Maternal thyroid axis perturbation following gestational exposure to a syringetin-3-O-glucoside-enriched Syzygium cumini seed isolate in Sprague Dawley rats: Evidence for a sodium/iodide symporter-directed mechanism.

Syzygium cumini seed preparations are clinically used during pregnancy for gestational hyperglycaemia, yet the developmental safety of any defined flavonoid glycoside of the species has not been examined in a mammalian model. We examined whether oral exposure to a chemically standardised, syringetin-3-O-glucoside (S3G)-enriched isolate at 0, 20, 40, or 80 mg/kg/day from gestational day 5 through 19 perturbs the maternal-fetal thyroid axis in Sprague Dawley (SD) rats. Maternal serum TSH rose dose-dependently; total T4, T3, and rT3 declined; thyroglobulin rose six-fold at the high dose; and thyroid histopathology progressed through follicular hyperplasia and colloid depletion to solid cellular sheets. Reproductive indices and fetal body weight were unaffected, and fetal findings were limited to minor variations. RNA-sequencing of maternal thyroid identified 930 differentially expressed genes, with compensatory upregulation of Tpo, Slc5a5/NIS, Tg, and Iyd. The isolate inhibited iodide uptake at sub-cytotoxic concentrations in rat FRTL-5 thyrocytes (IC50 18.42 μg/mL) and was ∼3.4-fold less potent in human Nthy-ori 3-1 cells (IC50 62.15 μg/mL). Intrathyroidal syringetin, the bioavailable aglycone, reached 440.0 ± 36.7 nM, and molecular docking prioritised NIS among favourably scored targets. These convergent findings localise the lesion to post-transcriptional NIS inhibition and distinguish S3G from the classic flavonoid-thyroid peroxidase inhibitor class.