Increased Expression of Glial Fibrillary Acidic Protein in Cerebellum and Hippocampus: Differential Effects on Neonatal Brain Regional Acetylcholinesterase Following Maternal Exposure to Combined Chlorpyrifos and Nicotine

Abdel-Rahman, Ali; Dechkovskaia, Anjelika; Mehta-Simmons, Heena; Guan, Xiangrong; Khan, Waris; Abou‐Donia, Mohamed B.

doi:10.1080/713853982

Cited by 26 publications

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“…Our results did not show any significant changes in the ligand binding densities for m2 muscarinic and a4b2 and a7 nicotinic acetylcholine receptors at PND 60 in both the male and female offspring, while in our previous studies on PND 30 we did observe a slight increase in [ 3 H]cytisine binding (Abdel-Rahman et al 2003), following nicotine exposure, which is consistent with the known effects of nicotine on a4b2 receptor density (Slotkin 1998;Perry et al 1999;Eriksson et al 2000;Hellstrom-Lindahl and Court 2000). Furthermore, nicotinic agonists have been shown to produce synaptic modulation in developing cerebellar Purkinje neuronal cells (Kawa 2002).…”

Section: Discussioncontrasting

confidence: 78%

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Maternal exposure to nicotine and chlorpyrifos, alone and in combination, leads to persistently elevated expression of glial fibrillary acidic protein in the cerebellum of the offspring in late puberty

et al. 2004

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We previously showed that maternal exposure to nicotine, alone or in combination with chlorpyrifos, caused an increase in glial fibrillary acidic protein (GFAP) immunostaining in the CA1 subfield of hippocampus and cerebellum in postnatal day (PND) 30 offspring. In the present study, PND 60 offspring were evaluated for histopathological and cholinergic effects following maternal exposure to nicotine and chlorpyrifos, alone and in combination. Timed-pregnant Sprague-Dawley rats (300-350 g) were treated daily with nicotine (1 mg/kg, s.c., in normal saline) or chlorpyrifos (0.1 mg/kg, dermal, in ethanol) or a combination of nicotine and chlorpyrifos from gestational days (GD) 4 to 20. Control animals were treated with saline and ethanol. On PND 60, the offspring were evaluated for cholinergic changes and pathological effects. Plasma butyrylcholinesterase (BChE) activity in the female offspring from chlorpyrifos treated mothers showed a significant increase (approximately 183% of control). Male offspring from mothers treated with either chlorpyrifos or nicotine alone showed a significant increase in the acetylcholinesterase (AChE) activity in the brainstem while female offspring from mothers treated with either nicotine or a combination of nicotine and chlorpyrifos showed a significant increase (approximately 134 and 126% of control, respectively) in AChE activity in the brainstem. No significant changes were observed in the ligand binding densities for alpha4beta2 and alpha7 nicotinic acetylcholine receptors in the cortex. Histopathological evaluation using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum of the offspring from nicotine treated mothers. An increase in GFAP immunostaining in cerebellar white matter was observed in the offspring from the mothers treated with nicotine. These results suggest that maternal exposure to real-life levels of nicotine and/or chlorpyrifos causes differential regulation of brainstem AChE activity. Also, nicotine caused a decrease in the surviving neurons and an increased expression of GFAP in cerebellar white matter of the offspring on PND 60. These changes can lead to long-term neurological adverse health effects later in life.

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Section: Discussioncontrasting

confidence: 78%

“…Cigarette smoking during pregnancy has been suggested to cause neurobehavioral and cognitive deficit, and susceptibility to diseases in the offspring (Naeye 1992;Johnson et al 2000;Abdel-Rahman et al 2003). These deficiencies may continue at all the developmental stages, including adulthood.…”

Section: Introductionmentioning

confidence: 96%

Maternal exposure to nicotine and chlorpyrifos, alone and in combination, leads to persistently elevated expression of glial fibrillary acidic protein in the cerebellum of the offspring in late puberty

et al. 2004

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“…Indeed, although they are not classical neurotrophic factors, both sets of genes are critical for normal brain development [16,98] and specifically control the architectural development of the hippocampus and neocortex [32,52,54,70,100], two areas that are known to be targeted for disruption by organophosphates [1,65,72,73,91]. 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].…”

Section: Discussionmentioning

confidence: 99%

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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“…Nevertheless, the number of neural cells eventually recovers and even becomes supranormal, with an elevated cell-packing density, largely because of reactive gliosis (Abdel-Rahman et al, 2003, 2004Sabherwal, 1994, 1998;Roy et al, 2002); the same phenomenon occurs in the brains of children whose mothers smoked during pregnancy (Storm et al, 1999). Accordingly, by adolescence, many of the biochemical features of neuronal loss are absent, although detailed morphological examination reveals the underlying imbalances in neuron/glia ratios and in the density of the neuropil Sabherwal, 1994, 1998;Roy et al, 2002).…”

Section: Prenatal Nicotine Exposurementioning

confidence: 99%

“…Here, the biochemical approach is limited by the fact that each brain region is heterogeneous, so that relatively large changes in specific layers or subregions may be 'washed out' by the inclusion of larger amounts of unaffected areas. Obviously, detailed morphologic examination, such as that conducted in younger animals (Abdel-Rahman et al, 2003, 2004Sabherwal, 1994, 1998;Roy et al, 2002), can resolve these issues. Nevertheless, our findings indicate that the permanence of the adverse effects of prenatal nicotine exposure are more readily demonstrated through indices of synaptic function than of neural cell number and size.…”

Section: Prenatal Nicotine Exposurementioning

confidence: 99%

Permanent, Sex-Selective Effects of Prenatal or Adolescent Nicotine Exposure, Separately or Sequentially, in Rat Brain Regions: Indices of Cholinergic and Serotonergic Synaptic Function, Cell Signaling, and Neural Cell Number and Size at 6 Months of Age

Slotkin

MacKillop

Rudder

et al. 2006

Neuropsychopharmacol

146

113

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Nicotine is a neuroteratogen that disrupts neurodevelopment and synaptic function, with vulnerability extending into adolescence. We assessed the permanence of effects in rats on indices of neural cell number and size, and on acetylcholine and serotonin (5HT) systems, conducting assessments at 6 months of age, after prenatal nicotine exposure, adolescent exposure, or sequential exposure in both periods. For prenatal nicotine, indices of cell number and size showed few abnormalities by 6 months, but there were persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to the presynaptic choline transporter, a pattern consistent with cholinergic hypoactivity; these effects were more prominent in males than females. The expression of 5HT receptors also showed permanent effects in males, with suppression of the 5HT 1A subtype and upregulation of 5HT 2 receptors. In addition, cell signaling through adenylyl cyclase showed heterologous uncoupling of neurotransmitter responses. Nicotine exposure in adolescence produced lasting effects that were similar to those of prenatal nicotine. However, when animals were exposed to prenatal nicotine and received nicotine subsequently in adolescence, the adverse effects then extended to females, whereas the net effect in males was similar to that of prenatal nicotine by itself. Our results indicate that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function that transcend the recovery of less-sensitive indices of structural damage; further, prenatal exposure sensitizes females to the subsequent adverse effects of adolescent nicotine, thus creating a population that may be especially vulnerable to the lasting behavioral consequences of nicotine intake in adolescence.

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Increased Expression of Glial Fibrillary Acidic Protein in Cerebellum and Hippocampus: Differential Effects on Neonatal Brain Regional Acetylcholinesterase Following Maternal Exposure to Combined Chlorpyrifos and Nicotine

Cited by 26 publications

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Maternal exposure to nicotine and chlorpyrifos, alone and in combination, leads to persistently elevated expression of glial fibrillary acidic protein in the cerebellum of the offspring in late puberty

Maternal exposure to nicotine and chlorpyrifos, alone and in combination, leads to persistently elevated expression of glial fibrillary acidic protein in the cerebellum of the offspring in late puberty

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

Permanent, Sex-Selective Effects of Prenatal or Adolescent Nicotine Exposure, Separately or Sequentially, in Rat Brain Regions: Indices of Cholinergic and Serotonergic Synaptic Function, Cell Signaling, and Neural Cell Number and Size at 6 Months of Age

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