Abstract
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by diminished degradation of the glycosaminoglycans heparan sulfate (HS) and dermatan sulfate (DS). Patients present with a variety of symptoms, including severe skeletal disease. Current therapeutic strategies have only limited effects on bone disease. The isoflavone genistein has been studied as a potential therapy for the mucopolysaccharidoses because of its putative ability to inhibit GAG synthesis and subsequent accumulation. Cell, animal, and clinical studies, however, showed variable outcomes. To determine the effects of genistein on MPS I-related bone disease, wild-type (WT) and MPS I mice were fed a genistein-supplemented diet (corresponding to a dose of approximately 160 mg/kg/day) for 8 weeks. HS and DS levels in bone and plasma remained unchanged after genistein supplementation, while liver HS levels were decreased in genistein-fed MPS I mice as compared to untreated MPS I mice. Unexpectedly, genistein-fed mice exhibited significantly decreased body length and femur length. In addition, 60% of genistein-fed MPS I mice developed a scrotal hernia and/or scrotal hydrocele, manifestations, which were absent in WT or untreated MPS I mice. In contrast to studies in MPS III mice, our study in MPS I mice demonstraes no beneficial but even potential adverse effects of genistein supplementation. Our results urge for a cautious approach on the use of genistein, at least in patients with MPS I.
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Acknowledgments
We thank Ronald Wanders, Henk van Lenthe, Wim Kulik, and Jos Ruijter for technical assistance and helpful discussions. We thank Axcentua for providing genistein. This work was financially supported by the foundation “Steun Emma Kinderziekenhuis AMC” and the “WE Foundation.”
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Communicated by: Ashok Vellodi
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Take-Home Message
Genistein-fed mucopolysaccharidosis type I mice exhibit scrotal hernias/hydroceles and decreased skeletal growth, emphasizing the need for caution when using genistein in patients with MPS.
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Sandra Kingma, Tom Wagemans, Lodewijk IJlst, Jurgen Seppen, Marion Gijbels, Frits Wijburg, and Naomi van Vlies declare that they have no conflicts of interest.
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This article does not contain any studies with human subjects performed by any of the authors.
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All institutional and national guidelines for the care and use of laboratory animals were followed.
Contributions of the Individual Authors
Sandra D.K. Kingma: designing, conducting, reporting, and revising the work described in the article.
Tom Wagemans: conducting the work described in the article.
Lodewijk IJlst: designing and revising the work described in the article.
Jurgen Seppen: conducting and revising the work described in the article.
Marion J.J. Gijbels: conducting and revising the work described in the article.
Frits A. Wijburg: designing, reporting, and revising the work described in the article.
Naomi van Vlies: designing, reporting, and revising the work described in the article.
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Kingma, S.D.K. et al. (2015). Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 23. JIMD Reports, vol 23. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_432
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DOI: https://doi.org/10.1007/8904_2015_432
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