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Abstract
Trisomy of human chromosome 21 (Down syndrome, DS) alters development of multiple organ systems, including the face and underlying skeleton. Besides causing stigmata, these facial dysmorphologies can impair vital functions such as hearing, breathing, mastication, and health. To investigate the therapeutic potential of green tea extracts containing epigallocatechin-3-gallate (GTE-EGCG) for alleviating facial dysmorphologies associated with DS, we performed an experimental study with continued pre- and postnatal treatment with two doses of GTE-EGCG supplementation in a mouse model of DS, and an observational study of children with DS whose parents administered EGCG as a green tea supplement. We evaluated the effect of high (100 mg/kg/day) or low doses (30 mg/kg/day) of GTE-EGCG, administered from embryonic day 9 to post-natal day 29, on the facial skeletal development in the Ts65Dn mouse model. In a cross-sectional observational study, we assessed the facial shape in DS and evaluated the effects of self-medication with green tea extracts in children from 0 to 18 years old. The main outcomes are 3D quantitative morphometric measures of the face, acquired either with micro-computed tomography (animal study) or photogrammetry (human study). The lowest experimentally tested GTE-EGCG dose improved the facial skeleton morphology in a mouse model of DS. In humans, GTE-EGCG supplementation was associated with reduced facial dysmorphology in children with DS when treatment was administered during the first 3 years of life. However, higher GTE-EGCG dosing disrupted normal development and increased facial dysmorphology in both trisomic and euploid mice. We conclude that GTE-EGCG modulates facial development with dose-dependent effects. Considering the potentially detrimental effects observed in mice, the therapeutic relevance of controlled GTE-EGCG administration towards reducing facial dysmorphology in young children with Down syndrome has yet to be confirmed by clinical studies.
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1 University of Central Florida, Department of Anthropology, Orlando, USA (GRID:grid.170430.1) (ISNI:0000 0001 2159 2859); Indiana University Robert H. McKinney School of Law, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919)
2 KU Leuven, Department of Imaging and Pathology, Biomedical MRI Unit/Molecular Small Animal Imaging Center (MoSAIC), Flanders, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884)
3 Universitat de Barcelona (UB), GREAB-Research Group in Biological Anthropology, Department of Evolutionary Biology, Ecology and Environmental Sciences (BEECA), Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247)
4 The Barcelona Institute of Science and Technology, Center for Genomic Regulation (CRG), Barcelona, Spain (GRID:grid.473715.3) (ISNI:0000 0004 6475 7299); Universitat Pompeu Fabra (UPF), Barcelona, Spain (GRID:grid.5612.0) (ISNI:0000 0001 2172 2676); CIBER Rare Diseases-CIBERER, Barcelona, Spain (GRID:grid.5612.0)
5 Universitat Ramon Llull, GTM-Grup de Recerca en Tecnologies Mèdia, Barcelona, Spain (GRID:grid.6162.3) (ISNI:0000 0001 2174 6723)
6 The Barcelona Institute of Science and Technology, Center for Genomic Regulation (CRG), Barcelona, Spain (GRID:grid.473715.3) (ISNI:0000 0004 6475 7299); Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain (GRID:grid.425902.8) (ISNI:0000 0000 9601 989X); EMBL Barcelona, European Molecular Biology Laboratory, Barcelona, Spain (GRID:grid.495034.f)
7 IMIM-Hospital del Mar Medical Research Institute, Integrative Pharmacology and Systems Neuroscience, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); CIBER Physiopathology of Obesity and Nutrition-CIBERobn, Madrid, Spain (GRID:grid.20522.37)
8 Universitat de Barcelona (UB), GREAB-Research Group in Biological Anthropology, Department of Evolutionary Biology, Ecology and Environmental Sciences (BEECA), Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); The Barcelona Institute of Science and Technology, Center for Genomic Regulation (CRG), Barcelona, Spain (GRID:grid.473715.3) (ISNI:0000 0004 6475 7299); EMBL Barcelona, European Molecular Biology Laboratory, Barcelona, Spain (GRID:grid.495034.f)