Developmental toxicity of diesel exhaust: A review of studies in experimental animals

Reproductive Toxicology

Volumn 42, Issue , 2013, Pages 1-17

  Ema, Makoto ^a   Naya, Masato ^a   Horimoto, Masao ^b   Kato, Haruhisa ^c  

^a NATIONAL INSTITUTE OF ADVANCED INDUSTRIAL SCIENCE AND TECHNOLOGY AIST   (Japan)

^b CHIBA INSTITUTE OF SCIENCE   (Japan)

^c NATIONAL INSTITUTE OF ADVANCED INDUSTRIAL SCIENCE AND TECHNOLOGY AIST   (Japan)

Author keywords

Carbon black; Developmental toxicity; Diesel exhaust; Diesel exhaust particles; Nanoparticles; Reproductive system; Reproductive toxicity; Testicular toxicity

Indexed keywords

BLACK CARBON; NANOPARTICLE;

AIR POLLUTANT; CENTRAL NERVOUS SYSTEM; DEVELOPMENTAL TOXICITY; DIESEL EXHAUST PARTICLE; ECOTOXICITY; ENVIRONMENTAL EXPOSURE; EXHAUST GAS; EXPERIMENTAL ANIMAL; FEMALE GENITAL SYSTEM; GENE EXPRESSION; GENOTOXICITY; GONAD DEVELOPMENT; IMMUNE SYSTEM; IMMUNOTOXICITY; INFLAMMATION; MALE GENITAL SYSTEM; NEUROTOXICITY; NONHUMAN; REPRODUCTIVE TOXICITY; REVIEW; TOXIC INHALATION;

CARBON BLACK; DEVELOPMENTAL TOXICITY; DIESEL EXHAUST; DIESEL EXHAUST PARTICLES; NANOPARTICLES; REPRODUCTIVE SYSTEM; REPRODUCTIVE TOXICITY; TESTICULAR TOXICITY;

AIR POLLUTANTS; ANIMALS; FEMALE; MATERNAL-FETAL EXCHANGE; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS; REPRODUCTION; SOOT; VEHICLE EMISSIONS;

EID: 84880982988     PISSN: 08906238     EISSN: 18731708     Source Type: Journal    
DOI: 10.1016/j.reprotox.2013.06.074     Document Type: Review

References (90)

1. HEI (The Health Effects Institute) Executive summary: diesel exhaust: critical analysis of emissions, exposure, and health effects 1995, available from:, [cited 17.04.12]. http://www.healtheffects.org/Pubs/diesum.htl.
2. Kagawa J. Health effects of diesel exhaust emissions-a mixture of air pollutants of worldwide concern. Toxicology 2002, 181-182:349-353.
3. US EPA (United State Environmental Protection Agency) Health assessment document for diesel engine exhaust May 2002, Office of Research and Development, National Center for Environmental Assessment, Washington Office, Washington, D.C., available from:, [cited 17.04.12], EPA/600/8-90/057F. http://www.epa.gov/ncea.
4. Donaldson K., Tran L., Jimenez L.A., Duffin R., Newby D.E., Mils N., et al. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure. Part Fibre Toxicol 2005, 2(10). 10.1186/1743-8977-2-10.
5. Murray A.R., Kisin E., Leonard S.S., Young S.H., Kommineni C., Kagan V.E., et al. Oxidative stress and inflammatory response in derma toxicity of single-walled carbon nanotubes. Toxicology 2009, 257:161-171.
6. Vandenberg L.N., Maffini M.V., Sonnenschein C., Rubin B.S., Soto A. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 2009, 30:75-95.
7. Šrám R.J., Binková B., Dejmek J., Bobak M. Ambient air pollution and pregnancy outcome: a review of the literature. Environ Health Perspect 2005, 113:375-382.
8. Shah P.S., Balkhair T. Air pollution and birth outcomes: a systemic review. Environ Int 2011, 37:498-516.
9. Stieb D.M., Chen L., Eshoul M., Judek S. Ambient air pollution, birth weight and preterm birth: a systemic review and meta-analysis. Environ Res 2012, 117:100-111.
10. De Rosa M., Zarrilli S., Paesano L., Carbone U., Boggia B., Petretta M., et al. Traffic pollutants affect fertility in men. Human Reprod 2003, 18:1055-1061.
11. IARC (International Agency for Research on Cancer) Diesel and gasoline engine exhausts and some nitroarenes. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 46 1989.
12. IPCS (International Programme on Chemical Safety) Diesel fuel and exhaust emissions 1996, Environ Health Crit 171, Geneva.
13. Hesterberg T.W., Bunn W.B., Chase G.R., Valberg P.A., Slavin T.J., Lapin C.A., et al. A critical assessment of studies on the carcinogenic potential of diesel exhaust. Crit Rev Toxicol 2006, 36:727-776.
14. McClellan R.O., Hesterberg T.W., Wall J.C. Evaluation of carcinogenic hazard of diesel engine exhaust needs to consider revolutionary changes in diesel technology. Regul Toxicol Pharmacol 2012, 63:225-258.
15. Jackson P., Hougaard K.S., Boisen A.M.Z., Jacobsen N.R., Jensen K.A., Møller P., et al. Pulmonary exposure to carbon black by inhalation or instillation in pregnant mice: effects on liver DNA strand breaks in dams and offspring. Nanotoxicology 2012, 6:486-500.
16. US EPA (United State Environmental Protection Agency) Teratogenic effects of long-term exposure to diesel exhaust emissions (rats) 1980, U.S. Enviro. Prot. Agency, Cincinnati, Ohio, available from:, [cited 08.01.13], EPA-600/1-80-010. http://nepis.epa.gov/Exe/ZyPURL.cgi%3FDockey=9100SISS.txt.
17. Pepelko W.E., Peirano W.B. Health effects of exposure to diesel engine emissions. A summary of animal studies conducted by the U.S. Environmental Protection Agency's Health Effects Research Laboratories at Cincinnati, Ohio. J Am Coll Toxicol 1983, 2:253-306.
18. US EPA (United State Environmental Protection Agency) Teratogenic effects of long-term exposure to diesel exhaust emissions (rabbits) 1980, Cincinnati, Ohio, U.S. Enviro. Prot. Agency, available from:, [cited 08.01.13], EPA-600/1-80-011. http://nepis.epa.gov/Adobe/PDF/9100SITX.PDF.
19. Watanabe N., Kurita M. The masculinization of the fetus during pregnancy due to inhalation of diesel exhaust. Environ Health Perspect 2001, 109:111-119.
20. Tsukue N., Tsubone H., Takeda K. Diesel exhaust affects the abnormal delivery in pregnant mice and the growth of their young. Inhal Toxicol 2002, 14:635-651.
21. Tsukue N., Yoshida S., Sugawara I., Takeda K. Effect of diesel exhaust on development of fetal reproductive function in ICR female mice. J Health Sci 2004, 50:174-180.
22. Yoshida M., Yoshida S., Sugawara I., Takeda K. Maternal exposure to diesel exhaust decreases expression of steroidogenic foactor-1 and Müllerian inhibiting substance in the murine fetus. J Health Sci 2002, 48:317-324.
23. Umezawa M., Sakata C., Tabata M., Takano M., Tanaka N., Kudo S., et al. Diesel exhaust exposure enhances the persistence of endometriosis model in rats. J Health Sci 2008, 54:503-507.
24. Umezawa M., Sakata C., Tanaka N., Tabata M., Takeda K., Ihara T., et al. Pathological study for the effects of in utero and postnatal exposure to diesel exhaust on a rat endometriosis model. J Toxicol Sci 2011, 36:493-498.
25. Li C., Li X., Suzuki A., Zhang Y., Fujitani Y., Nagaoka K., et al. Effects of exposure to nanoparticle-rich diesel exhaust on pregnant rats. J Reprod Dev 2013, 59:145-150.
26. Watanabe N. Decreased number of sperms and Sertoli cells in mature rats exposed to diesel exhaust as fetuses. Toxicol Lett 2005, 155:51-58.
27. Yoshida S., Yoshida M., Sugawara I., Takeda K. Mice strain differences in effects of fetal exposure to diesel exhaust gas on male gonadal differentiation. Environ Sci 2006, 13:117-123.
28. Yoshida S., Ono N., Tsukue N., Oshio S., Umeda T., Takano H., et al. In utero exposure to diesel exhaust increased accessory reproductive gland weight and serum testosterone concentration in male mice. Environ Sci 2006, 13:139-147.
29. Ono N., Oshio S., Niwata Y., Yoshida E., Tsukue N., Sugawara I., et al. Prenatal exposure to diesel exhaust impairs mouse spermatogenesis. Inhal Toxicol 2007, 19:275-281.
30. Ono N., Oshio S., Niwata Y., Yoshida E., Tsukue N., Sugawara I., et al. Detrimental effects of prenatal exposure to filtered diesel exhaust on mouse spermatogenesis. Arch Toxicol 2008, 82:851-859.
31. Hemmingsen J.G., Hougaaard K.S., Talsness C., Wellejus A., Loft S., Wallin H., et al. Prenatal exposure to diesel exhaust particles and effect on the male reproductive system in mice. Toxicology 2009, 264:61-68.
32. Li C.M., Taneda S., Taya K., Watanabe G., Li X., Fujitani Y., et al. Effects of in utero exposure to nanoparticle-rich diesel exhaust on testicular function in immature male rats. Toxicol Lett 2009, 185:1-8.
33. Kubo-Irie M., Oshio S., Niwata Y., Ishihara A., Sugawara I., Takeda K. Pre- and postnatal exposure to low-dose diesel exhaust impairs murine spermatogenesis. Inhal Toxicol 2011, 23:805-813.
34. Suzuki T., Oshio S., Iwata M., Saburi H., Odagiri T., Udagawa T., et al. In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male rats. Part Fibre Toxicol 2010, 7:7. 10.1186/1743-8977-7-7.
35. Sugamata M., Ihara T., Takano H., Oshio S., Takeda K. Maternal diesel exhaust damages newborn murine brains. J Health Sci 2006, 52:82-84.
36. Sugamata M., Ihara T., Sugamata M., Takeda K. Maternal exposure to diesel exhaust leads to pathological similarity to autism in newborns. J Health Sci 2006, 52:486-488.
37. Hougaard K.S., Jensen K.A., Nordly P., Taxvig C., Vogel U., Saber A.T., et al. Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Part Fibre Toxicol 2008, 5:3. 10.1186/1743-8977-5-3.
38. Yokota S., Mizuo K., Moriya N., Oshio S., Sugawara I., Takeda K. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett 2009, 449:38-41.
39. Tsukue N., Watanabe M., Kumamoto T., Takano H., Takeda K. Perinatal exposure to diesel exhaust affects gene expression in mouse cerebrum. Arch Toxicol 2009, 83:985-1000.
40. Yokota S., Moriya N., Iwata M., Umezawa M., Oshio S., Takeda K. Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice. J Toxicol Sci 2013, 38:13-23.
41. Watanabe N., Ohsawa M. Elevated serum immunoglobulin E to Cryptomeria japonica pollen in rats exposed to diesel exhaust during fetal and neonatal periods. BMC Pregnancy Childbirth 2002, 2:1-9.
42. Fujimoto A., Tsukue N., Watanabe M., Sugawara I., Yanagisawa R., Takano H., et al. Diesel exhaust affects immunological action in the placentas of mice. Environ Toxicol 2005, 20:431-440.
43. CEPA/OEHHA (California Environmental Protection Agency/Office of Environmental Health Hazard Assessment) Safe drinking water and toxic enforcement ACT of 1986 (Position 65) 2003, Notice to interested parties, February 21, 2003. Chemical listed effective February 21, 2003 as known to the State of California to cause cancer, available from:, [cited 17.04.12]. http://oehha.ca.gov/prop65/prop65_list/files/22103not.pdf.
44. Fedulov A.V., Leme A., Yang Z., Dahl M., Lim R., Mariani T.J., et al. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility. Am J Respir Mol Biol 2008, 38:57-67.
45. Sharkhuu T., Doerfler D.L., Krantz Q.T., Luebke R.W., Linak W.P., Gilmour K.I. Effects of prenatal diesel exhaust inhalation on pulmonary inflammation and development of specific immune responses. Toxicol Lett 2010, 196:12-20.
46. Corson L., Zhu H., Quan C., Grunig G., Ballaney M., Jin X., et al. Prenatal allergen and diesel exhaust exposure and their effects on allergy in adult offspring mice. Allergy Asthma Clin Immunol 2010, 6:7. 10.1186/1710-1492-6-7.
47. Auten R.L., Gilmour M.I., Krantz Q.T., Potts E.N., Mason S.N., Foster W.M. Maternal diesel inhalation increases airway hyperactivity in ozone-exposed offspring. Am J Respir Cell Biol 2012, 46:454-460.
48. Pereira M.A., McMillan L., Kaur P., Gulati D.K., Sabharwal P.S. Effect of diesel exhaust emissions, particulates, and extract on sister chromatid exchange in transplacentally exposed fetal hamster liver. Environ Mutagen 1982, 4:215-220.
49. Reliene R., Hlavacova A., Mahadevan B., Baird W.M., Schiestl R.H. Diesel exhaust particles cause increased levels of DNA deletions after transplacental exposure in mice. Mutat Res 2005, 570:245-252.
50. Singh P., DeMarini D.M., Dick C.A., Ryan J.V., Linak W.P., et al. Sample characterization of automobile and forklift diesel exhaust particles and comparative pulmonary toxicity in mice. Environ Health Perspect 2004, 112:820-825.
51. Ritz C., Ruminski W., Hougaard K.S., Wallin H., Vogel U., Yauk C.L. Germline mutation rates in mice following in utero exposure to diesel exhaust particles by maternal inhalation. Mutat Res 2011, 712:55-58.
52. Utsunomiya S., Jensen K., Keeler G.J., Ewing R.C. Direct identification of trace metals in fine and ultrafine particles in the Detroit urban atmosphere. Environ Sci Technol 2004, 38:2289-2297.
53. Ema M., Kobayashi N., Naya M., Hanai S., Nakanishi J. Reproductive and developmental toxicity studies of manufactured nanomaterials. Reprod Toxicol 2010, 30:343-352.
54. Yoshida S., Hiyoshi K., Oshio S., Takano H., Takeda K., Ichinose T. Effect of fetal exposure to carbon nanoparticles on reproductive function in male offspring. Fertil Steril 2010, 33:1695-1699.
55. Umezawa M., Kudo S., Yanagita S., Shinkai Y., Niki R., Oyabu T., et al. Maternal exposure to carbon black nanoparticle increases collagen type VIII expression in the kidney of offspring. J Toxico Sci 2011, 36:461-468.
56. Jackson P., Lund S.P., Kristiasen G., Andersen O., Vogel U., Wallin H., et al. An experimental protocol for maternal pulmonary exposure in developmental toxicology. Basic Clin Pharmacol Toxicol 2011, 108:202-207.
57. Jackson P., Vogel U., Wallin H., Hougaard K.S. Prenatal exposure to carbon black (Printex 90): effects of sexual development and neurofunction. Basic Clin Pharmacol Toxicol 2011, 109:434-437.
58. Jackson P., Hougaard K.S., Vogel U., Wu D., Casavant L., Williams A., et al. Exposure of pregnant mice to carbon black by intratracheal instillation: toxicogenomic effects in dams and offspring. Mutat Res 2012, 745:73-83.
59. Holson J.F., Nemec M.D., Stump D.G., Kaufman L.E., Lindström P., Varsho B.J. Significance, reliability, and interpretation of developmental and reproductive toxicity study findings. Developmental and reproductive toxicology: a practical approach 2006, 329-424. CRC Press, Boca Raton. 2nd ed. R.D. Hood (Ed.).
60. Buelke-Sam J., Kimmel C.A., Adams J., Nelson C.J., Vorhees C.V., Wright D.C., et al. Collaborative behavioral teratology study: results. Neurobehav Toxicol teratol 1985, 7:591-624.
61. Kimmel C.A., Price C.J. Developmental toxicity studies. Handbook of in vivo toxicity testing 1990, 271-301. Academic Press, Inc, San Diego. D.L. Arnold, H.C. Grice, D.R. Krewski (Eds.).
62. ILSI (International Life Sciences institute) Risk Science Institute Workshop Participants. The relevance of the rat lung response to particle overload for human risk assessment: a workshop consensus report. Inhal Toxicol 2000, 12:1-17.
63. Bermudez E., Mangum J.B., Asgharian B., Wong B.A., Reverdy E.E., Janszen D.B., et al. Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicol Sci 2002, 70:86-97.
64. Tozuka Y., Watanabe N., Osawa M., Toriba A., Kizu R., Hayakawa K. Transfer of polycyclic aromatic hydrocarbons to fetuses and breast milk of rats exposed to diesel exhaust. J Health Sci 2004, 50:497-502.
65. Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Lunts A., et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 2002, 65:1531-1543.
66. Kreyling W., Semmler-Behnke M., Seitz J., Scymczak W., Wenk A., Mayer P., et al. Size dependence of the translocation of inhaled iridium and carbon nanoparticles aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol 2009, 21 (S1):55-60.
67. Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Kreyling W., et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 2004, 16:437-445.
68. Jani P.U., McCarthy D.E., Florence A.T. Titanium dioxide (rutile) particle uptake from the rat GI and translocation to systemic organs after oral administration. Int J Pharm 1994, 105:157-168.
69. Wang J., Zhou G., Chen C., Yu H., Wang T., Ma Y., et al. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 2007, 168:176-185.
70. Takeda K., Suzuki K., Ishihara A., Kubo-Irie M., Fujimoto R., Tabata M., et al. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve system. J Health Sci 2009, 55:95-102.
71. 14C]C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. J Appl Toxicol 2010, 30:354-360.
72. Komatsu T., Tabata M., Kubo-Irie M., Shimizu T., Suzuki K., Nihei Y., et al. The effects of nanoparticles on mouse testis Leydig cells in vitro. Toxicol in Vitro 2008, 22:1825-1831.
73. Buerki-Thurnherr T., von Mandach U., Wick P. Knocking at the door of the unborn child: engineered nanoparticles at the human placental barrier. Swiss Med Wky 2012, 10.4414/smw.2012.13559.
74. Veras M.M., Damaceno-Rodrigues N.R., Caldini E.G., Ribeiro A.A.C., Mayfew T.M., Saldiva P.H.N., et al. Particulate urban air pollution affects the functional morphology of mouse placenta. Biol Reprod 2008, 79:578-584.
75. Veras M.M., Damaceno-Rodrigues N.R., Silva R.M.G., Scoriza J.N., Saldiva P.H.N., Caldini E.G., et al. Chronic exposure to fine particulate matter emitted by traffic affects reproductive and fetal outcomes in mice. Environ Res 2009, 109:536-543.
76. Veras M.M., Guimarães-Silva R.M., Caldini E.G., Saldiva P.H.N., Dolhnikoff M., Mayhew T.M. The effects of particulate ambient air pollution on the murine umbilical cord and its vessels: a quantitative morphological and immunohistochemical study. Reprod Toxicol 2012, 34:598-606.
77. US EPA (United State Environmental Protection Agency) Indoor air quality. Residential air cleaners (2nd ed): A summary of available information 2009, Office of Air and Radiation Indoor Environments Division, Washington, DC, available from:. Reviewed August 2009 [cited 07.02.13]], EPA 402-F-09-002. http://www.epa.gov/iaq/pdfs/residential_air_cleaners.pdf.
78. OEHHA and ALAC (Office of Environmental Health Hazard Assessment and American Lung Association of California) Health effects of diesel exhaust. A fact sheet by Cal/EPA office of Environmental Health Hazard Assessment and the American Lung Association) 2007.
79. Shepard T.H., Lemire R.J. Catalog of teratogenic agents 2004, The Johns Hopkins University Press, Baltimore. 11th ed.
80. Ema M., Naya M., Yoshida K., Nagaosa R. Reproductive and developmental toxicity of degradation products of refrigerants in experimental animals. Reprod Toxicol 2010, 29:1-9.
81. Takeda K., Tsukue N., Yoshida S. Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles. Environ Sci 2004, 11:33-45.
82. Tobias H.J., Beving D.E., Ziemann P.J., Sakurai H., Zuk M., Mcmurry P.H., et al. Chemical analysis of diesel engine nanoparticles using a nano-DMA/thermo desorption particle beam mass spectrometer. Environ Sci Technol 2001, 35:2233-2243.
83. ISO (The International Organization for Standardization) Nanotechnologies-Health and safety practices in occupational settings relevant to nanotechnologies 2008, Technical report, Reference number ISO/TR 12885:2008(E), Geneva.
84. Pagano G., de Biase A., Deeva I.B., Degan P., Doronin Y.K., Laccarino M., et al. The role of oxidative stress in developmental and reproductive toxicity of tamoxifen. Life Sci 2001, 68:1735-1749.
85. Lavranos G., Balla M., Tzortzopoulou A., Syriou K., Angelopoulou R. Investigating ROS sources in male infertility: a common end for numerous pathways. Reprod Toxicol 2012, 34:298-307.
86. Hansen J.M., Harris C. Redox control of teratogenesis. Reprod Toxicol 2012, 35:165-179.
87. Møller P., Jacobsen N.R., Folkmann A.K., Danielsen P.H., Mikkeksen L., Hemmingsen J.G., et al. Role of oxidative damage in toxicity of particles. Free Radic Res 2010, 44:1-46.
88. Sagai M., Saito H., Ichinose T., Kodama M., Mori Y. Biological effects of diesel exhaust particles. Free Radic Biol Med 1993, 14:37-47.
89. Hesterberg T.W., Bunn W.B., McClellan R.O., Hart G.A., Lapin C.A. Carcinogenicity studies of diesel exhausts in laboratory animals: a review of past studies and a discussion of future research needs. Crit Rev Toxicol 2005, 35:379-411.
90. Hesterberg T.W., Long C.M., Sax S.N., Lapin C.A., McClellan R.O., Bunn W.B., et al. Particulate matter in New Technology Diesel Exhaust (NTDE) is quantitatively and qualitatively very different from that found Traditional Diesel Exhaust (TDE). J Air Waste Manag Assoc 2011, 61:894-913.