Intergenerational Transmission of Low-calorie Sweeteners via Breast Milk

低热量甜味剂（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非常有限，特别是在生命早期就开始接触时。我们以前已经证明，三氯蔗糖和乙酰磺胺钾（ace-K）存在于人类母乳中，并被哺乳的婴儿摄入。三氯蔗糖和ace-K经过了广泛的安全评估，并被全球许多监管机构批准为食品添加剂。虽然从毒理学角度来看，三氯蔗糖和ace-K的安全性是公认的，但它们会引起显著的代谢影响。而且，越来越多的流行病学和机制证据表明，生命早期接触LCS可能会对未来的心脏代谢疾病风险产生不利影响。例如，在控制相关协变量后，在怀孕期间经常饮用低脂饮料的母亲所生的婴儿在一岁时体重较高。在啮齿类动物中，妊娠期和/或哺乳期以生理相关剂量暴露于三氯蔗糖和a - k，会导致后代肝脏解毒途径受损，肠道微生物群组成紊乱，这与肥胖和心脏代谢疾病中观察到的模式一致。此外，在子宫内或通过母乳接触到ace-K会导致啮齿动物后代对甜味的偏好增加。鉴于早期接触会影响心脏代谢疾病的后期发展，通过母乳长期接触三氯蔗糖和ace-K可能会导致心脏代谢风险的发育规划。拟议的R21项目旨在测量母体母乳和血浆中广泛消耗的lcs，三氯蔗糖和乙酰氨基酚，在预先指定的72小时内的时间点，并在单个婴儿血浆样本中（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服务中心、儿童国家医院的新生儿学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，进行一项严格控制的药代动力学研究。48对母婴将被纳入研究。在摄入含有三氯蔗糖和ace-K的饮食饮料后，母亲将留在室内，在预先确定的12小时时间点进行有监督的连续样本采集，并在随后连续三天（72小时）提供额外的样本，以捕获两种lcs的全部分布情况。将使用液相色谱-质谱法（LC-MS）测量三氯蔗糖和ace-K浓度，与我们之前的出版物一致。所产生的数据将为设计更大、更长期、前瞻性的研究提供信息，这些研究迫切需要在随后的R01应用中调查人类早期接触LCS的临床相关后果。这些研究对于制定目前缺乏的关于哺乳期妇女食用LCS或反对LCS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.