(R3040) Non-Nutritive Sweeteners Disturb P-Glycoprotein Function and Liver Detoxification

Laura Danner (Medical College of Wisconsin)| Stephanie Olivier-Van Stichelen (Medical College of Wisconsin)

Over the course of 9 months, nearly all pregnant women are exposed to toxins, potentially including environmental chemicals, prescription drugs, over-the-counter medicine, social substances, illicit drugs, etc. In this critical window of development, slight fetal exposures to toxic molecules can be teratogenic, leading to severe neurological and growth defects. In our previously published mouse study, we emphasized that pregnancy consumption of Non-Nutritive Sweeteners (NNS) increased fetal toxicity, including lower liver detoxification enzymes and increased intermediary metabolites.  

About 35% of adults in the United States acknowledge consuming NNS, seeking to limit sugars consumption and their adverse health effects. While increasingly prevalent in food products, three in four adults cannot identify NNS and may therefore be involuntary exposed. Although recognized as safe for the general population, NNS's effects on a specific population or period of human development are incompletely understood. According to various studies, NNS alter gut hormonal secretion, glucose absorption, appetite, kidney function, in vitro insulin secretion, and adipogenesis. Most NNS circulate in the body and are found in blood, urine, amniotic fluid, and breast milk and bind sweet receptors in target organs. Despite an apparent maternofetal transmission, little is known about NNS  consequences during pregnancy on fetal toxicity. To protect the fetus, the placenta and both mother's and fetus' livers are essential cleansing organs. Mainly, transporters such as the P-Glycoprotein (Pgp) are critical to flush foreign metabolites out of the cells and back to mother's blood circulation. In rats, Abou-Donia et al. previously demonstrated that the intestinal Pgp and various Cytochromes P450 expression varies according to sucralose consumption. Therefore we hypothesize that NNS directly impact Pgp expression and activity in the liver, increasing fetal toxicity.

Using human hepatic cells, we demonstrated that in vitro incubation of a combined sucralose and Acesulfame-K mixture significantly altered detoxification actors' expression, including aldehyde dehydrogenases and alcohol dehydrogenases, the aspartate aminotransferase (AST) and efflux transporters such as the Pgp. Individually, both sucralose and Acesulfame-K slightly decrease Pgp expression at low concentrations. On the contrary, elevated concentrations of both NNS increased Pgp expression in hepatic cells, suggesting an elevated detoxification response and often associated with multi-drug resistant cells. Finally, in both in vitro and cell-free assays, NNS inhibited Pgp-mediated drug transport. Altogether, these preliminary data suggest that NNS disturb drug metabolism by changing Pgp expression and function in vitro, and potentially participate in pregnancy complication and fetal development defects.