Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Feb;118(2):210-5.
doi: 10.1289/ehp.0901237.

Neonatal organophosphorus pesticide exposure alters the developmental trajectory of cell-signaling cascades controlling metabolism: differential effects of diazinon and parathion

Affiliations

Neonatal organophosphorus pesticide exposure alters the developmental trajectory of cell-signaling cascades controlling metabolism: differential effects of diazinon and parathion

Abayomi A Adigun et al. Environ Health Perspect. 2010 Feb.

Abstract

Background: Organophosphorus pesticides (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism.

Objectives/methods: We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days 14 at doses straddling the threshold for systemic signs of exposure and assessed the effects on hepatic and cardiac cell signaling mediated through the adenylyl cyclase (AC) cascade.

Results: In the liver, DZN elicited global sensitization, characterized by parallel up-regulation of AC activity itself and of the responses to stimulants acting at beta-adrenergic receptors, glucagon receptors, or G-proteins. The effects intensified over the course from adolescence to adulthood. In contrast, PRT elicited up-regulation in adolescence that waned by adulthood. Superimposed on these general patterns were effects on glucagon receptor coupling to AC and on responses mediated through the Gi inhibitory protein. The effects on the liver were more substantial than those in the heart, which displayed only transient effects of DZN on AC function in adolescence and no significant effects of PRT. Furthermore, the hepatic effects were greater in magnitude than those in a brain region (cerebellum) that shares similar AC cascade elements.

Conclusions: These findings indicate that OPs alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Notably, the various OPs differ in their net impact on peripheral AC signaling, making it unlikely that the effects on signaling reflect their shared property as cholinesterase inhibitors.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Effects of neonatal exposure to DZN (AC) or PRT (DF) on liver AC activity on PND30 (A, D), PND60 (B, E), and PND100 (C, F). Abbreviations: Fsk, forskolin; Glu, glucagon; Iso, isoproterenol; NaF, sodium fluoride; NS, not significant. ANOVA incorporating the factors of treatment, sex, and AC stimulant appears at the top of each panel, and lower-order tests are shown within the panels. Where there was a significant treatment × stimulant interaction, asterisks denote specific responses that differ from the control animals (males and females combined); separate tests for males and females were not carried out because of the absence of treatment × sex interactions.
Figure 2
Figure 2
Effects of neonatal exposure to DZN (AC) or PRT (DF) on heart AC activity on PND30 (A, D), PND60 (B, E), and PND100 (C, F). Abbreviations: Fsk, forskolin; Glu, glucagon; Iso, isoproterenol; NaF, sodium fluoride; NS, not significant. ANOVA incorporating the factors of treatment, sex, and AC stimulant appears at the top of each panel, and lower-order tests are shown in (A). Where there was a significant treatment × stimulant interaction, asterisks denote specific responses that differ from the control animals.
Figure 3
Figure 3
Effects of neonatal DZN or PRT exposure on liver and heart receptors. (A) βAR binding in DZN-exposed animals. (B) βAR binding in PRT-exposed animals. (C) Cardiac m2AChR binding in animals exposed to DZN or PRT. ANOVA incorporating the factors of treatment, sex, age, and tissue appears at the top of each panel, and lower-order tests are shown within the panels. Asterisks in (B), where there was a treatment × age interaction, show ages for which the PRT group differs from the control.
Figure 4
Figure 4
Effects of neonatal exposure to DZN (top) or PRT (bottom) on the cerebellum, evaluated at PND100. Abbreviations: Fsk, forskolin; Iso, isoproterenol; NaF, sodium fluoride. Multivariate ANOVA appears at the top of the panel, and lower-order tests are shown within the panels.

Similar articles

Cited by

References

    1. Barker DJP. The developmental origins of adult disease. Eur J Epidemiol. 2003;18:733–736. - PubMed
    1. Casida JE, Quistad GB. Organophosphate toxicology: safety aspects of nonacetylcholinesterase secondary targets. Chem Res Toxicol. 2004;17:983–998. - PubMed
    1. Curtin BF, Pal N, Gordon RK, Nambiar MP. Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells. Mol Cell Biochem. 2006;290:23–32. - PubMed
    1. Eskenazi B, Rosas LG, Marks AR, Bradman A, Harley K, Holland N, et al. Pesticide toxicity and the developing brain. Basic Clin Pharmacol Toxicol. 2008;102:228–236. - PubMed
    1. Gao XM, Agrotis A, Autelitano DJ, Percy E, Woodcock EA, Jennings GL, et al. Sex hormones and cardiomyopathic phenotype induced by cardiac β2-adrenergic receptor overexpression. Endocrinology. 2003;144:4097–4105. - PubMed

Publication types