• Corpus ID: 88179971

Pode a exposição humana ao inseticida clorpirifós alterar o desenvolvimento do sistema nervoso central? Contribuições de experimentos em animais

@inproceedings{Meyer2005PodeAE,
  title={Pode a exposiç{\~a}o humana ao inseticida clorpirif{\'o}s alterar o desenvolvimento do sistema nervoso central? Contribuiç{\~o}es de experimentos em animais},
  author={Armando Meyer},
  year={2005}
}

• Armando Meyer
• Published 2005
• Biology

There is increasing evidence that the mechanism for systemic toxicity,
named cholinergic hyperstimulation consequent to inhibition of
cholinesterase, is not the primary mechanism for adverse effects of
chlorpyrifos (CPF) during development. In fact, many studies have shown
that CPF disrupts the fundamental processes of brain development. In
addition, neonatal exposure to CPF alters cell signaling mediated by adenylyl cyclase, the enzyme responsible for cyclic AMP production, a major controller of cell replication and differentiation. In the present study, we evaluated the immediate effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling cascade and b-adrenergic receptors (bAR) in rat brain. We also investigated whether exposure to CPF during specific gestational or neonatal periods would lead to long term alterations on AC activity. In addition, we evaluated the immediate and long-term effects of CPF exposure of rats during, gestational (GD) and postnatal (PN) days, on the adenylyl cyclase (AC) signaling cascade in the heart and liver. For gestational studies, dams were injected during GD9-12 or GD17-20. For postnatal studies, animals were treated during PN1-4 or PN11-14. AC activity was assessed using different stimulants. In addition to basal activity, we evaluated the responses to direct AC stimulants (forskolin, Mn2+); to isoproterenol, which activates
signaling through b-adrenoceptors coupled to stimulatory G-proteins, to
sodium fluoride, which activates G-proteins that couple the receptor to AC. Besides, the studies using heart and liver, we also probed AC response to glucagon, which activate signaling through specific membrane receptors. CPF administered to pregnant rats on gestational days (GD) 9–12 elicited little or no change in any components of AC activity or βARs. However, shifting the treatment window to GD17–20 produced regionally selective augmentation of AC activity. In the brainstem, the response to forskolin or Mn2+ was markedly stimulated by doses at or below the threshold for observable toxicity of CPF or for inhibition of fetal brain cholinesterase, whereas comparable effects were seen in the forebrain only at higher doses. In addition, low doses of CPF
reduced βAR binding without impairing receptor-mediated stimulation of AC. CPF exposure in any of the four periods (GD9-12, GD17-20, PN1-4, PN11-14) elicited significant long term changes in AC signaling in a wide variety of brain regions in adulthood (PN60). In general, GD9–12 was the least sensitive stage, requiring doses above the threshold for impaired maternal weight gain, whereas effects were obtained at subtoxic doses for all other regimens. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus shared by multiple stimulants. Superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses, in G-protein function, and in AC expression and subtypes. Exposures conducted at GD17–20 and later all produced sex-selective alterations. On the AC signaling in the heart and liver, few immediate effects 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. These results indicate that signal transduction through the AC cascade is a target for CPF during a discrete developmental period in late gestation, an effect that is likely to contribute to the noncholinergic component of CPF’s developmental neurotoxicity. Results also show that developmental exposure to CPF elicits long-lasting alterations in cell-signaling cascades in the brain that are shared
by multiple neurotransmitter and hormonal inputs; the resultant abnormalities of synaptic communication are thus likely to occur in
widespread neural circuits and their corresponding behaviors. At last,
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.