Intergenerational Transmission of Low-calorie Sweeteners via Breast Milk

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Low-calorie sweetener (LCS) consumption is highly prevalent among lactating women, yet the current understanding of LCS effects on diet, weight, and health is extremely limited, especially when exposure begins early in life. We have previously demonstrated that sucralose and acesulfame-potassium (ace-K) are present in human breast milk and are ingested by nursing infants. Sucralose and ace-K have undergone extensive safety evaluations and are approved as food additives by numerous regulatory bodies worldwide. While their safety is well-established from a toxicological perspective, sucralose and ace-K elicit striking metabolic effects. And, accumulating epidemiologic and mechanistic evidence demonstrates that early life LCS exposure may adversely impact future cardiometabolic disease risk. For example, infants born to mothers who regularly consume beverages with LCSs during pregnancy are of higher body weight at one year of age, after controlling for relevant covariates. In rodents, sucralose and ace-K exposure during pregnancy and/or lactation, at physiologically relevant dosages, results in impaired hepatic detoxification pathways and disturbed gut microbiota composition in the offspring, consistent with patterns observed in obesity and cardiometabolic diseases. Furthermore, exposure to ace-K in utero or via breast milk leads to a heightened preference for sweetness in rodent offspring. Given that early exposures impact later development of cardiometabolic disease, chronic sucralose and ace-K exposure via the breast milk may lead to developmental programming of cardiometabolic risk. The proposed R21 project aims to measure the widely consumed LCSs, sucralose and ace-K, in maternal breast milk and plasma, at pre-specified, time-points over the course of 72 hours, and in a single sample of infants’ plasma (analyzed using a population pharmacokinetics approach). We will perform a tightly controlled, pharmacokinetic study in collaboration with the George Washington University Midwifery Service, a neonatologist and clinical pharmacologist at Children’s National Hospital, and experts in pharmacokinetics at the Center for Translational Medicine at the University of Maryland. Forty-eight mother- infant dyads will be enrolled. Following ingestion of a diet beverage containing sucralose and ace-K, mothers will remain in-house for supervised serial sample collection at pre-determined time points over 12 hours, and will provide additional samples on three subsequent consecutive days (72 hours) in order to capture the entire disposition of both LCSs. Sucralose and ace-K concentrations will be measured using liquid chromatography- mass spectrometry (LC-MS), consistent with our prior publications. The data generated will inform the design of larger, longer term, prospective studies urgently needed to investigate clinically-relevant consequences of early life LCS exposure in humans in a subsequent R01 application. Such studies are critical to inform the development of currently lacking recommendations for or against LCS consumption in lactating women.