Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary

2,3,7,8-TCDD (TCDD) is a reproductive toxicant and endocrine disruptor in nearly all vertebrates, yet the mechanisms by which TCDD induces these reproductive alterations have not been fully characterized. Fish are among the most sensitive vertebrates to the toxic effects of TCDD, and even subtle physiologic changes induced by TCDD can impair reproduction. Previously, we have shown that chronic, sub-lethal exposure to TCDD decreased reproductive capacity, reduced serum estradiol and vitellogenin concentrations, and altered follicular development. Here we investigate the transcriptional changes in zebrafish ovary as they relate to observed attenuated estradiol concentrations and ovarian development. We used quantitative RT-PCR to assess TCDDs effects on the expression of several candidate genes important in the regulation of follicular development and steroidogenesis. Additionally, global changes in gene expression in the ovary caused by TCDD exposure were identified using Affymetrix Gene Chip Analysis. Our data suggest that TCDD may inhibit follicle maturation via attenuated gonadotropin responsiveness and/or depressed estradiol biosynthesis. Additionally, genes involved in glucose and lipid metabolism, regulation of transcription, and immune function were dysregulated by at least 2-fold suggesting that TCDD alters various integrated networks of signaling pathways. Approximately 89% of dysregulated transcripts contain putative AHR response elements (AHRE) within 5kb upstream of the predicted transcriptional start site suggesting ovarian toxicity is AHRE driven. Furthermore, approximately 49% of dysregulated transcripts contain putative estrogen response elements (ERE) suggesting that dysregulation of estrogen-responsive genes may also contribute to TCDD-induced attenuated follicular development. Patterns in gene expression were correlated with putative EREs and AHREs, and suggest that impacts on the regulation of transcription may play a large role in TCDDs ovarian toxicity. Taken together, these data illustrate the complexity of TCDDs ovarian toxicity.

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Heiden TC, Struble CA, Rise ML, Hessner MJ, Hutz RJ, Carvan MJ 3rd