Intergenerational Transmission of Low-calorie Sweeteners via Breast Milk

低卡路里甜味剂(LCS)的消费在哺乳期妇女中非常普遍，但目前对LCS对饮食、体重和健康的影响的了解极其有限，特别是在生命早期开始接触的情况下。我们之前已经证明，三氯蔗糖和安赛蜜-钾(ACE-K)存在于人类母乳中，并被哺乳婴儿摄入。三氯蔗糖和ACE-K已经通过了广泛的安全性评估，并被世界各地的许多监管机构批准为食品添加剂。虽然从毒理学的角度来看，三氯蔗糖和ACE-K是安全可靠的，但它们会引起显著的代谢效应。而且，越来越多的流行病学和机械学证据表明，早期接触LCS可能会对未来的心脏代谢性疾病风险产生不利影响。例如，母亲在怀孕期间经常饮用含LCSs的饮料，在控制了相关协变量后，婴儿在一岁时的体重较高。在啮齿动物中，在怀孕和/或哺乳期暴露于三氯蔗糖和ACE-K，在生理上相关的剂量，会导致子代肝脏解毒途径受损和肠道微生物区系紊乱，这与肥胖和心脏代谢疾病中观察到的模式一致。此外，在子宫中或通过母乳暴露于ACE-K会导致啮齿动物后代对甜味的高度偏好。鉴于早期接触会影响心脏代谢性疾病的后期发展，通过母乳长期接触三氯蔗糖和ACE-K可能导致心脏代谢风险的发育规划。拟议的R21项目旨在测量母亲母乳和血浆中广泛消费的LCSs、三氯蔗糖和ACE-K，在72小时内的预定时间点，以及婴儿血浆的单一样本中(使用群体药代动力学方法进行分析)。我们将与乔治华盛顿大学助产士、国立儿童医院的新生儿专家和临床药理学家以及马里兰大学转化医学中心的药代动力学专家合作，进行一项严格受控的药代动力学研究。48名母婴双胞胎将被录取。在摄入含有三氯蔗糖和ACE-K的减肥饮料后，母亲们将留在室内，在预定的时间点进行超过12小时的监督连续样本采集，并在随后的三天(72小时)提供额外的样本，以捕获两种LCS的全部处置情况。三氯蔗糖和ACE-K的浓度将使用液质联用(LC-MS)进行测量，这与我们之前的出版物一致。所产生的数据将为设计更大的、更长期的前瞻性研究提供信息，这些研究迫切需要在随后的R01应用中调查人类早期生命LCS暴露的临床相关后果。这类研究对于发展目前缺乏支持或反对哺乳妇女摄入低碳水化合物的建议至关重要。

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.