PMID- 14754571
OWN - NLM
STAT- MEDLINE
DCOM- 20040506
LR  - 20181113
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 112
IP  - 2
DP  - 2004 Feb
TI  - Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical 
      periods for immediate and delayed-onset effects on cardiac and hepatic cell 
      signaling.
PG  - 170-8
AB  - 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, Mn2+); 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.
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 - 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  - EC 4.6.1.1 (Adenylyl Cyclases)
RN  - JCS58I644W (Chlorpyrifos)
SB  - IM
MH  - Adenylyl Cyclases/*pharmacology
MH  - Animals
MH  - Chlorpyrifos/*toxicity
MH  - Female
MH  - Heart/*embryology
MH  - Homeostasis
MH  - Insecticides/*toxicity
MH  - Liver/*cytology/*embryology
MH  - Myocardium/*cytology
MH  - Pregnancy
MH  - *Prenatal Exposure Delayed Effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*drug effects
PMC - PMC1241826
EDAT- 2004/02/03 05:00
MHDA- 2004/05/07 05:00
PMCR- 2004/02/01
CRDT- 2004/02/03 05:00
PHST- 2004/02/03 05:00 [pubmed]
PHST- 2004/05/07 05:00 [medline]
PHST- 2004/02/03 05:00 [entrez]
PHST- 2004/02/01 00:00 [pmc-release]
AID - 10.1289/ehp.6690 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2004 Feb;112(2):170-8. doi: 10.1289/ehp.6690.