Disturbing behavior: neurotoxic effects in children.

May, Michael M.

doi:10.1289/ehp.108-a262

Cited by 44 publications

(16 citation statements)

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“…Specifically, does Mn-exposure during early development increase the risk for developing neurodegenerative diseases in later life? It is known that changes in Mncontaining proteins have been observed in many neurodegenerative diseases, including Alzheimer's disease (Markesbery, 1997), amyotrophic lateral sclerosis, and Parkinsonian-like syndrome (Pal et al, 1999;Malecki, 2001), as well neurobehavioral deficits (May, 2000;Normandin et al, 2002) are associated with Mn-exposure. Therefore longitudinal studies that examine both markers of oxidative stress and neurotransmitter biology in subjects who have a history of Mn exposure during critical neurodevelopmental periods are necessary.…”

Section: Direction For Future Researchmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

224

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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Section: Direction For Future Researchmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

224

141

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“…Despite their widespread use [17], organophosphate insecticides are a major concern for human health because of their propensity to damage the developing brain at exposures below the threshold for signs of systemic intoxication [55,56,62,72,73,86,87,108]. Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112].…”

Section: Introductionmentioning

confidence: 99%

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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“…The potential for organophosphate insecticides, notably chlorpyrifos (CPF), to elicit developmental neurotoxicity has led to increasing concern and restricted use Landrigan 2001;Landrigan et al 1999;May 2000;Physicians for Social Responsibility 1995;Pope 1999;Rice and Barone 2000;Slotkin 1999, In press a; U.S. Environmental Protection Agency (EPA) 2000a(EPA) , 2000b. The systemic toxicity of organophosphates reflects their ability to inhibit cholinesterase, but it is now evident that other mechanisms are at least equally, if not more, important in determining the long-term liability of fetal or neonatal CPF exposure Das and Barone 1999;Pope 1999;Schuh et al 2002;Slotkin 1999, In press a).…”

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confidence: 99%

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Meyer

Seidler

Slotkin

2004

Environ Health Perspect

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The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn 2+ ); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.

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Disturbing behavior: neurotoxic effects in children.

Cited by 44 publications

References 0 publications

Manganese neurotoxicity: A focus on the neonate

Manganese neurotoxicity: A focus on the neonate

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

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

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