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Peroxisome proliferators disrupt retinoic acid receptor alpha signaling in the testis
Jannette M Dufour1, My-Nuong Vo, Nandini Bhattacharya
1School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA.
Abstract:
Peroxisome proliferators include a diverse group of chemicals, some of which have been demonstrated to be testicular toxicants. However, the mechanism by which peroxisome proliferators, such as phthalates, cause testicular damage is not clear. It is known that retinoic acid receptor alpha (RARalpha) and its retinoic acid ligand, the acid form of vitamin A, are required for spermatogenesis. It has been demonstrated that the absence of RARalpha gene or vitamin A in the animal leads to testis degeneration and sterility. Therefore, any compound that disrupts the action of vitamin A in the testis could potentially be damaging to male fertility. The current investigation examined a novel hypothesis that a mechanism of degeneration by peroxisome proliferators in the testis is due, in part, to disruption of the critical RARalpha signaling pathway. We show that peroxisome proliferators were able to disrupt the retinoic acid-induced nuclear localization of RARalpha and the retinoic acid-stimulated increase in transcriptional activity of a retinoic acid-responsive reporter gene in Sertoli cells. Concomitantly, peroxisome proliferators increased the nuclear localization of PPARalpha and the transcriptional activity of a peroxisome proliferator-responsive reporter gene in these cells. These results indicate that peroxisome proliferators can indeed shift the balance of nuclear localization for RARalpha and PPARalpha, resulting in deactivation of the critical RARalpha transcriptional activity in Sertoli cells.
Insights
Peroxisome proliferators disrupt male fertility by interfering with vitamin A signaling in Sertoli cells. This leads to the deactivation of retinoic acid receptor alpha (RARalpha), crucial for spermatogenesis.
Area of Science:
- Toxicology
- Reproductive Biology
- Molecular Endocrinology
Background:
- Peroxisome proliferators are diverse chemicals, some identified as testicular toxicants.
- The precise mechanism of peroxisome proliferator-induced testicular damage remains unclear.
- Retinoic acid receptor alpha (RARalpha) and vitamin A are essential for spermatogenesis, with their absence causing sterility.
Purpose of the Study:
- To investigate the hypothesis that peroxisome proliferators cause testicular degeneration by disrupting the RARalpha signaling pathway.
- To elucidate the molecular mechanisms underlying peroxisome proliferator-induced male reproductive toxicity.
Main Methods:
- Utilized Sertoli cells to examine the effects of peroxisome proliferators on nuclear localization and transcriptional activity of RARalpha and PPARalpha.
- Employed reporter gene assays to quantify retinoic acid-responsive and peroxisome proliferator-responsive transcriptional activity.
Main Results:
- Peroxisome proliferators disrupted retinoic acid-induced nuclear localization of RARalpha in Sertoli cells.
- These compounds decreased retinoic acid-stimulated transcriptional activity of RARalpha-responsive reporter genes.
- Concurrently, peroxisome proliferators increased nuclear localization and transcriptional activity of PPARalpha.
Conclusions:
- Peroxisome proliferators disrupt the balance of nuclear receptors RARalpha and PPARalpha in Sertoli cells.
- This disruption leads to the deactivation of RARalpha transcriptional activity, potentially explaining their testicular toxicity.
- Findings suggest a novel mechanism for male infertility linked to environmental chemical exposure.