title: Enhanced TGF-beta1 is involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced oxidative stress in C57BL/6 mouse testis.
abstract: 2,3,7,8-Tedtrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic endocrine disruptors and has been reported to induce oxidative stress in the reproductive organs. However, the mechanism by which TCDD induces oxidative stress is unclear. The aim of this study is to examine the role of the general cytokine, TGF-beta1, in TCDD-induced oxidative stress in the male reproductive system. To examine the effect of TCDD on antioxidant enzyme activity, we administered TCDD orally to C57BL/6 mice at 1 microgkg/day for 4 days. Using Smad2-siRNA, we examined the involvement of Smad and non-Smad pathways in TCDD-induced oxidative stress. We also measured the mRNA levels of typical antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and analyzed the activation of TGF-beta1, and the downstream signals, Smad2, Smad4, transcription factors (c-Jun, ATF3), and three major MAPKs (JNK, ERK, p38). After TCDD treatment, the mRNA levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were significantly decreased. In addition, TGF-beta1 activity increased and the receptor-activated protein, Smad2, was activated while Smad4 was not. The levels of major transcription factors, c-Jun and ATF3, and the regulator of these transcription factors, MAPK, were also increased by TCDD administration. The mRNA levels of the 3 antioxidant enzymes in the Smad2-siRNA and TCDD co-treated group were higher than that of the TCDD-only treated group but still decreased when compared to control. C-Jun and ATF3 levels were also increased in Smad2-siRNA and TCDD co-treated testes compared to control. However, the levels of c-Jun and ATF3 were lower than those in the group treated with TCDD only. Of the three MAPKs which showed increase in expression after TCDD treatment, p38 was the only one that showed a decrease with Smad2 inhibition, while both ERK and JNK expression were unaffected. In conclusion, we found that the activated TGF-beta1-Smad pathway is involved in TCDD-induced oxidative stress. Furthermore, the effects of TCDD on the testes are caused by the coordinated action of both Smad and non-Smad pathways.
authors.affiliation: Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Jin
authors.forename: Chang Hee
authors.initials: CH
authors.lastname: Hong
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Han
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D010088:Oxidoreductases