Maternal rebaudioside A and acesulfame-K exposure reprograms offspring submandibular gland development in a sex-dependent manner.

Non-nutritive sweeteners (NNS) are increasingly consumed during pregnancy, yet their distinct metabolic fates obscure a unified mechanism for developmental programming. We tested whether maternal NNS exposure acts upstream of metabolism by targeting the oral-submandibular gland (SMG) axis. Wistar Han dams received saccharin, acesulfame-K or rebaudioside A from gestation day 0 through lactation. Offspring were followed from weaning to adulthood and assessed by repeated two-bottle choice tests, meal-microstructure metrics, SMG histomorphometry and targeted transcript profiling. Maternal exposure did not alter litter outcomes, growth, fasting glycaemia or detectable sweet preference under the present high-preference paradigm. By contrast, rebaudioside A and acesulfame-K remodelled SMG architecture, reducing granular convoluted tubule representation, expanding striated ducts and attenuating sexual dimorphism. Unsupervised clustering of expression profiles separated rebaudioside A/acesulfame-K from control/saccharin glands and revealed coordinated suppression of trophic factors (Egf and kallikrein transcripts) with selective induction of amylase or cystatin genes, without evidence of an inflammatory transcriptional signature. These findings support sex-dependent, structural and transcriptional remodeling of the SMG after perinatal NNS exposure. However, because salivary protein output and downstream physiology were not measured, the SMG should be viewed here as a candidate pre-metabolic target rather than proof of a defined causal mechanism."