Milestones

2000-MERIT R37 – Research on the developmental reproductive toxicity of TCDD

Research

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant which elicits a wide range of toxic responses. The developing male rat reproductive system is 100 times more sensitive to TCDD than is its adult counterpart. In utero and lactational exposure to a single low dose delays testis descent and preputial separation, decreases testis, epididymis, and accessory sex organ weights, and decreases daily sperm production, epididymal sperm reserves, and ejaculated sperm numbers throughout development. The mechanism underlying the spectrum of toxic responses elicited by TCDD is poorly understood. TCDD binds the aryl hydrocarbon receptor (AhR), which translocates to the nucleus and dimerizes with the AhR nuclear translocator (ARNT). This complex, a ligand-activated transcription factor, binds to enhancer elements (DREs) in the 5′ regulatory region of genes and activates transcription. Although none of the TCDD-responsive genes identified to date have been directly linked to toxicity, it is thought that induction or repression of transcription of genes which have not yet been identified may play a key role in eliciting toxic responses. To better understand the mechanism by which TCDD selectively impairs the developing male reproductive system, we are characterizing the ontogeny and distribution of the AhR and ARNT within this organ system. In addition, we are working to identify genes that are transcriptionally modulated by in utero and lactational TCDD exposure in the prostate and epididymis, two organs which are particularly sensitive to this treatment. The identification of a TCDD-responsive gene(s) with known function may provide insight into the mechanism by which TCDD affects growth and/or function of the prostate, epididymis, and perhaps other organs as well. Novel genes will require characterization before mechanistic hypotheses can be formulated.

Publications

• Vezina CM, Allgeier SH, Moore RW, Lin TM, Bemis JC, Hardin HA, Gasiewicz TA, Peterson RE. Dioxin Causes Ventral Prostate Agenesis by Disrupting Dorsoventral Patterning in Developing Mouse Prostate. Toxicol Sci. 2008 Sep 8. [Epub ahead of print]
• Allgeier SH, Lin TM, Vezina CM, Moore RW, Fritz WA, Chiu SY, Zhang C, Peterson RE. WNT5A selectively inhibits mouse ventral prostate development. Dev Biol. 2008 Aug 29. [Epub ahead of print]
• King Heiden, T.C., Wiecinski, P., Mangham, A., Metz, K.M., Nesbit, D., Pedersen, J.A., Hamers, R.J., Heideman, W., and Peterson, R.E.: Developmental Toxicity of Quantum Dots in Zebrafish Embryos: Shedding Light on Potential Ecotoxicological Risks of Engineered Nanoparticles. Env. Sci. Technol. . 2008. (Submitted).
• Mehta, V., Peterson, R.E., and Heideman, W.: 2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure prevents cardiac valve formation in developing zebrafish. Toxicol. Sci. : – , 2008. (In Press).
• Fritz, W.A., Lin, T.L., and Peterson, R.E.: The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates. Carcinogenesis : – , 2008. (In Press)

Mentor to METC Graduate Students:

• Joe Gawdzik (current T32 Trainee), Monica Yue (current), Sarah Allgeier (2007),
• Emmie Dengler (MS 2007), Sara Carney (2005), Amy Prasch (2004),
• Eric Andreasen (2001), Christian Abnet (1998), Michael Hornung (1998),
• James Kleeman (1998), Beth Roman (1997), Erik Zabel (1995),
• Jack VandenHeuvel (1991), Mary Walker (1991), and Mark Seefeld (1982)

Mentor to METC Post-Doc:

• Amanda Branam (2010-2012), Wayne Fritz (2003), Carl Potter (1982-1983),
• Mary Vomachka (1984-1985), Shahanara Saroya (1991-1992), Robert Tanguay
• (1996-1997), Tisha King Heiden (2006-2008), Susan Bello (2000-2001)