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: 10488236
• 负责人: Allison Sylvetsky
• 金额: $ 25.18万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488236
• 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; 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极为有限，特别是当生命早期就开始接触低热量甜味剂时。我们之前已经证明，三氯蔗糖和安赛蜜钾 (ace-K) 存在于人母乳中，并被哺乳婴儿摄入。三氯蔗糖和 ace-K 经过了广泛的安全评估，并被全球众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 的安全性已得到证实，但它们会引起惊人的代谢效应。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，在怀孕期间经常饮用含有 LCS 的饮料的母亲所生的婴儿在一岁时体重会较高。在啮齿类动物中，怀孕和/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并扰乱肠道微生物群组成，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 ace-K 会导致啮齿动物后代对甜味的偏好增强。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展规划。拟议的 R21 项目旨在测量母乳和血浆中广泛消耗的 LCS、三氯蔗糖和 ace-K，在 72 小时内预先指定的时间点以及婴儿血浆的单个样本中（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严格控制的药代动力学研究。将登记 48 名母婴组合。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 12 小时内的预定时间点进行监督连续样本采集，并将在随后的连续三天（72 小时）提供额外样本，以了解两种 LCS 的全部处置情况。三氯蔗糖和 ace-K 浓度将使用液相色谱-质谱法 (LC-MS) 进行测量，与我们之前的出版物一致。生成的数据将为设计更大规模、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接触 LCS 的临床相关后果。此类研究对于制定目前缺乏支持或反对哺乳期妇女摄入 LCS 的建议至关重要。