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Neurotoxicity Research

, 3:557 | Cite as

Behavioral effects induced by acute exposure to benzo(a)pyrene in F-344 rats

  • Crystal R. Saunders
  • Dolores C. Shockley
  • Maurice E. Knuckles
Article

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are highly persistent environmental pollutants which pose potential adverse effects on human health. Benzo(a)-pyrene (B(a)P) is the prototypical representative of these widely dispersed lipophilic contaminants. (B(a)P) exposure in experimental animals results in an array of tissue- and organ-specific responses including carcinogenicity, teratogenicity, reproductive and immunotoxicity. However, no previous studies have examined the potential neuro-behavioral toxicity of B(a)Pin vivo. The present study was conducted to investigate the behavioral effects induced by single oral doses of (B(a)P) in 8-week-old male and female F-344 rats. Rats were exposed to 0, 12.5, 25, 50, 100 and 200 mg/kg of B(a)P by oral gavage. Motor activity measurements and the functional observational battery (FOB) were used to assess behavioral changes induced by B(a)P at 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h post treatment. Statistical analyses revealed significant (p < 0.001) dose, sex and time interactions. (B(a)P) doses ranging from 25 to 200 mg/kg produced a significant suppression (up to 60%) in four motor activity parameters: horizontal activity, total distance, stereotype and vertical activity in both sexes within 2 and 4h of dosing. B(a)P treated male and female animals also showed significant (p < 0.001) changes in neuromuscular, autonomic, sensorimotor and physiological functions within 2 and 4h post B(a)P administration except in the 12.5 mg/kg treatment group. The 12.5 mg/kg dose did not produce significant (p > 0.05) behavioral toxicity in either males or females.

All treated animals (25–200 mg/kg) recovered from the toxic effects of B(a)P by 72 h. Significant (p < 0.05) gender differences were noted in FOB tests measures with males displaying greater sensitivity to B(a)P. These data suggest that motor activity and FOB measurements can be used as indices to detect B(a)P neurotoxicity.

Keywords

Benzo(a)pyrene (B(a)P) locomotor activity functional observational battery (FOB) neurotoxicity behavior 

References

  1. Adams, J.O., Mara, K. and Hoffman, D. (1987) “Toxic and carcinogenic agents in undiluted mainstream smoke and side stream smoke of different types of cigarettes”,Carcinogenesis 8, 729–731.PubMedCrossRefGoogle Scholar
  2. Adler, S., Candrian, R., Eisner, J. and Zbinden, G. (1986) “Neurobehavioral screening in rats: validation study”,Methods Fund. Exp. Clin. Pharmacol. 8, 279–289.Google Scholar
  3. ATSDR (1995) Toxicological profile for Polycyclic Aromatic Hydrocarbons (PAHs) (Agency for Toxic Substances and Disease Registry, Atlanta, GA).Google Scholar
  4. Burstyn, I., Kromhout, H. and Boffetta, P. (2000) “Literature review of levels and determinants of exposure to potential carcinogens and other agents in the road construction industry”,AIHAJ 5, 715–726.CrossRefGoogle Scholar
  5. Childers, J.W., Witherspoon, C.L., Smith, L.B. and Pleil, J.D. (2000) “Real-time and integrated measurement of potential human exposure to particle bound polycyclic aromatic hydrocarbons from aircraft exhaust”,Environ. Health Perspect. 108, 853–862.PubMedCrossRefGoogle Scholar
  6. Crofton, K. and Howard, J. (1991) “Interlaboratory comparison of motor activity experiments: implications for neurotoxicological assessments”,Neurotoxicol. Teratol. 13, 599–609.PubMedCrossRefGoogle Scholar
  7. Darby, F. and Willis, A. (1986) “Occupational health hazards from road construction and sealing work”,Ann. Occup. Hgy. 30, 445–454.CrossRefGoogle Scholar
  8. Das, M., Mukhtar, H. and Seth, P. (1985) “Distribution of benzo(fl)pyrene in discrete regions of the rat brain”,Bull. Environ. Contam. Toxicol. 35, 500–504.PubMedCrossRefGoogle Scholar
  9. Davies, G., Hodkinson, A. and Divetta, C. (1986) “Measurement and analysis of occupational exposures to coke oven emissions”,Ann. Occup. Hyg. 30, 51–62.PubMedCrossRefGoogle Scholar
  10. Eaton, D. (1995) “Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity”,Pharmacogenetics 5, 259–274.PubMedCrossRefGoogle Scholar
  11. Environmental Protection Agency (EPA) (1985) An exposure and risk assessment for benzo(a)pyrene and other polycyclic aromatic hydrocarbons (Office of Water, Washington, DC) Vol. IV, EPA 440/4-85-020-V4.Google Scholar
  12. Freeman, D.J. and Cantell, C.R. (1990) “Woodburning as a source of atmospheric polycyclic aromatic hydrocarbons”,Environ. Sci. Technol. 24, 1581–1585.CrossRefGoogle Scholar
  13. Gammage, R. (1983) In: Bjouseth, ed, Handbook of PAHs (Dekker, New York, NY), pp 653–707.Google Scholar
  14. Grimmer, G. (1983) In: Grimmer, G., ed, Polycyclic Aromatic Hydrocarbons (CRC Press, Boca Raton, FL).Google Scholar
  15. Haggerty, G.C. (1989) “Development of a tier neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies”,J. Am. Coll. Toxicol. 8, 53–70.Google Scholar
  16. Hammond, E.D., Selikoff, J.J. and Lawther, P.O. (1976) “Inhalation of B(a)P and cancer in man”,Ann. NY. Acad. Sci. 271, 116–124.PubMedCrossRefGoogle Scholar
  17. Haugen, A., Becher, G., Benestad, K.V., Trivers, G.E., Newman, M.J. and Harris, C.C. (1988) Biomonitoring of individuals exposed to high levels of PAH in the work environment. Polynuclear Aromatic Hydrocarbons: A decade of progress (Batelle Press, Columbus, Ohio).Google Scholar
  18. Hecht, S., Grabowski, W. and Groth, K. (1979) “Analysis of feces for B(≪)P after consumption of charcoal-broiled beef by rats and humans”,Food Cosmet. Toxicol. 17, 223–227.PubMedCrossRefGoogle Scholar
  19. Hoffman, D., Harley, N., Fisenne, I. and Adams, J. (1986) “Carcinogenic agents in snuff”,J. Natl.Cancer Inst. 76, 435–437.Google Scholar
  20. Hood, D.B., Nayyar, T., Ramesh, A., Greenwood, A. and Inyang, F. (2000) “Modulation in the developmental expression profiles of spl subsequent to transplacental exposure of fetal rats to desorbed benzo(≪)pyrene following maternal inhalation”,Inhalation Toxicol. 12, 101–125.Google Scholar
  21. Iwagawa, M. and Maeda, T. (1992) “Comparative dose-response study on the pulmonary carcinogenicity of 1,6-dinitropyrene and benzo(fl)pyrene in F-344 rats”,Carcinogenesis 10, 1285–1290.CrossRefGoogle Scholar
  22. Jerina, D., Sayer, J. and Thakker, D. (1980) “Carcinogenicity of polycyclic aromatic hydrocarbons. The bay region theory”, In: Gelboin, H., ed, Carcinogenesis: Fundamental mechanisms and environmental effects (Reidel Publishing, Massachusetts), pp 1–12.Google Scholar
  23. Jett, D., Navoa, R.V. and Lyons, M. (1999) “Additive inhibitory action of chlorpyrifos and PAHs on acetylcholinesterase activity in vitro”,Toxicol. Lett. 105, 223–229.PubMedCrossRefGoogle Scholar
  24. Kim, K.B. and Lee, B.M. (1997) “Oxidative stress to DNA, protein and antioxidant enzymes (superoxide dismutase and catalase) in rats treated with Benzo(a)pyrene”,Cancer Lett. 113, 205–212.PubMedCrossRefGoogle Scholar
  25. Knecht, U. and Elliehausen, H. (1987) “Polycyclic aromatic hydrocarbons (PAH) in abraded particles of brake and clutch linings”,Int. J. Environ Occup. Soc. Med. 28, 227–236.Google Scholar
  26. Laher, J.M., Rigler, M.W. and Vetter, R.D. (1984) “Similiar bioavailability and lymphatic transport of benzo(≪)pyrene when administered to rats in different amounts of dietary fat”,J. Lipid Res. 12, 1337–1342.Google Scholar
  27. Lavoie, E., Bradley, J. and Rice, J. (1987) “Tumorigenic activity of nonalternant polynuclear aromatic hydrocarbons in newborn mice”,Cancer Let. 34, 15–20.CrossRefGoogle Scholar
  28. Lebel, C. (1991) “Oxygen radicals: common mediators of neurotoxicity”,Neurotox. Teratol. 13, 341–346.CrossRefGoogle Scholar
  29. Legraverend, C, Harrison, D. and Ruscetti, W. (1983) “Bone marrow toxicity induced by oral benzo(a)pyrene”,Toxicol. Appl. Pharmacol. 70, 390–410.PubMedCrossRefGoogle Scholar
  30. Lesage, J., Perrault, G. and Durand, P. (1987) “Evaluation of worker exposure to polycyclic aromatic hydrocarbons”,Am. Ind. Hyg. Assoc. J 48, 753–759.PubMedGoogle Scholar
  31. Likhachev, A., Beniashvili, D. and Bykov, V. (1992) “Relevance of quantitation of benzo(≪)pyrene metabolites in animal excretes to evaluate individual human cancer risk”,Prig. Cain. Biol. Res. 374, 435–452.Google Scholar
  32. Lioy, P., Waldman, J. and Greenberg, A. (1988) “The total human exposure study to benzo(a)pyrene: Comparison of the food and inhalation pathway”,Arch. Environ. Health 43, 304–312.PubMedGoogle Scholar
  33. Lloyd, J.W. (1971) “Long-term mortality study of steelwor-kers: V. Respiratory cancer in coke plant workers”,J. Occup. Med. 13, 53–68.PubMedCrossRefGoogle Scholar
  34. Maclure, K.M. and MacMahon, B. (1980) “An epidemiologic perspective of environmental carcinogenesis”,Epidemiol. Rev. 2, 19–48.PubMedGoogle Scholar
  35. MacPhail, R., Peele, R. and Crofton, K. (1989) “Motor activity and screening for neurotoxicity”,J. AM. Coll. Toxicol. 10, 661–669.Google Scholar
  36. Majachrzak, R., Sroczynski, J. and Chelmeska, E. (1990) “Evaluation of the nervous system in workers in the furnace and coal divisions of the coke-producing plants”,Med. Pr. 2, 108–113.Google Scholar
  37. Menzie, C. and Santodonato, J. (1992) “Ambient concentrations and exposure to carcinogenic PAHs in the environment”,Environ. Sci. Technol. 26, 1278–1284.CrossRefGoogle Scholar
  38. Moser, V, McCormick, J., Creason, J. and MacPhail, R. (1988) “Comparison of chlordimeform and carbaryl using a functional observational battery”,Fundam. Appl. Toxicol. 11, 189–216.PubMedCrossRefGoogle Scholar
  39. Moser, V. (1990) “Approaches to assessing the validity of a functional observational battery”,Neurotoxicol. Teratol. 12, 483–488.PubMedCrossRefGoogle Scholar
  40. Mounho, B. and Burchiel, S. (1997) “Alterations in human B cell calcium homeostasis by PAH: Possible associations with CYP1 Al metabolism and increased protein tyrosine phosphorylation”,Toxicol. Appl. Pharmacol. 148, 80–89.Google Scholar
  41. Nebert, D., Roe, A. and Dieter, M. (2000) “Role of the aromatic hydrocarbon and the Ah gene battery in the oxidative stress response, cell cycle control and apoptosis”,Biochem. Pharmacol. 59, 65–85.PubMedCrossRefGoogle Scholar
  42. Rahmann, A. (1986) “The influences of bile in the bioavailability of PAHs from rat intestine”,J. Physiol. Pharmacol. 64, 1214–1248.Google Scholar
  43. Ramesh, A., Inyang, F. and Hood, D. (1999) “Oral bioavailability and metabolic profile of Benzo(a)pyrene in F-344 rats”,ISSX Proc. 15, 236.Google Scholar
  44. Ramesh, A., Inyang, F. and Hood, D. (2000) “Aryl hydrocarbon hydroxylase (AHH) activity in F-344 rats subchronically exposed to Benzo(a)pyrene (B(a)P) and Fluoranthene (FLA) through the diet”,J. Biochem. Mol. Toxicol. 14, 155–161.PubMedCrossRefGoogle Scholar
  45. Redmond, E., Strobina, B. and Cypress, R. (1976) “Cancer experience among coke by-product workers”,Ann. NY Acad. Sci. 2, 102–111.CrossRefGoogle Scholar
  46. Salas, V. and Burchiel, S. (1998) “Apoptosis in the daudi human B cells in reponse to benzo(a)pyrene and benzo(fl)pyrene-7,8-dihydrodiol”,Toxicol. Appl. Pharmacol. 151, 367–376.PubMedCrossRefGoogle Scholar
  47. Schulze, G.E. and Boysen, B.G. (1991) “A neurotoxicity screening battery for use in safety evaluations: Effects of acrylamide and 3′, 3′-iminodipropionitrile”,Fund. Appl. Toxicol. 16, 602–615.CrossRefGoogle Scholar
  48. Schulze, G.E. (1990) “Large scale assessment of motor activity in rodents: Procedure for routine use in toxicology studies”,J. AM. Coll. Toxicol. 9, 455–463.Google Scholar
  49. Spencer, P. (1992) “Are human neurodegenerative disorders linked to environmental chemicals with excitotoxic properties?”,Ann. NY. Acad. Sci. 648, 154–160.PubMedCrossRefGoogle Scholar
  50. Stengard, K. (1994) “The effects of toluene on striatal dopamine and acetylcholinesterase activity”,Pharmacol. Toxicol. 75, 115–118.PubMedCrossRefGoogle Scholar
  51. Stephanou, P. (1998) “Alterations in central monoaminergic neurotransmission induced by polycyclic aromatic hydrocarbons in rats”,Europ. J. Drug Metab. 23, 475–481.Google Scholar
  52. Sutter, T.R. and Greenlee, W.F. (1992) “Classification of members of the Ah gene battery”,Chemosphere 25, 223–226.CrossRefGoogle Scholar
  53. Tilson, H. (1990) “Neurotoxicology in the 1990s”,Neurotoxicol. Teratol. 12, 293–300.PubMedCrossRefGoogle Scholar
  54. Tilson, H. (1987a) “Behavioral indices of neurotoxicity: What can be measured?”,Neurotoxicol. Teratol. 9, 427–448.PubMedCrossRefGoogle Scholar
  55. Tilson, H. (1987b) “Neurobehavioral techniques to assess the effects of chemicals on the nervous system”,Annu. Rev. Pharmacol. Toxicol. Appl. 24, 425–450.CrossRefGoogle Scholar
  56. Varona, A., Echevarria, E., Irazusta, J., Serrano, R., Gil, J. and Casia, L. (1998) “Effects of acute benzene on brain enkephalin immunostaining and degradation”,Neurotoxicol. Teratol. 20, 611–616.PubMedCrossRefGoogle Scholar
  57. Wang, D. and Meresz, O. (1982) “Occurrence and potential uptake of polynuclear aromatic hydrocarbons of highway traffic origin by proximally grown food crops”, In: Cook, M., Dennis, A. and Fisher, G, eds, Polynuclear Aromatic Hydrocarbons: Physical and Biological Chemistry Sixth International Symposium, (Battelle Press, Columbus, Ohio), pp 885–896.Google Scholar
  58. Waxman, D.J., Dannan, G.A. and Guengerich, F.P. (1985) “Regulation of rat hepatic cytochrome P- 450: Age-dependent expression, hormonal imprinting and xeno-biotic inducibility of sex-specific isoenzymes”,Biochemistry 24, 4409–4417.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2001

Authors and Affiliations

  • Crystal R. Saunders
    • 1
  • Dolores C. Shockley
    • 1
  • Maurice E. Knuckles
    • 1
  1. 1.Department of PharmacologyMeharry Medical CollegeNashvilleUSA

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