to the demonstrated need for such knowledge. First, there is the essential dichotomy between the requirement to evaluate large numbers of compounds and the costly, cumbersome protocols prescribed for standard tests in animals (Colborn 2006; Makris 2006; Slotkin 2004b; U.S. EPA 2006). Second, testing compounds one at a time may produce results that are difficult to compare (Colborn 2006; U. …

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