Crossover Study on Human Exposure to Phthalates and Male Fertility

人类接触邻苯二甲酸盐与男性生育能力的交叉研究

• 批准号: 7889107
• 负责人: RUSS B HAUSER
• 金额: $ 52.34万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889107
• 关键词: Affect; Age; Animal Model; Animals; Area; Back; Biological Markers; Birth; Blood; Blood specimen; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Child; Clinical; Clinical Markers; Collection; Cross-Over Studies; Crossover Design; DNA Damage; Development; Diagnosis; Dibutyl Phthalate; Dose; Drug usage; Endocrine; Enteral; Environment; Environmental Epidemiology; Environmental Health; Exposure to; Family; Fertility; Food Packaging; General Population; Health; Human; Inflammatory Bowel Diseases; Intake; Life; Medical; Mesalamine; Messenger RNA; National Health and Nutrition Examination Survey; Outcome; Patients; Pharmaceutical Preparations; Physicians; Plastics; Population; Pregnancy; Process; Proxy; Public Health; Recruitment Activity; Reporting; Reproductive Health; Research Personnel; Risk; Self Care; Seminal fluid; Serum; Signal Transduction; Source; Synthesis Chemistry; Techniques; Testis; Testosterone; Toy; Transcript; Urine; Visit; cell motility; design; experience; exposed human population; flexibility; inhibin B; innovation; male; man; men; molecular marker; monobutyl phthalate; novel; phthalates; pill; public health relevance; reproductive; reproductive hormone; sperm cell; sperm quality; toxicant; urinary; Affect; Age; Animal Model; Animals; Area; Back; Biological Markers; Birth; Blood; Blood specimen; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Child; Clinical; Clinical Markers; Collection; Cross-Over Studies; Crossover Design; DNA Damage; Development; Diagnosis; Dibutyl Phthalate; Dose; Drug usage; Endocrine; Enteral; Environment; Environmental Epidemiology; Environmental Health; Exposure to; Family; Fertility; Food Packaging; General Population; Health; Human; Inflammatory Bowel Diseases; Intake; Life; Medical; Mesalamine; Messenger RNA; National Health and Nutrition Examination Survey; Outcome; Patients; Pharmaceutical Preparations; Physicians; Plastics; Population; Pregnancy; Process; Proxy; Public Health; Recruitment Activity; Reporting; Reproductive Health; Research Personnel; Risk; Self Care; Seminal fluid; Serum; Signal Transduction; Source; Synthesis Chemistry; Techniques; Testis; Testosterone; Toy; Transcript; Urine; Visit; cell motility; design; experience; exposed human population; flexibility; inhibin B; innovation; male; man; men; molecular marker; monobutyl phthalate; novel; phthalates; pill; public health relevance; reproductive; reproductive hormone; sperm cell; sperm quality; toxicant; urinary

DESCRIPTION (provided by investigator): Phthalates are a class of widely used modern synthetic chemicals that have been shown in experimental animals to be testicular toxicants. Although there is widespread exposure of the U.S. general population to phthalates, there are limited human studies on their potential health risks. In our ongoing study on the environment and reproductive health, we found a suggestive association between exposure to dibutyl phthalate (DBP) and reduced semen quality. Unexpectedly, we identified one man with urinary concentrations of monobutyl phthalate (MBP), the main DBP metabolite, that was two orders of magnitude higher than the 95th percentile reported in the U.S. population. The source of DBP exposure was Asacol (mesalamine, with enteric coating containing DBP) used to treat inflammatory bowel disease (IBD). The estimated DBP intake of 224 5g/kg/day, obtained from the urinary concentration of MBP, was higher than the U.S. EPA reference dose (RfD) for DBP (100 5g/kg/day). Among additional men, we have since confirmed that Asacol contributes to high DBP exposure. Because DBP is included in some medications to treat IBD but not in others used for the same indications, and patient's and prescriber's are unlikely to be aware of their exposure with respect to DBP, there is the unique opportunity to implement innovative designs to study the impact of high exposure to phthalates on human health. Confounding by underlying medical indication is unlikely because inactive ingredients, i.e., DBP, are present in some drugs used for a given indication but not in other drugs used for the same indication. In the proposed study, we will recruit 100 men of reproductive age with a physician diagnosis of mild IBD who were prescribed mesalamine. Some men are treated with mesalamine that contains DBP phthalate in the coating (e.g., Asacol) while some men are treated with mesalamine that does not contain DBP in the coating (e.g., Pentasa). We propose a crossover study in which men participate in six study visits. The first two study visits (two weeks apart) include collection of a baseline semen, urine and blood sample while the man is on his physician prescribed mesalamine medication (i.e., Asacol or Pentasa). After the second visit, men will be asked to switch to the other mesalamine product. Thus, men on Asacol at recruitment are switched to Pentasa, and those on Pentasa at recruitment are switched to Asacol. Subjects continue on the alternate mesalamine product for a 3-month 'washout' period after which they return for study visit 3 and 4 (two weeks apart) and provide a semen, urine and blood sample. After study visit 4, the men switch back to their original mesalamine medication. After a 3-month 'washout' period back on their original medication, each subject returns for study visit 5 and 6 (two weeks apart) to provide a semen, urine, and blood sample. The project specific aims are to determine the association of high exposure to DBP with intermediate and clinical markers of male fertility, including semen quality, sperm DNA damage, reproductive hormone profiles, and sperm transcript profiling. Modern techniques of transcript profiling (i.e., microarrays and deep sequencing) provide a non-invasive proxy for the testis. We will assess their use as biomarkers of exposure to DBP, reflective of the pathological mechanism impacting male fertility. In summary, the crossover strategy is a powerful design in which we will compare alterations in biomakers of male fertility in the same man when he is taking Asacol (high DBP exposure) as compared to when he is on Pentasa (low DBP exposure). PUBLIC HEALTH RELEVANCE: Over the last several decades the U.S. male population has experienced a decline in semen quality. Phthalates are a family of widely used chemicals that adversely affect male fertility in animal models. The proposed crossover study will define the impact of high exposure to phthalates on clinical and molecular markers of male fertility requisite for a healthy child.

描述（研究人员提供）：邻苯二甲酸酯是一类使用的现代合成化学物质，在实验动物中已显示为睾丸毒物。尽管美国普通民众对邻苯二甲酸群的暴露有限，但人类对其潜在健康风险的研究有限。在我们正在进行的有关环境和生殖健康的研究中，我们发现了暴露于邻苯二甲酸二丁酯（DBP）和精液质量降低之间的暗示性关联。出乎意料的是，我们确定了一名尿浓度单丁二字酸酯（MBP）的人，邻苯二甲酸酯（MBP）是主要的DBP代谢产物，这比美国人群中报道的第95个百分位数高两个数量级。 DBP暴露的来源是用于治疗炎症性肠病（IBD）（IBD）的肠氨酸（含有DBP的肠涂层）。从MBP的尿液浓度获得的估计的DBP摄入量为224 5G/kg/天，对于DBP（100 5G/kg/day），MBP的尿液浓度高于美国EPA参考剂量（RFD）。此后，在其他男性中，我们已经确认Asacol会导致DBP高暴露。由于某些药物中包括DBP来治疗IBD，但在其他药物中不包括同样的迹象，并且患者和处方者的不太可能意识到它们对DBP的暴露，因此有独特的机会来实施创新的设计，以研究高暴露于人类健康对人类健康的影响。通过基本的医学指征混淆的不可能是不可能的，因为非活性成分（即DBP）存在于某些用于给定指征的药物中，但在其他用于相同指征的药物中不存在。在拟议的研究中，我们将招募100名生殖年龄的男性，医师诊断为处方甲撒拉胺的温和IBD。有些男性被含有涂料中的DBP邻苯二甲酸酯的甲撒明（例如）治疗（例如，asacol），而有些男性则接受了涂料中不含DBP的美撒甲胺治疗（例如，五颗）。我们提出了一项跨界研究，其中男性参加了六次研究访问。前两次研究访问（相距两周）包括收集基线精液，尿液和血液样本，而该男子则在其医师开处方的美撒胺药物（即曲霉或pentasa）处方。第二次访问后，将要求男人改用其他美撒甲胺产品。因此，在招募时在阿索科尔的男性转向五角洲，而招募时五角星的人则转向asacol。受试者继续使用替代美撒甲胺产品，进行了3​​个月的“洗涤”期，然后他们返回学习访问3和4（相隔两个星期），并提供精液，尿液和血液样本。研究访问4后，男子改回了他们的原始美沙甲胺药物。经过3个月的“清洗”期间，他们的原始药物进行了研究，每个受试者返回学习访问5和6（相隔两个星期），以提供精液，尿液和血液样本。该项目的特定目的是确定高暴露于DBP与男性生育能力的中间和临床标记的关联，包括精液质量，精子DNA损伤，生殖激素概况和精子转录本谱分析。成绩单分析的现代技术（即微阵列和深度测序）为睾丸提供了无创的代理。我们将评估它们作为暴露于DBP的生物标志物的用途，反映了影响男性生育能力的病理机制。总而言之，交叉策略是一种强大的设计，在该设计中，我们将比较同一男人的生物制造商在服用Asacol（高DBP暴露）时与他在Pentasa上（低DBP暴露）相比的变化。 公共卫生相关性：在过去的几十年中，美国男性人口的精液质量下降。邻苯二甲酸酯是一个广泛使用的化学物质家族，在动物模型中会对男性生育产生不利影响。拟议的跨界研究将定义邻苯二甲酸盐暴露于健康儿童所需的男性生育能力的临床和分子标记的影响。