Triazine Herbicides and Their Chlorometabolites Alter Steroidogenesis in BLTK1 Murine Leydig Cells

Toxicological Sciences

Volumn 134, Issue 1, 2013, Pages 155-167

  Forgacs, Agnes ^a,b   D'Souza, Michelle ^a   Huhtaniemi, Ilpo T ^c   Rahman, Nafis A ^c   Zacharewski, Timothy R ^a,b  

^a Michigan State University   (United States)

^b MICHIGAN STATE UNIVERSITY   (United States)

^c UNIVERSITY OF TURKU   (Finland)

Author keywords

Gene expression; Leydig; Microarray; Testosterone; Triazine

Indexed keywords

ATRAZINE; DES ETHYL S ATRAZINE; DES ISOPROPYL S ATRAZINE; DIAMINOCHLOROTRIAZINE; DRUG METABOLITE; MESSENGER RNA; PROGESTERONE; PROPAZINE; RECOMBINANT CHORIONIC GONADOTROPIN; SIMAZINE; STEROID HORMONE; TERBUTYLAZINE; TESTOSTERONE; TRIAZINE; UNCLASSIFIED DRUG; CHLORINATED HYDROCARBON; HERBICIDE; SEX HORMONE; TRIAZINE DERIVATIVE;

ANIMAL CELL; ARTICLE; CHOLESTEROL METABOLISM; CONCENTRATION RESPONSE; CYP17A1 GENE; GENE; GENE CONTROL; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENE IDENTIFICATION; GENOME; HSD17B3 GENE; HSD3B1 GENE; HSD3B6 GENE; LEYDIG CELL; MICROARRAY ANALYSIS; MOUSE; NONHUMAN; SRD5A1 GENE; STAR GENE; STEROIDOGENESIS; TESTOSTERONE SYNTHESIS; ANIMAL; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; CULTURE TECHNIQUE; DNA MICROARRAY; DOSE RESPONSE; DRUG EFFECTS; GENETIC ASSOCIATION; GENETICS; MALE; METABOLISM; REAL TIME POLYMERASE CHAIN REACTION; TOXICITY;

ANIMALS; CELL CULTURE TECHNIQUES; CELL LINE; DOSE-RESPONSE RELATIONSHIP, DRUG; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENOME-WIDE ASSOCIATION STUDY; GONADAL STEROID HORMONES; HERBICIDES; HYDROCARBONS, CHLORINATED; LEYDIG CELLS; MALE; MICE; MOLECULAR STRUCTURE; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS; REAL-TIME POLYMERASE CHAIN REACTION; TRIAZINES;

EID: 84880256778     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kft096     Document Type: Article

References (66)

1. Ascoli, M. (1981). Regulation of gonadotropin receptors and gonadotropin responses in a clonal strain of Leydig tumor cells by epidermal growth factor. J. Biol. Chem. 256, 179-183.
2. Barr, D. B., Panuwet, P., Nguyen, J. V., Udunka, S., and Needham, L. L. (2007). Assessing exposure to atrazine and its metabolites using biomonitoring. Environ. Health Perspect. 115, 1474-1478.
3. Burgoon, L. D., Eckel-Passow, J. E., Gennings, C., Boverhof, D. R., Burt, J. W., Fong, C. J., and Zacharewski, T. R. (2005). Protocols for the assurance of microarray data quality and process control. Nucleic Acids Res. 33, e172.
4. Burgoon, L. D., and Zacharewski, T. R. (2007). dbZach toxicogenomic information management system. Pharmacogenomics 8, 287-291.
5. Burgoon, L. D., and Zacharewski, T. R. (2008). Automated quantitative doseresponse modeling and point of departure determination for large toxicogenomic and high-throughput screening data sets. Toxicol. Sci. 104, 412-418.
6. Chen, H., Midzak, A., Luo, L., and Zirkin, B. R. (2007). Aging and the decline of androgen production. In The Leydig Cell in Health and Disease (A. H. Payne and M. P. Hardy, Eds.). Humana Press Inc.; Totowa, NJ: 117-131.
7. Cooper, R. L., Laws, S. C., Das, P. C., Narotsky, M. G., Goldman, J. M., Lee Tyrey, E., and Stoker, T. E. (2007). Atrazine and reproductive function: Mode and mechanism of action studies. Birth Defects Res. B. Dev. Reprod. Toxicol. 80, 98-112.
8. Crain, D. A., Guillette, L. J., Jr, Rooney, A. A., and Pickford, D. B. (1997). Alterations in steroidogenesis in alligators (Alligator mississippiensis) exposed naturally and experimentally to environmental contaminants. Environ. Health Perspect. 105, 528-533.
9. Dufau, M. L., Winters, C. A., Hattori, M., Aquilano, D., Barañao, J. L., Nozu, K., Baukal, A., and Catt, K. J. (1984). Hormonal regulation of androgen production by the Leydig cell. J. Steroid Biochem. 20, 161-173.
10. Eckel, J. E., Gennings, C., Chinchilli, V. M., Burgoon, L. D., and Zacharewski, T. R. (2004). Empirical bayes gene screening tool for time-course or doseresponse microarray data. J. Biopharm. Stat. 14, 647-670.
11. Eckel, J. E., Gennings, C., Therneau, T. M., Burgoon, L. D., Boverhof, D. R., and Zacharewski, T. R. (2005). Normalization of two-channel microarray experiments: A semiparametric approach. Bioinformatics 21, 1078-1083.
12. EFSA (2011). Conclusion on the peer review of the pesticide risk assessment of the active substance terbuthylazine. EFSA J. 9, 1969.
13. European Commission (2003a). Review Report for the Active Substance Atrazine (SCFCH, Eds.). European Commission; Brussels, Belgium.
14. European Commission (2003b). Review Report for the Active Substance Simazine (SCFCAH, Eds.). European Commission; Brussels, Belgium.
15. Evgenidou, E., and Fytianos, K. (2002). Photodegradation of triazine herbicides in aqueous solutions and natural waters. J. Agric. Food Chem. 50, 6423-6427.
16. Forgacs, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A., and Zacharewski, T. R. (2012). BLTK1 murine Leydig cells: A novel steroidogenic model for evaluating the effects of reproductive and developmental toxicants. Toxicol. Sci. 127, 391-402.
17. Fraites, M. J., Cooper, R. L., Buckalew, A., Jayaraman, S., Mills, L., and Laws, S. C. (2009). Characterization of the hypothalamic-pituitary-adrenal axis response to atrazine and metabolites in the female rat. Toxicol. Sci. 112, 88-99.
18. Friedmann, A. S. (2002). Atrazine inhibition of testosterone production in rat males following peripubertal exposure. Reprod. Toxicol. 16, 275-279.
19. Gilliom, R. J., Barbash, J. E., Crawford, C. G., Hamilton, P. A., Martin, J. D., Nakagaki, N., Nowell, L. H., Scott, J. C., Stackelberg, P. E., Thelin, G. P., et al. (2006). The Quality of Our Nation's Waters: Pesticides in the Nation's Streams and Ground Water, 1992-2001 (U.S. Department of the Interior, Eds.). U.S. Geological Survey; Reston, VA.
20. Good, N. E. (1961). Inhibitors of the Hill reaction. Plant Physiol. 36, 788-803.
21. Hales, D. B., Sha, L. L., and Payne, A. H. (1987). Testosterone inhibits cAMPinduced de Novo synthesis of Leydig cell cytochrome P-450(17 alpha) by an androgen receptor-mediated mechanism. J. Biol. Chem. 262, 11200-11206.
22. Hanioka, N., Jinno, H., Tanaka-Kagawa, T., Nishimura, T., and Ando, M. (1999). In vitro metabolism of simazine, atrazine and propazine by hepatic cytochrome P450 enzymes of rat, mouse and guinea pig, and oestrogenic activity of chlorotriazines and their main metabolites. Xenobiotica. 29, 1213-1226.
23. Hayes, T. B., Collins, A., Lee, M., Mendoza, M., Noriega, N., Stuart, A. A., and Vonk, A. (2002). Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses. Proc. Natl. Acad. Sci. U. S. A. 99, 5476-5480.
24. Hayes, T. B., Khoury, V., Narayan, A., Nazir, M., Park, A., Brown, T., Adame, L., Chan, E., Buchholz, D., Stueve, T., et al. (2010). Atrazine induces complete feminization and chemical castration in male African clawed frogs (Xenopus laevis). Proc. Natl. Acad. Sci. U. S. A. 107, 4612-4617.
25. Houck, K. A., Dix, D. J., Judson, R. S., Kavlock, R. J., Yang, J., and Berg, E. L. (2009). Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J. Biomol. Screen. 14, 1054-1066.
26. Houk, C. P., Pearson, E. J., Martinelle, N., Donahoe, P. K., and Teixeira, J. (2004). Feedback inhibition of steroidogenic acute regulatory protein expression in vitro and in vivo by androgens. Endocrinology 145, 1269-1275.
27. Jin, Y., Wang, L., and Fu, Z. (2013). Oral exposure to atrazine modulates hormone synthesis and the transcription of steroidogenic genes in male peripubertal mice. Gen. Comp. Endocrinol. 184, 120-127.
28. Kananen, K., Markkula, M., el-Hefnawy, T., Zhang, F. P., Paukku, T., Su, J. G., Hsueh, A. J., and Huhtaniemi, I. (1996). The mouse inhibin alpha-subunit promoter directs SV40 T-antigen to Leydig cells in transgenic mice. Mol. Cell. Endocrinol. 119, 135-146.
29. Kaufman, D. D., and Blake, J. (1970). Degradation of atrazine by soil fungi. Soil Biol. Biochem. 2, 73-80.
30. Kucka, M., Pogrmic-Majkic, K., Fa, S., Stojilkovic, S. S., and Kovacevic, R. (2012). Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4. Toxicol. Appl. Pharmacol. 265, 19-26.
31. Laws, S. C., Ferrell, J. M., Stoker, T. E., and Cooper, R. L. (2003). Pubertal development in female Wistar rats following exposure to propazine and atrazine biotransformation by-products, diamino-S-chlorotriazine and hydroxyatrazine. Toxicol. Sci. 76, 190-200.
32. Laws, S. C., Ferrell, J. M., Stoker, T. E., Schmid, J., and Cooper, R. L. (2000). The effects of atrazine on female wistar rats: An evaluation of the protocol for assessing pubertal development and thyroid function. Toxicol. Sci. 58, 366-376.
33. Laws, S. C., Hotchkiss, M., Ferrell, J., Jayaraman, S., Mills, L., Modic, W., Tinfo, N., Fraites, M., Stoker, T., and Cooper, R. (2009). Chlorotriazine herbicides and metabolites activate an ACTH-dependent release of corticosterone in male Wistar rats. Toxicol. Sci. 112, 78-87.
34. Narotsky, M. G., Best, D. S., Guidici, D. L., and Cooper, R. L. (2001). Strain comparisons of atrazine-induced pregnancy loss in the rat. Reprod. Toxicol. 15, 61-69.
35. Payne, A. H., and Youngblood, G. L. (1995). Regulation of expression of steroidogenic enzymes in Leydig cells. Biol. Reprod. 52, 217-225.
36. Pogrmic, K., Fa, S., Dakic, V., Kaisarevic, S., and Kovacevic, R. (2009). Atrazine oral exposure of peripubertal male rats downregulates steroidogenesis gene expression in Leydig cells. Toxicol. Sci. 111, 189-197.
37. Pogrmic-Majkic, K., Fa, S., Dakic, V., Kaisarevic, S., and Kovacevic, R. (2010). Upregulation of peripubertal rat Leydig cell steroidogenesis following 24 h in vitro and in vivo exposure to atrazine. Toxicol. Sci. 118, 52-60.
38. Rahman, N. A., and Huhtaniemi, I. T. (2004). Testicular cell lines. Mol. Cell. Endocrinol. 228, 53-65.
39. Rebois, R. V. (1982). Establishment of gonadotropin-responsive murine leydig tumor cell line. J. Cell Biol. 94, 70-76.
40. Roberge, M., Hakk, H., and Larsen, G. (2004). Atrazine is a competitive inhibitor of phosphodiesterase but does not affect the estrogen receptor. Toxicol. Lett. 154, 61-68.
41. Roberge, M. T., Hakk, H., and Larsen, G. (2006). Cytosolic and localized inhibition of phosphodiesterase by atrazine in swine tissue homogenates. Food Chem. Toxicol. 44, 885-890.
42. Ross, M. K., Jones, T. L., and Filipov, N. M. (2009). Disposition of the herbicide 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (Atrazine) and its major metabolites in mice: A liquid chromatography/mass spectrometry analysis of urine, plasma, and tissue levels. Drug Metab. Dispos. 37, 776-786.
43. Saeed, A. I., Sharov, V., White, J., Li, J., Liang, W., Bhagabati, N., Braisted, J., Klapa, M., Currier, T., Thiagarajan, M., et al. (2003). TM4: A free, opensource system for microarray data management and analysis. Biotechniques 34, 374-378.
44. Sanderson, J. T. (2006). The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicol. Sci. 94, 3-21.
45. Sass, J. B., and Colangelo, A. (2006). European Union bans atrazine, while the United States negotiates continued use. Int. J. Occup. Environ. Health 12, 260-267.
46. Spanò, L., Tyler, C. R., van Aerle, R., Devos, P., Mandiki, S. N., Silvestre, F., Thomé, J. P., and Kestemont, P. (2004). Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus). Aquat. Toxicol. 66, 369-379.
47. Stoker, T. E., Guidici, D. L., Laws, S. C., and Cooper, R. L. (2002). The effects of atrazine metabolites on puberty and thyroid function in the male Wistar rat. Toxicol. Sci. 67, 198-206.
48. Stoker, T. E., Laws, S. C., Guidici, D. L., and Cooper, R. L. (2000). The effect of atrazine on puberty in male wistar rats: An evaluation in the protocol for the assessment of pubertal development and thyroid function. Toxicol. Sci. 58, 50-59.
49. Thurman, E. M., Goolsby, D. A., Meyer, M. T., and Kolpin, D. W. (1991). Herbicides in surface waters of the midwestern United States: The effect of spring flush. Environ. Sci. Tech. 25, 1794-1796.
50. Thurman, E. M., Goolsby, D. A., Meyer, M. T., Mills, M. S., Pomes, M. L., and Kolpin, D. W. (1992). A reconnaissance study of herbicides and their metabolites in surface water of the midwestern United States using immunoassay and gas chromatography/mass spectrometry. Environ. Sci. Tech. 26, 2440-2447.
51. Tillitt, D. E., Papoulias, D. M., Whyte, J. J., and Richter, C. A. (2010). Atrazine reduces reproduction in fathead minnow (Pimephales promelas). Aquat. Toxicol. 99, 149-159.
52. Tinfo, N. S., Hotchkiss, M. G., Buckalew, A. R., Zorrilla, L. M., Cooper, R. L., and Laws, S. C. (2011). Understanding the effects of atrazine on steroidogenesis in rat granulosa and H295R adrenal cortical carcinoma cells. Reprod. Toxicol. 31, 184-193.
53. Tischer, W., and Strotmann, H. (1977). Relationship between inhibitor binding by chloroplasts and inhibition of photosynthetic electron transport. Biochim. Biophys. Acta 460, 113-125.
54. Trentacoste, S. V., Friedmann, A. S., Youker, R. T., Breckenridge, C. B., and Zirkin, B. R. (2001). Atrazine effects on testosterone levels and androgendependent reproductive organs in peripubertal male rats. J. Androl. 22, 142-148.
55. Tsai, L. C., and Beavo, J. A. (2011). The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. Curr. Opin. Pharmacol. 11, 670-675.
56. USEPA, Eds. (1995). Reregistration Eligibility Decision (RED) Terbuthylazine. U.S. Environmental Protection Agency, Washington, DC.
57. USEPA (2002). The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity (D. H. Edwards, Ed.). U.S. Environmental Protection Agency, Washington, DC.
58. USEPA, Eds. (2006a). Decision Documents for Atrazine: Finalization of Interim Registration Eligibility Decision and Completion of Tolerance Reassessment and Reregistration Eligibility Process. Office of Prevention, Pesticides and Toxic Substances, Washington, DC.
59. USEPA, Eds. (2006b). Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Propazine. U.S. Environmental Protection Agency, Washington, DC.
60. USEPA, Eds. (2006c). Reregistration Eligibility Decision for Simazine. U.S. Environmental Protection Agency, Washington, DC.
61. USEPA, Eds. (2006d). Triazine Cumulative Risk Assessment. Office of Prevention, Pesticides and Toxic Substances, Washington, DC.
62. USEPA, Eds. (2012a). Common Mechanism Groups; Cummulative Exposure and Risk Assessment. Available at: http://www.epa.gov/oppsrrd1/cumulative/common_mech_groups.htmed. Accessed January 22, 2013.
63. USEPA, Eds. (2012b). ToxCastDB [Atrazine]. U.S. Environmental Protection Agency, Washington, DC.
64. Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A., and Speleman, F. (2002). Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034.
65. Victor-Costa, A. B., Bandeira, S. M., Oliveira, A. G., Mahecha, G. A., and Oliveira, C. A. (2010). Changes in testicular morphology and steroidogenesis in adult rats exposed to Atrazine. Reprod. Toxicol. 29, 323-331.
66. Zorrilla, L. M., Gibson, E. K., and Stoker, T. E. (2010). The effects of simazine, a chlorotriazine herbicide, on pubertal development in the female Wistar rat. Reprod. Toxicol. 29, 393-400.