Dose dependent effects of green tea extracts in the skeletal development of a Down syndrome mouse model

Abstract

Down syndrome (DS) is a congenital disorder caused by trisomy of chromosome 21. The genetic imbalance results in intellectual disability, but also alters the development of different body systems, including the cranial and postcranial skeleton. To normalize altered development and to rescue skeletal phenotypes, green tea extracts enriched in EGCG (GTE‐EGCG) have been proposed for therapy. In this study, we longitudinally followed the skeletal postnatal development in a mouse model for DS, Ts65Dn, and assessed the effects of both a high dose and a low dose of pre‐ and postnatal GTE‐EGCG treatment. We administered a green tea extract containing 45% EGCG at doses of 100 or 30 mg/kg/day to pregnant Ts65Dn females, starting at embryonic day 9 and continued until adulthood. We longitudinally scanned wild‐type and Ts65Dn mice at postnatal days 3, 14 and 29 using in vivo micro‐computed tomography (µCT).Quantitative morphometric analyses showed that TS mice have a significantly different skull and mandibular shape than WT mice, as well as reduced bone mineral density (BMD) of the premaxilla and humerus bones that were detected already after birth. Moreover, Ts65Dn mice presented shorter faces, humerus and scapula, with significant differences appearing later in development, at the juvenile stage. Treatment with GTE‐EGCG generally deviated both WT and TS mice from normal growth trajectories, exacerbating some morphological anomalies, such as skull brachycephaly and reduced bone dimensions and mineral density. However, the effects of pre‐ and postnatal GTE‐EGCG administration were dose‐dependent, and low dose GTE‐EGCG treatment presented rescuing effects in facial shape. Our results underscore the complex nature of the DS phenotype and the need of further research to characterize the diverse effects of GTE‐EGCG treatment on different systems and structures and to fine‐tune dose and timing to achieve optimal safety and therapeutic potential.