Long-term consequences of prenatal saccharin exposure: evidence of sex-specific molecular programing in the prefrontal cortex and behavior of adolescent rats

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IntroductionCertain events that occur in early life, such as changes in nutrition, can induce structural and functional modifications in brain development, leading to behavioral programing in the offspring. These effects depend on the timing, intensity, and duration of exposure, and may contribute to chronic disorders in adulthood. Artificial non-nutritive sweeteners (NNS), such as saccharin, have recently been proposed as potential developmental disruptors. Saccharin consumption during pregnancy is discouraged, as it can cross the placenta and accumulate in the fetus.MethodsIn this study, pregnant rats were administered 0.1% saccharin in drinking water throughout gestation. On postnatal day 21, offspring were assessed for behavioral outcomes using the open field and elevated plus maze tests. During sacrifice, the prefrontal cortex of the animals was collected.ResultsGestational saccharin exposure induced sex-specific behavioral changes: offspring of saccharin-consuming mothers spent more time in the center of the arena, while only females showed increased open-arm entries. These alterations were coupled with changes in prefrontal endocannabinoid, glutamatergic, and GABAergic gene expression. Only saccharin-exposed male pups showed significant alterations in Dagla, Daglb and Gpr55 along with increased expression of glutamatergic receptors (Grin1, Grin2a, Grin2c, Gria1, Grm3). Females exhibited reduced expression of GABAergic receptor genes (Gabrg2, Gabbr2), and significant changes in the phosphorylated expression of proteins involved in the insulin pathway (IRS-1, PI3K, AKT, GSK3b).DiscussionThese findings suggest that developmental NNS exposure produces long-lasting behavioral outcomes in offspring, which are linked to alterations in multiple signaling pathways within the prefrontal cortex.

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Pacheco-Sánchez, B., Pacheco-Sánchez, B., López-Merchán, R., Rubio, P., García-Martos, P., Suárez, J., Suárez, J., Sanjuan, C., Rubio, L., Rubio, L., Martín-de-Las-Heras, S., Martín-de-Las-Heras, S., de Fonseca, F. R., de Fonseca, F. R., Alén, F., de Ceglia, M., de Ceglia, M., Rivera, P., & Rivera, P. (2026). Long-term consequences of prenatal saccharin exposure: evidence of sex-specific molecular programing in the prefrontal cortex and behavior of adolescent rats. Frontiers in Behavioral Neuroscience. https://doi.org/10.3389/fnbeh.2026.1815692