Intergenerational Transmission of Low-calorie Sweeteners via Breast Milk

低热量甜味剂通过母乳的代际传递

• 批准号: 10270002
• 负责人: Allison Sylvetsky
• 金额: $ 21.99万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10270002
• 关键词: 1 year old; Accounting; Address; Area; Beverages; Biological; Body Weight; Bread; Breastfed infant; Calories; Cardiometabolic Disease; Child; Chronic; Clinical; Collaborations; Consumption; Data; Desire for food; Development; Diet; Drug Kinetics; Drug Metabolic Detoxication; Enrollment; Epidemiology; Evaluation; Exclusive Breastfeeding; Exposure to; Fiber; Food; Food Additives; Fruit; Future; Goals; Hawaiian population; Health; Heel; Hepatic; Hospitals; Hour; Human; Human Milk; Ice Cream; Impairment; Infant; Infant Health; Ingestion; Lactation; Lead; Life; Liquid substance; Low Prevalence; Maryland; Measures; Metabolic; Midwifery; Mothers; Nursing infant; Obesity; Pathway interactions; Pattern; Physiological; Plasma; Population; Potassium; Pregnancy; Prospective Studies; Public Health; Publications; Recommendation; Research Personnel; Rodent; Safety; Sampling; Services; Specific qualifier value; Supervision; Sweetening Agents; Taste preferences; Time; Toxicology; United States; United States Food and Drug Administration; Universities; Washington; Weight; Woman; base; cardiometabolic risk; cardiometabolism; chemical property; clinically relevant; consumer product; design; disorder risk; dosage; gut microbiome; gut microbiota; in utero; intergenerational; liquid chromatography mass spectrometry; microbiome composition; mother nutrition; offspring; physical property; preference; sample collection; soft drink; sugar; translational medicine; transmission process; trend

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.

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，体重和健康影响的了解非常有限，特别是在生命早期开始接触时。我们以前已经证明，三氯蔗糖和安赛蜜钾（ace-K）存在于人类母乳中，并被哺乳期婴儿摄入。三氯蔗糖和乙酰丙酮钾已经过广泛的安全性评估，并被全球众多监管机构批准为食品添加剂。虽然从毒理学的角度来看，它们的安全性是公认的，但三氯蔗糖和ace-K会引起显著的代谢效应。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，怀孕期间经常饮用含LCS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，在妊娠和/或哺乳期间暴露于生理相关剂量的三氯蔗糖和ace-K会导致后代肝脏解毒途径受损和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暴露于ace-K导致啮齿动物后代对甜味的偏好增加。鉴于早期暴露会影响心脏代谢疾病的后期发展，通过母乳长期暴露于三氯蔗糖和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使用的LCS，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（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、国立儿童医院的药理学家和临床药理学家以及马里兰州大学转化医学中心的药代动力学专家合作，进行一项严格对照的药代动力学研究。将入组48对母婴。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12小时内的预定时间点进行监督的连续样品采集，并将在随后连续三天（72小时）提供额外样品，以捕获两种LCS的整个处置情况。将使用液相色谱-质谱法（LC-MS）测量三氯蔗糖和乙酰丙酮-K浓度，与我们之前的出版物一致。生成的数据将为更大规模、更长期、前瞻性研究的设计提供信息，这些研究迫切需要在随后的R 01应用中研究人类早期生命LCS暴露的临床相关后果。这些研究对于告知目前缺乏的关于哺乳期妇女服用LCS的建议的发展至关重要。