Project Summary:
For decades, non-nutritive sweeteners (NNSs) have been used as food additives in the United States and are found ubiquitously in diet foods, beverages, medicines, lip balm, chewing gum, tabletop sweeteners, and yogurts. Sucralose (name brand: Splenda) is commonly used, with 600x the sweetness power of table sugar and negligible caloric input.
Following toxicology studies in animal models, the FDA defined a maximum acceptable daily intake (ADI) for all NNSs, including sucralose (e.g., 5 mg/kg of body weight/day), which for an adult of 70 kg, represents roughly one large bottle of diet soda.
While advertised in weight loss programs, the effectiveness of NNSs for successful weight loss and their impact on blood sugar control has been controversial, casting doubts over their potential beneficial effects. Indeed, in 2023, the World Health Organization released guidelines to not use NNSs for weight loss and called for more research to investigate the role of Aspartame in cancers. Additionally, researchers worldwide have demonstrated the harmful effects of NNSs, including changes in glucose absorption and microbiome. Thus, despite proper approval, novel deleterious effects of NNSs are still being discovered in various conditions or specific periods of development.
This project’s research team has demonstrated NNSs’s adverse effect on offspring when mothers are fed sucralose during pregnancy. They also found that this effect was partly due to sucralose inhibiting the key drug and xenobiotic transporter P-glycoprotein (PGP). They have also reviewed the existing literature on NNS consumption in pregnancy and estimated that more than 30% of pregnant women consume NNSs daily.
P-Glycoprotein (PGP) in the Human Placenta is critical to preventing fetal exposure to toxic compounds.
Because most drugs and xenobiotics can passively cross the placenta and harm the fetus, the villous placental trophoblast layer on the maternal side compensates for the underdeveloped fetal liver and expresses efflux ATP-binding cassette (ABC) transporters that return toxic compounds and fetal waste to the mother’s blood. This application focuses on one of the most relevant ABC transporters in the placenta: the ABCB1/MDR (multidrug resistance)1/PGP (P-glycoprotein), expressed on syncytiotrophoblasts facing maternal blood. Inhibition or deletion of these transporters leads to increased fetal toxic exposures and increased congenital disabilities, including heart and septal defects. Therefore, it is essential to identify substances that alter PGP function to prevent harmful exposure to the fetus. During pregnancy, the use of drugs, including PGP substrate, is increasingly common and includes antihypertensive and antidiabetic medications.
Based on the project team’s preliminary data, they have shown that sucralose is a PGP inhibitor in liver and kidney cells.
Furthermore, it is estimated that about 30% of pregnant women consume NNS daily, either voluntarily 10 or involuntarily, through NNS-containing foods and beverages, increasing the probability of pregnant mothers encountering both toxic and NNS exposures.
This project will test the hypothesis that maternal sucralose consumption increases the retention of PGP substrate compound in the fetal compartment.
This study is the first assessment of NNS consumption in pregnancy in Wisconsin and only the second one in the U.S. It is also the first clinical study on the impact of sucralose on detoxification transporters.
The project will be a key steppingstone for this research program. Indeed, other ABC transporters show large substrate overlap with PGP and, therefore, are also potentially inhibited by sucralose. Furthermore, we will also investigate the impact of other common NNS, such as acesulfame-K or the trending Stevia, on the various ABC transporters. With no guidelines in place for NNS consumption during pregnancy, evaluation of the impact of NNS on placental detoxification efficiency will be imperative to define, if necessary, new safe limits of NNS consumption specific to pregnancy.
The discovery of clinically relevant interaction between sucralose consumption and PGP will also impact many scientific fields beyond obstetrics, including cancer- or HIV-related research, in which PGP (also known as multi-drug resistant receptor 1 in the cancer field) has been associated with drug resistance.