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. 2003 Dec;111(16):1871–1876. doi: 10.1289/ehp.6468

Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: when is adenylyl cyclase a target?

Armando Meyer 1, Frederic J Seidler 1, Mandy M Cousins 1, Theodore A Slotkin 1
PMCID: PMC1241759  PMID: 14644659

Abstract

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.

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Selected References

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  1. Andersen Helle Raun, Vinggaard Anne Marie, Rasmussen Thomas Hoj, Gjermandsen Irene Marianne, Bonefeld-Jørgensen Eva Cecilie. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro. Toxicol Appl Pharmacol. 2002 Feb 15;179(1):1–12. doi: 10.1006/taap.2001.9347. [DOI] [PubMed] [Google Scholar]
  2. Auman J. T., Seidler F. J., Slotkin T. A. Neonatal chlorpyrifos exposure targets multiple proteins governing the hepatic adenylyl cyclase signaling cascade: implications for neurotoxicity. Brain Res Dev Brain Res. 2000 May 11;121(1):19–27. doi: 10.1016/s0165-3806(00)00021-3. [DOI] [PubMed] [Google Scholar]
  3. Barone S., Jr, Das K. P., Lassiter T. L., White L. D. Vulnerable processes of nervous system development: a review of markers and methods. Neurotoxicology. 2000 Feb-Apr;21(1-2):15–36. [PubMed] [Google Scholar]
  4. Bhat N. R., Shanker G., Pieringer R. A. Cell proliferation in growing cultures of dissociated embryonic mouse brain: macromolecule and ornithine decarboxylase synthesis and regulation by hormones and drugs. J Neurosci Res. 1983;10(2):221–230. doi: 10.1002/jnr.490100210. [DOI] [PubMed] [Google Scholar]
  5. Buznikov G. A., Nikitina L. A., Bezuglov V. V., Lauder J. M., Padilla S., Slotkin T. A. An invertebrate model of the developmental neurotoxicity of insecticides: effects of chlorpyrifos and dieldrin in sea urchin embryos and larvae. Environ Health Perspect. 2001 Jul;109(7):651–661. doi: 10.1289/ehp.01109651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Campbell C. G., Seidler F. J., Slotkin T. A. Chlorpyrifos interferes with cell development in rat brain regions. Brain Res Bull. 1997;43(2):179–189. doi: 10.1016/s0361-9230(96)00436-4. [DOI] [PubMed] [Google Scholar]
  7. Claycomb W. C. Biochemical aspects of cardiac muscle differentiation. Possible control of deoxyribonucleic acid synthesis and cell differentiation by adrenergic innervation and cyclic adenosine 3':5'-monophosphate. J Biol Chem. 1976 Oct 10;251(19):6082–6089. [PubMed] [Google Scholar]
  8. Crumpton T. L., Seidler F. J., Slotkin T. A. Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation. Brain Res. 2000 Feb 28;857(1-2):87–98. doi: 10.1016/s0006-8993(99)02357-4. [DOI] [PubMed] [Google Scholar]
  9. Dam K., Garcia S. J., Seidler F. J., Slotkin T. A. Neonatal chlorpyrifos exposure alters synaptic development and neuronal activity in cholinergic and catecholaminergic pathways. Brain Res Dev Brain Res. 1999 Aug 5;116(1):9–20. doi: 10.1016/s0165-3806(99)00067-x. [DOI] [PubMed] [Google Scholar]
  10. Dam K., Seidler F. J., Slotkin T. A. Developmental neurotoxicity of chlorpyrifos: delayed targeting of DNA synthesis after repeated administration. Brain Res Dev Brain Res. 1998 Jun 15;108(1-2):39–45. doi: 10.1016/s0165-3806(98)00028-5. [DOI] [PubMed] [Google Scholar]
  11. Das K. P., Barone S., Jr Neuronal differentiation in PC12 cells is inhibited by chlorpyrifos and its metabolites: is acetylcholinesterase inhibition the site of action? Toxicol Appl Pharmacol. 1999 Nov 1;160(3):217–230. doi: 10.1006/taap.1999.8767. [DOI] [PubMed] [Google Scholar]
  12. Dreyfus C. F. Neurotransmitters and neurotrophins collaborate to influence brain development. Perspect Dev Neurobiol. 1998;5(4):389–399. [PubMed] [Google Scholar]
  13. Erdtsieck-Ernste B. H., Feenstra M. G., Boer G. J. Pre- and postnatal developmental changes of adrenoceptor subtypes in rat brain. J Neurochem. 1991 Sep;57(3):897–903. doi: 10.1111/j.1471-4159.1991.tb08235.x. [DOI] [PubMed] [Google Scholar]
  14. Gao M. H., Lai N. C., Roth D. M., Zhou J., Zhu J., Anzai T., Dalton N., Hammond H. K. Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice. Circulation. 1999 Mar 30;99(12):1618–1622. doi: 10.1161/01.cir.99.12.1618. [DOI] [PubMed] [Google Scholar]
  15. Gao M., Ping P., Post S., Insel P. A., Tang R., Hammond H. K. Increased expression of adenylylcyclase type VI proportionately increases beta-adrenergic receptor-stimulated production of cAMP in neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1038–1043. doi: 10.1073/pnas.95.3.1038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Garcia S. J., Seidler F. J., Crumpton T. L., Slotkin T. A. Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Res. 2001 Feb 9;891(1-2):54–68. doi: 10.1016/s0006-8993(00)03189-9. [DOI] [PubMed] [Google Scholar]
  17. Garcia Stephanie J., Seidler Frederic J., Qiao Dan, Slotkin Theodore A. Chlorpyrifos targets developing glia: effects on glial fibrillary acidic protein. Brain Res Dev Brain Res. 2002 Feb 28;133(2):151–161. doi: 10.1016/s0165-3806(02)00283-3. [DOI] [PubMed] [Google Scholar]
  18. Guidotti A., Weiss B., Costa E. Adenosine 3',5'-monophosphate concentrations and isoproterenol-induced synthesis of deoxyribonucleic acid in mouse parotid gland. Mol Pharmacol. 1972 Sep;8(5):521–530. [PubMed] [Google Scholar]
  19. Güven M., Bayram F., Unlühizarci K., Keleştimur F. Endocrine changes in patients with acute organophosphate poisoning. Hum Exp Toxicol. 1999 Oct;18(10):598–601. doi: 10.1191/096032799678839419. [DOI] [PubMed] [Google Scholar]
  20. Hohmann C. F., Berger-Sweeney J. Cholinergic regulation of cortical development and plasticity. New twists to an old story. Perspect Dev Neurobiol. 1998;5(4):401–425. [PubMed] [Google Scholar]
  21. Howard Marcia D., Pope Carey N. In vitro effects of chlorpyrifos, parathion, methyl parathion and their oxons on cardiac muscarinic receptor binding in neonatal and adult rats. Toxicology. 2002 Jan 15;170(1-2):1–10. doi: 10.1016/s0300-483x(01)00498-x. [DOI] [PubMed] [Google Scholar]
  22. Huff R. A., Abou-Donia M. B. In vitro effect of chlorpyrifos oxon on muscarinic receptors and adenylate cyclase. Neurotoxicology. 1995 Summer;16(2):281–290. [PubMed] [Google Scholar]
  23. Huff R. A., Abu-Qare A. W., Abou-Donia M. B. Effects of sub-chronic in vivo chlorpyrifos exposure on muscarinic receptors and adenylate cyclase of rat striatum. Arch Toxicol. 2001 Oct;75(8):480–486. doi: 10.1007/s002040100269. [DOI] [PubMed] [Google Scholar]
  24. Huff R. A., Corcoran J. J., Anderson J. K., Abou-Donia M. B. Chlorpyrifos oxon binds directly to muscarinic receptors and inhibits cAMP accumulation in rat striatum. J Pharmacol Exp Ther. 1994 Apr;269(1):329–335. [PubMed] [Google Scholar]
  25. Hultgãrdh-Nilsson A., Querol-Ferrer V., Jonzon B., Krondahl U., Nilsson J. Cyclic AMP, early response gene expression, and DNA synthesis in rat smooth muscle cells. Exp Cell Res. 1994 Sep;214(1):297–302. doi: 10.1006/excr.1994.1261. [DOI] [PubMed] [Google Scholar]
  26. Johnson D. E., Seidler F. J., Slotkin T. A. Early biochemical detection of delayed neurotoxicity resulting from developmental exposure to chloropyrifos. Brain Res Bull. 1998;45(2):143–147. doi: 10.1016/s0361-9230(97)00329-8. [DOI] [PubMed] [Google Scholar]
  27. Kulkarni Vaishali A., Jha Shanker, Vaidya Vidita A. Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci. 2002 Nov;16(10):2008–2012. doi: 10.1046/j.1460-9568.2002.02268.x. [DOI] [PubMed] [Google Scholar]
  28. Kwon J. H., Eves E. M., Farrell S., Segovia J., Tobin A. J., Wainer B. H., Downen M. Beta-adrenergic receptor activation promotes process outgrowth in an embryonic rat basal forebrain cell line and in primary neurons. Eur J Neurosci. 1996 Oct;8(10):2042–2055. doi: 10.1111/j.1460-9568.1996.tb00724.x. [DOI] [PubMed] [Google Scholar]
  29. Landrigan P. J., Claudio L., Markowitz S. B., Berkowitz G. S., Brenner B. L., Romero H., Wetmur J. G., Matte T. D., Gore A. C., Godbold J. H. Pesticides and inner-city children: exposures, risks, and prevention. Environ Health Perspect. 1999 Jun;107 (Suppl 3):431–437. doi: 10.1289/ehp.99107s3431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Landrigan P. J. Pesticides and polychlorinated biphenyls (PCBs): an analysis of the evidence that they impair children's neurobehavioral development. Mol Genet Metab. 2001 May;73(1):11–17. doi: 10.1006/mgme.2001.3177. [DOI] [PubMed] [Google Scholar]
  31. Lauder J. M., Schambra U. B. Morphogenetic roles of acetylcholine. Environ Health Perspect. 1999 Feb;107 (Suppl 1):65–69. doi: 10.1289/ehp.99107s165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Levin E. D., Addy N., Nakajima A., Christopher N. C., Seidler F. J., Slotkin T. A. Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats. Brain Res Dev Brain Res. 2001 Sep 23;130(1):83–89. doi: 10.1016/s0165-3806(01)00215-2. [DOI] [PubMed] [Google Scholar]
  33. Levin Edward D., Addy Nii, Baruah Avanti, Elias Alana, Christopher N. Channelle, Seidler Frederic J., Slotkin Theodore A. Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations. Neurotoxicol Teratol. 2002 Nov-Dec;24(6):733–741. doi: 10.1016/s0892-0362(02)00272-6. [DOI] [PubMed] [Google Scholar]
  34. Limbird L. E., Hickey A. R., Lefkowitz R. J. Unique uncoupling of the frog erythrocyte adenylate cyclase system by manganese. Loss of hormone and guanine nucleotide-sensitive enzyme activities without loss of nucleotide-sensitive, high affinity agonist binding. J Biol Chem. 1979 Apr 25;254(8):2677–2683. [PubMed] [Google Scholar]
  35. Liu Jing, Chakraborti Tamal, Pope Carey. In vitro effects of organophosphorus anticholinesterases on muscarinic receptor-mediated inhibition of acetylcholine release in rat striatum. Toxicol Appl Pharmacol. 2002 Jan 15;178(2):102–108. doi: 10.1006/taap.2001.9326. [DOI] [PubMed] [Google Scholar]
  36. May M. Disturbing behavior: neurotoxic effects in children. Environ Health Perspect. 2000 Jun;108(6):A262–A267. doi: 10.1289/ehp.108-a262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mileson B. E., Chambers J. E., Chen W. L., Dettbarn W., Ehrich M., Eldefrawi A. T., Gaylor D. W., Hamernik K., Hodgson E., Karczmar A. G. Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxicol Sci. 1998 Jan;41(1):8–20. doi: 10.1006/toxs.1997.2431. [DOI] [PubMed] [Google Scholar]
  38. Morris G., Seidler F. J., Slotkin T. A. Stimulation of ornithine decarboxylase by histamine or norepinephrine in brain regions of the developing rat: evidence for biogenic amines as trophic agents in neonatal brain development. Life Sci. 1983 Apr 4;32(14):1565–1571. doi: 10.1016/0024-3205(83)90862-7. [DOI] [PubMed] [Google Scholar]
  39. Navarro H. A., Kudlacz E. M., Kavlock R. J., Slotkin T. A. Prenatal terbutaline treatment: tissue-selective dissociation of perinatal changes in beta-adrenergic receptor binding from regulation of adenylate cyclase activity. Life Sci. 1991;48(3):269–274. doi: 10.1016/0024-3205(91)90354-e. [DOI] [PubMed] [Google Scholar]
  40. Navarro H. A., Kudlacz E. M., Slotkin T. A. Control of adenylate cyclase activity in developing rat heart and liver: effects of prenatal exposure to terbutaline or dexamethasone. Biol Neonate. 1991;60(2):127–136. doi: 10.1159/000243398. [DOI] [PubMed] [Google Scholar]
  41. Olivier K., Jr, Liu J., Pope C. Inhibition of forskolin-stimulated cAMP formation in vitro by paraoxon and chlorpyrifos oxon in cortical slices from neonatal, juvenile, and adult rats. J Biochem Mol Toxicol. 2001;15(5):263–269. doi: 10.1002/jbt.10002. [DOI] [PubMed] [Google Scholar]
  42. Pittman R. N., Minneman K. P., Molinoff P. B. Ontogeny of beta 1- and beta 2-adrenergic receptors in rat cerebellum and cerebral cortex. Brain Res. 1980 Apr 28;188(2):357–368. doi: 10.1016/0006-8993(80)90037-2. [DOI] [PubMed] [Google Scholar]
  43. Pope C. N. Organophosphorus pesticides: do they all have the same mechanism of toxicity? J Toxicol Environ Health B Crit Rev. 1999 Apr-Jun;2(2):161–181. doi: 10.1080/109374099281205. [DOI] [PubMed] [Google Scholar]
  44. Popovik E., Haynes L. W. Survival and mitogenesis of neuroepithelial cells are influenced by noradrenergic but not cholinergic innervation in cultured embryonic rat neopallium. Brain Res. 2000 Jan 24;853(2):227–235. doi: 10.1016/s0006-8993(99)02242-8. [DOI] [PubMed] [Google Scholar]
  45. Qiao Dan, Seidler Frederic J., Padilla Stephanie, Slotkin Theodore A. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect. 2002 Nov;110(11):1097–1103. doi: 10.1289/ehp.021101097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Qiao Dan, Seidler Frederic J., Tate Charlotte A., Cousins Mandy M., Slotkin Theodore A. Fetal chlorpyrifos exposure: adverse effects on brain cell development and cholinergic biomarkers emerge postnatally and continue into adolescence and adulthood. Environ Health Perspect. 2003 Apr;111(4):536–544. doi: 10.1289/ehp.5828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rice D., Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000 Jun;108 (Suppl 3):511–533. doi: 10.1289/ehp.00108s3511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rodier P. M. Structural--functional relationships in experimentally induced brain damage. Prog Brain Res. 1988;73:335–348. doi: 10.1016/S0079-6123(08)60514-2. [DOI] [PubMed] [Google Scholar]
  49. Roy T. S., Andrews J. E., Seidler F. J., Slotkin T. A. Chlorpyrifos elicits mitotic abnormalities and apoptosis in neuroepithelium of cultured rat embryos. Teratology. 1998 Aug;58(2):62–68. doi: 10.1002/(SICI)1096-9926(199808)58:2<62::AID-TERA7>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  50. Schuh Rosemary A., Lein Pamela J., Beckles Rondell A., Jett David A. Noncholinesterase mechanisms of chlorpyrifos neurotoxicity: altered phosphorylation of Ca2+/cAMP response element binding protein in cultured neurons. Toxicol Appl Pharmacol. 2002 Jul 15;182(2):176–185. doi: 10.1006/taap.2002.9445. [DOI] [PubMed] [Google Scholar]
  51. Schwartz J. P., Nishiyama N. Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull. 1994;35(5-6):403–407. doi: 10.1016/0361-9230(94)90151-1. [DOI] [PubMed] [Google Scholar]
  52. Seamon K. B., Daly J. W. Forskolin: its biological and chemical properties. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1986;20:1–150. [PubMed] [Google Scholar]
  53. Shaywitz A. J., Greenberg M. E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–861. doi: 10.1146/annurev.biochem.68.1.821. [DOI] [PubMed] [Google Scholar]
  54. Slotkin T. A., Baker F. E., Dobbins S. S., Eylers J. P., Lappi S. E., Seidler F. J. Prenatal terbutaline exposure in the rat: selective effects on development of noradrenergic projections to cerebellum. Brain Res Bull. 1989 Oct-Nov;23(4-5):263–265. doi: 10.1016/0361-9230(89)90206-2. [DOI] [PubMed] [Google Scholar]
  55. Slotkin T. A. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect. 1999 Feb;107 (Suppl 1):71–80. doi: 10.1289/ehp.99107s171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Slotkin T. A., Lau C., Seidler F. J. Beta-adrenergic receptor overexpression in the fetal rat: distribution, receptor subtypes, and coupling to adenylate cyclase activity via G-proteins. Toxicol Appl Pharmacol. 1994 Dec;129(2):223–234. doi: 10.1006/taap.1994.1247. [DOI] [PubMed] [Google Scholar]
  57. Slotkin T. A., Tate C. A., Cousins M. M., Seidler F. J. Beta-adrenoceptor signaling in the developing brain: sensitization or desensitization in response to terbutaline. Brain Res Dev Brain Res. 2001 Nov 26;131(1-2):113–125. doi: 10.1016/s0165-3806(01)00282-6. [DOI] [PubMed] [Google Scholar]
  58. Slotkin Theodore A., Auman J. Todd, Seidler Frederic J. Ontogenesis of beta-adrenoceptor signaling: implications for perinatal physiology and for fetal effects of tocolytic drugs. J Pharmacol Exp Ther. 2003 Apr 7;306(1):1–7. doi: 10.1124/jpet.102.048421. [DOI] [PubMed] [Google Scholar]
  59. Song X., Seidler F. J., Saleh J. L., Zhang J., Padilla S., Slotkin T. A. Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade. Toxicol Appl Pharmacol. 1997 Jul;145(1):158–174. doi: 10.1006/taap.1997.8171. [DOI] [PubMed] [Google Scholar]
  60. Song X., Violin J. D., Seidler F. J., Slotkin T. A. Modeling the developmental neurotoxicity of chlorpyrifos in vitro: macromolecule synthesis in PC12 cells. Toxicol Appl Pharmacol. 1998 Jul;151(1):182–191. doi: 10.1006/taap.1998.8424. [DOI] [PubMed] [Google Scholar]
  61. Stachowiak E. K., Fang X., Myers J., Dunham S., Stachowiak M. K. cAMP-induced differentiation of human neuronal progenitor cells is mediated by nuclear fibroblast growth factor receptor-1 (FGFR1). J Neurochem. 2003 Mar;84(6):1296–1312. doi: 10.1046/j.1471-4159.2003.01624.x. [DOI] [PubMed] [Google Scholar]
  62. Vinggaard A. M., Hnida C., Breinholt V., Larsen J. C. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. Toxicol In Vitro. 2000 Jun;14(3):227–234. doi: 10.1016/s0887-2333(00)00018-7. [DOI] [PubMed] [Google Scholar]
  63. Ward T. R., Mundy W. R. Organophosphorus compounds preferentially affect second messenger systems coupled to M2/M4 receptors in rat frontal cortex. Brain Res Bull. 1996;39(1):49–55. doi: 10.1016/0361-9230(95)02044-6. [DOI] [PubMed] [Google Scholar]
  64. Whitney K. D., Seidler F. J., Slotkin T. A. Developmental neurotoxicity of chlorpyrifos: cellular mechanisms. Toxicol Appl Pharmacol. 1995 Sep;134(1):53–62. doi: 10.1006/taap.1995.1168. [DOI] [PubMed] [Google Scholar]
  65. Yanai Joseph, Vatury Ori, Slotkin Theodore A. Cell signaling as a target and underlying mechanism for neurobehavioral teratogenesis. Ann N Y Acad Sci. 2002 Jun;965:473–478. doi: 10.1111/j.1749-6632.2002.tb04188.x. [DOI] [PubMed] [Google Scholar]
  66. Zeiders J. L., Seidler F. J., Iaccarino G., Koch W. J., Slotkin T. A. Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. J Mol Cell Cardiol. 1999 Feb;31(2):413–423. doi: 10.1006/jmcc.1998.0875. [DOI] [PubMed] [Google Scholar]
  67. Zeiders J. L., Seidler F. J., Slotkin T. A. Ontogeny of regulatory mechanisms for beta-adrenoceptor control of rat cardiac adenylyl cyclase: targeting of G-proteins and the cyclase catalytic subunit. J Mol Cell Cardiol. 1997 Feb;29(2):603–615. doi: 10.1006/jmcc.1996.0303. [DOI] [PubMed] [Google Scholar]
  68. Zhang Hengshan, Liu Jing, Pope Carey N. Age-related effects of chlorpyrifos on muscarinic receptor-mediated signaling in rat cortex. Arch Toxicol. 2002 Jan;75(11-12):676–684. doi: 10.1007/s00204-001-0309-3. [DOI] [PubMed] [Google Scholar]
  69. van Wijk R., Wicks W. D., Bevers M. M., van Rijn J. Rapid arrest of DNA synthesis by N 6 ,O 2' -dibutyryl cyclic adenosine 3',5'-monophosphate in cultured hepatoma cells. Cancer Res. 1973 Jun;33(6):1331–1338. [PubMed] [Google Scholar]

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