PMID- 14644659
OWN - NLM
STAT- MEDLINE
DCOM- 20040302
LR  - 20181113
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 111
IP  - 16
DP  - 2003 Dec
TI  - Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: 
      when is adenylyl cyclase a target?
PG  - 1871-6
AB  - The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms over 
      and above cholinesterase inhibition. In the present study, we evaluated the 
      effects of gestational CPF exposure on the adenylyl cyclase (AC) signaling 
      cascade, which regulates the production of cyclic AMP, a major controller of cell 
      replication and differentiation. In addition to basal AC activity, we assessed 
      the AC response to direct enzymatic stimulants [forskolin, manganese (Mn(2+))]; 
      the response to isoproterenol, which activates signaling through 
      beta-adrenoceptors (betaARs); and the concentration of betaAR binding sites. CPF 
      administered to pregnant rats on gestational days (GD) 9-12 elicited little or no 
      change in any components of AC activity or betaARs. However, shifting the 
      treatment window to GD17-20 produced regionally selective augmentation of AC 
      activity. In the brainstem, the response to forskolin or Mn(2+) 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 
      betaAR binding without impairing receptor-mediated stimulation of AC. 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.
FAU - Meyer, Armando
AU  - Meyer A
AD  - Centro de Estudos da Saude do Trabalhador e Ecologia Humana, Escola Nacional de 
      Saude Publica, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.
FAU - Seidler, Frederic J
AU  - Seidler FJ
FAU - Cousins, Mandy M
AU  - Cousins MM
FAU - Slotkin, Theodore A
AU  - Slotkin TA
LA  - eng
GR  - ES10356/ES/NIEHS NIH HHS/United States
GR  - ES10387/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Insecticides)
RN  - 0 (Receptors, Adrenergic, beta)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
RN  - JCS58I644W (Chlorpyrifos)
SB  - IM
MH  - Adenylyl Cyclases/*drug effects/metabolism
MH  - Animals
MH  - Brain/*drug effects/*enzymology
MH  - Chlorpyrifos/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Embryonic and Fetal Development/*drug effects
MH  - Female
MH  - Insecticides/*toxicity
MH  - Maternal Exposure
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Adrenergic, beta/metabolism
PMC - PMC1241759
EDAT- 2003/12/04 05:00
MHDA- 2004/03/03 05:00
PMCR- 2003/12/01
CRDT- 2003/12/04 05:00
PHST- 2003/12/04 05:00 [pubmed]
PHST- 2004/03/03 05:00 [medline]
PHST- 2003/12/04 05:00 [entrez]
PHST- 2003/12/01 00:00 [pmc-release]
AID - 10.1289/ehp.6468 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2003 Dec;111(16):1871-6. doi: 10.1289/ehp.6468.