Early life aflatoxin B1 exposure and epigenetic programming in Nigerian Newborns

尼日利亚新生儿生命早期黄曲霉毒素 B1 暴露和表观遗传编程

• 批准号: 10706327
• 负责人: Oluwakemi Anuoluwapo Rotimi
• 金额: $ 8.68万
• 依托单位: COVENANT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706327
• 关键词: Adolescence; Aflatoxin B1; Aflatoxins; Africa; Africa South of the Sahara; African; Animal Feed; Area; Aspergillus; Binding; Biological Products; Birth; Blood; Blood specimen; Breast Feeding; Cancer Etiology; Carcinogens; Cessation of life; Chemical Agents; Child; Country; Cytochrome P450; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Disease susceptibility; Environment; Environmental Exposure; Environmental Pollutants; Enzymes; Epigenetic Process; Exposure to; First Pregnancy Trimester; Food; Food Contamination; Gene Expression; Gene Expression Profiling; Goals; Grain; Hepatotoxicity; Heritability; High Pressure Liquid Chromatography; Hospitals; Human; Incidence; Life; Link; Liver; Lysine; Malignant Neoplasms; Malignant neoplasm of liver; Membrane; Methylation; Modification; Molds; Molecular; Mothers; Mutation; Newborn Infant; Nigeria; Nigerian; Nucleic Acids; Nutrient; Onset of illness; Organ; Placenta; Plasma; Play; Poison; Polymerase Chain Reaction; Population; Predisposition; Pregnancy; Pregnant Women; Primary carcinoma of the liver cells; Process; Public Health; RNA; Regulation; Research; Research Personnel; Risk; Rodent; Role; Route; Rural; Testing; Third Pregnancy Trimester; Time; Toxic Environmental Substances; Tumor Suppressor Genes; Umbilical Cord Blood; Weaning; Woman; adduct; bisulfite; carcinogenesis; cohort; early childhood; early experience; early life exposure; early onset; epigenetic marker; epigenome; in utero; infancy; insight; liver development; prenatal exposure; pyrosequencing; recruit; urban area

Project Summary Aflatoxin B1 (AFB1) is a major cause of hepatocellular carcinoma (HCC) in Sub Saharan Africa, where aflatoxin contamination is common. In these areas, exposure to AFB1 starts early in life through maternal routes during pregnancy. Populations in these countries experience early onset of HCC, and in utero AFB1 exposure may be a contributing factor to the onset of the disease. Exposures to nutrients, toxic chemicals and biological agents during gestation and early childhood play a critical role in determining susceptibility to diseases later in life. The mechanism of early onset of carcinogenesis may include epigenetic changes in tumor suppressor genes (TSGs). Our previous rodent study showed that in utero AFB1 exposure can alter DNA methylation of TSGs. It is necessary to investigate the impact of in utero AFB1 exposure on methylation and expression of TSGs in humans. The overall hypothesis is that in utero AFB1 exposure will differentially methylate TSGs, and this methylation will inversely correlate with the expression of the TSGs. The overall objective of this project is to establish a pre-birth cohort and study the association between in utero exposure to AFB1 and DNA methylation changes in TSGs of newborns in Nigeria. To achieve this, we will recruit pregnant women in the first trimester from two Nigerian hospitals serving a rural and an urban area. We hypothesize that Nigerian women will have a range of AFB1 exposure levels detectable in plasma. We hypothesize that in utero AFB1 exposure will be associated with differential methylation and expression of TSGs in cord blood samples. The specific aims of this project are to 1) determine the levels of AFB1 in the plasma of pregnant women, using HPLC, collected during the first and third trimesters of pregnancy, and newborns (cord blood), 2) assess the DNA methylation of TSGs in the cord blood via pyrosequencing and to determine if AFB1 concentration is associated with the levels of DNA methylation, 3) determine the expression of TSGs in the cord blood using real-time quantitative PCR and determine if gene expression is inversely correlated with methylation changes in the TSGs. The findings of this study will provide data on AFB1 exposure among pregnant women in Nigeria and its subsequent effect on the epigenome of newborns. This data will provide direction for future research developing epigenetic biomarkers of AFB1 exposure as well as investigating epigenetic mechanisms associated with prenatal exposure to AFB1 and the risk of developing liver cancer in Africa. This research direction may provide insight into reducing the incidence of this cancer in sub-Saharan Africa, especially in countries such as Nigeria, where AFB1 exposure is highly prevalent. Through this research, the PI will become a leader in environmental epigenetics, studying how early-life exposure to environmental contaminants of Public Health concerns in Africa contributes to the development of non- communicable diseases later in life.

项目概要 黄曲霉毒素 B1 (AFB1) 是撒哈拉以南非洲地区肝细胞癌 (HCC) 的主要原因，其中 黄曲霉毒素污染很常见。在这些地区，AFB1 的暴露在生命早期就开始通过母亲 怀孕期间的路线。这些国家的人群患有 HCC 早期发病，并且在子宫内出现 AFB1 接触可能是导致疾病发作的一个因素。暴露于营养物质、有毒化学物质和 妊娠期和幼儿期的生物制剂在确定对病毒的易感性方面发挥着关键作用 以后生活中的疾病。早期发生癌变的机制可能包括表观遗传变化 肿瘤抑制基因（TSG）。我们之前的啮齿动物研究表明，子宫内 AFB1 暴露会改变 TSG 的 DNA 甲基化。有必要研究宫内AFB1暴露对甲基化的影响 以及 TSG 在人类中的表达。总体假设是，子宫内 AFB1 暴露会存在差异 TSG 甲基化，这种甲基化与 TSG 的表达呈负相关。整体 该项目的目标是建立一个出生前队列并研究子宫内暴露之间的关联 尼日利亚新生儿 TSG 中 AFB1 和 DNA 甲基化的变化。为了实现这一目标，我们将招募 来自尼日利亚农村和城市地区两家医院的妊娠早期孕妇。我们 假设尼日利亚妇女血浆中可检测到一定范围的 AFB1 暴露水平。我们 假设子宫内 AFB1 暴露与差异甲基化和表达有关 脐带血样本中的 TSG。该项目的具体目标是 1) 确定 AFB1 的水平 使用 HPLC 收集妊娠早期和晚期的孕妇血浆，以及 新生儿（脐带血），2) 通过焦磷酸测序评估脐带血中 TSG 的 DNA 甲基化，并 确定 AFB1 浓度是否与 DNA 甲基化水平相关，3) 确定表达 使用实时定量 PCR 检测脐带血中的 TSG，并确定基因表达是否呈反比 与 TSG 的甲基化变化相关。这项研究的结果将提供 AFB1 的数据 尼日利亚孕妇的暴露及其对新生儿表观基因组的后续影响。这 数据将为未来开发 AFB1 暴露的表观遗传生物标志物以及 研究与产前暴露于 AFB1 相关的表观遗传机制以及发生风险 非洲肝癌。该研究方向可能有助于降低这种癌症的发病率 撒哈拉以南非洲地区，尤其是尼日利亚等国家，AFB1 暴露在这些国家非常普遍。通过 在这项研究中，PI 将成为环境表观遗传学领域的领导者，研究生命早期如何暴露于 非洲公共卫生问题的环境污染物有助于非 晚年罹患传染病。