New Thinking on Neurodevelopment

Szpir, Michael

doi:10.1289/ehp.114-a100

Cited by 37 publications

(26 citation statements)

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“…This delay is in keeping with the later emergence of a neurobehavioral disorder that nevertheless originates from an insult during pregnancy. The time course thus supports recent views that chemical and physiologic insults during pregnancy may have long-lasting effects for brain structure and function (Stanwood and Levitt, 2004) and may contribute to the increase in the incidence of autism spectrum disorders as well as other neurodevelopmental disabilities (Szpir, 2006a). Equally important, if microglial activation proves to be part of the pathogenesis of autism, then our model suggests that there may be a window of opportunity when therapeutic interventions might be started.…”

Section: Discussionsupporting

confidence: 83%

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Zerrate¹,

Pletnikov²,

Connors

et al. 2007

J Pharmacol Exp Ther

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Autism is a neurodevelopmental disorder presenting before 3 years of age with deficits in communication and social skills and repetitive behaviors. In addition to genetic influences, recent studies suggest that prenatal drug or chemical exposures are risk factors for autism. Terbutaline, a ␤2-adrenoceptor agonist used to arrest preterm labor, has been associated with increased concordance for autism in dizygotic twins. We studied the effects of terbutaline on microglial activation in different brain regions and behavioral outcomes in developing rats. Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30. Immunohistochemical studies showed that administration of terbutaline on PN 2 to 5 produced a robust increase in microglial activation on PN 30 in the cerebral cortex, as well as in cerebellar and cerebrocortical white matter. None of these effects occurred in animals given terbutaline on PN 11 to 14. In behavioral tests, animals treated with terbutaline on PN 2 to 5 showed consistent patterns of hyper-reactivity to novelty and aversive stimuli when assessed in a novel open field, as well as in the acoustic startle response test. Our findings indicate that ␤2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. This study provides a useful animal model for understanding the neuropathological processes underlying autism spectrum disorders.

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Section: Discussionsupporting

confidence: 83%

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Zerrate¹,

Pletnikov²,

Connors

et al. 2007

J Pharmacol Exp Ther

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“…The same developmental mechanisms have been proposed to operate in the etiology of autism [27], a disorder in which organophosphate exposure has been implicated [24,88]. Our results thus provide some of the first mechanistic evidence to connect exposure to a specific set of environmental neurotoxicants to the subsequent emergence of major neurodevelopmental disorders [87,88].…”

Section: Discussionsupporting

confidence: 73%

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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“…Precoproporphyrin, a specific indicator of heavy-metal toxicity, was also elevated in autistic disorder. That chronic exposure to lead and mercury can contribute to developmental and behavioural disabilities in children is well documented (for example, Myers et al 1997;Landrigan et al 2002;Szpir 2006). For lead, impairment can occur even at relatively low levels (Canfield et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Bioavailability of trace metals in brownfield soils in an urban area in the UK

Thums

Farago

Thornton

2008

Environ Geochem Health

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Thirty-two brownfield sites from the city of Wolverhampton were selected from those with a former industrial use, wasteland or areas adjacent to industrial processes. Samples (<2 mm powdered soil fraction) were analysed, using inductively coupled plasma-atomic emission spectrometry (ICP-AES) for 20 elements. Loss on ignition and pH were also determined. A five-step chemical sequential extraction technique was carried out. Single leach extraction with 0.12 M hydrochloric acid of Pb, Cu and Zn in soil was determined as a first approximation of the bioavailability in the human stomach. Some of the sites were found to have high concentrations of the potentially toxic elements Pb, Zn, Cu and Ni. The partitioning of metals showed a high variability, however a number of trends were determined. The majority of Zn was partitioned into the least chemically stable phases (steps 1, 2 and 3). The majority of Cu was associated with the organic phase (step 4) and the majority of Ni was fractionated into the residue phase (step 5). The majority of Pb was associated with the residue fraction (step 5) followed by Fe-Mn oxide fraction (step 3). The variability reflects the heterogeneous and complex nature of metal speciation in urban soils with varied historic histories. There was a strong inverse linear relationship between the metals Ni, Zn and Pb in the readily exchangeable phase (step 1) and soil pH, significant at P < 0.01 level. There was a significant increase (P < 0.05) in the partitioning of Cu, Ni and Zn into step 4 (the organic phase) in soils with a higher organic carbon content (estimated by loss on ignition). Copper was highly partitioned into step 4 as it has a strong association with organics in soil but this phase was not important for the partitioning of Ni or Zn. The fractionation of Ni, Cu and Zn increased significantly in step 3 when the total metal concentration increases (P < 0.01). The Fe-Mn oxide fraction becomes more important in soils elevated in these metals, possibly due to the scavenging of metals by oxides. Cu and Pb extracted by HCl was statistically similar to the sum of the metals in steps 1 to 4 (P < 0.01) and HCl available Zn was statistically similar to the sum of Zn in steps 1 to 3 (P < 0.01). Step 4 (the organic phase) was not an important phase for Zn, so it was concluded that any Cu, Zn and Pb present in soil in a nonresidue phase would be potentially available for uptake into the human system once soil has been ingested.

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New Thinking on Neurodevelopment

Cited by 37 publications

References 0 publications

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

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

Bioavailability of trace metals in brownfield soils in an urban area in the UK

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