Development in a dish: an ex-vivo fetal mammary assay for toxicological research
培养皿中的发育:用于毒理学研究的离体胎儿乳腺测定
基本信息
- 批准号:10005424
- 负责人:
- 金额:$ 20.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptionAdultAffectAge-MonthsAnimal ModelAnimalsAreaBehaviorBiological AssayBypassChemical ActionsChemicalsComplexDataData ReportingDevelopmentDevelopmental ToxicantDiethylstilbestrolDiseaseDoseDuct (organ) structureEndocrineEndocrine DisruptorsEstrogensEthinyl EstradiolEuropeanEvaluationExposure toFetal DevelopmentGlandGoalsGrowthHealthHormonalHormonesHumanHyperplasiaImpairmentIn VitroIncidenceInfertilityIntraductal HyperplasiaLactationLengthLesionLifeLinkMalignant NeoplasmsMammary NeoplasmsMammary glandMeasurementMeasuresMetabolic DiseasesMethodsModelingMorphogenesisMorphologyNational Toxicology ProgramNeonatalNeoplasmsObesityOrganogenesisOutcomePathologyPerinatal ExposurePhenotypePhysiologicalPopulationPreventiveProcessQuantitative EvaluationsRegulationReporter GenesReproducibilityReproductionResearchRiskRodentSteroidal EstrogenSystemTestingTimeToxicologyValidationWomanWorkbisphenol Adevelopmental toxicityexposed human populationfetalhypothalamic pituitary ovarian axisin vivomalignant breast neoplasmmammary gland developmentneoplasticnonhuman primatepostnatalprenatal exposureresponsescreeningtooltoxicantxenoestrogen
项目摘要
Summary
More than 80,000 chemicals are registered for commercial use in the U.S. Many of them
are endocrine disruptors and pose major risks to human health, hence the need for
efficient evaluation of their developmental toxicity. Fetal organogenesis is a period of
increased vulnerability to toxicants, in particular to those that interfere with hormone
action. The fetal mammary gland is considered particularly vulnerable to hormonal
disruption; exposure to xenoestrogens like diethylstilbestrol (DES) increased breast
cancer incidence in women. Despite this finding, there is no data reporting the effects of
DES during fetal MG development (to be examined in S. Aim 1). Likewise, fetal
exposure to bisphenol A (BPA) and its replacements led to the development of pre-
neoplastic and neoplastic lesions that manifested postnatally, long after the end of
exposure (effect on fetal MG development will be examined in S. Aim 2).
There is currently no reproducible system that allows for the observation of the direct
effects of hormones and endocrine disruptors on the developing mammary gland while
bypassing the effect of endogenous hormones and the estrogen-trapping effect of
alphafetoprotein (AFP). Using an ex-vivo culture assay in which the mammary bud
completes fetal morphogenesis in-vitro, allowed us to observe this process in real time.
Validation of the ex-vivo method requires comparing the effects of selected chemicals
that do not bind to AFP in the ex-vivo and in-vivo assays. In this regard, we observed
that ethinyl estradiol, a steroidal estrogen that does not bind to AFP inhibited ductal
growth both ex-vivo and in-vivo. In contrast, low BPA concentrations increased ductal
development both in-vivo and in this ex-vivo explant method.
Aim 1: To examine the ex-vivo and in-vivo effects of DES on fetal mammary gland
development. Aim 2: To compare the ex-vivo and in-vivo fetal MG phenotype caused by
exposure to endocrine disruptors known to induce proliferative lesions and/or cancer in
rodents. We will use the BPA replacements BPS and BPAF. A validated ex-vivo culture
assay of the developing MG will greatly facilitate mechanistic and morphometric studies
of mammary gland development and provide toxicologists with a reliable, faster method
to test chemicals for potential developmental toxicity.
总结
超过80,000种化学品在美国注册用于商业用途,其中许多
是内分泌干扰物,对人类健康构成重大风险,因此需要
有效评价其发育毒性。胎儿器官形成是一个
增加对有毒物质的脆弱性,特别是那些干扰激素的物质
行动上胎儿乳腺被认为是特别容易受到激素的影响,
破坏;暴露于异种雌激素如己烯雌酚(DES)增加乳腺癌
女性癌症发病率。尽管有这一发现,没有数据报告的影响,
DES在胎儿MG发育过程中的作用(在S.目标1)。同样,胎儿
暴露于双酚A(BPA)及其替代品导致了前
肿瘤和肿瘤性病变,表现在出生后,结束后很久,
暴露(对胎儿MG发育的影响将在S.目标2)。
目前还没有一个可重复的系统,允许观察的直接
激素和内分泌干扰物对乳腺发育的影响,
绕过内源性激素的作用和雌激素的捕获作用,
甲胎蛋白(AFP)。使用离体培养测定,其中乳腺芽
在体外完成胎儿形态发生,使我们能够真实的观察这个过程。
离体方法的验证需要比较所选化学品的效果
其在离体和体内测定中不结合AFP。在这方面,我们观察到,
炔雌醇,一种不与AFP结合的类固醇雌激素,
离体和体内生长。相比之下,低BPA浓度增加了导管
在体内和这种离体外植体方法中的发育。
目的1:研究DES对胎儿乳腺的影响
发展目的2:比较体外和体内胎儿MG表型,
暴露于内分泌干扰物,已知可诱导增殖性病变和/或癌症,
啮齿动物我们将使用BPA替代BPS和BPAF。经验证的离体培养
对发育中MG的分析将极大地促进机理和形态学研究
为毒理学家提供了一种可靠、快速的方法
测试化学物质对发育的潜在毒性
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ANA SOTO其他文献
ANA SOTO的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ANA SOTO', 18)}}的其他基金
Does breast cancer start in the womb? BPA, mammogenesis and neoplasia
乳腺癌是从子宫里开始的吗?
- 批准号:
7940860 - 财政年份:2009
- 资助金额:
$ 20.63万 - 项目类别:
Does breast cancer start in the womb? BPA, mammogenesis and neoplasia
乳腺癌是从子宫里开始的吗?
- 批准号:
7857542 - 财政年份:2009
- 资助金额:
$ 20.63万 - 项目类别:
Mechanism of developmental toxicity of Bisphenol-A
双酚A的发育毒性机制
- 批准号:
7892741 - 财政年份:2009
- 资助金额:
$ 20.63万 - 项目类别:
Does breast cancer start in the womb? BPA, mammogenesis and neoplasia
乳腺癌是从子宫里开始的吗?
- 批准号:
8074160 - 财政年份:2009
- 资助金额:
$ 20.63万 - 项目类别:
Mechanism of developmental toxicity of Bisphenol-A
双酚A的发育毒性机制
- 批准号:
7291668 - 财政年份:2006
- 资助金额:
$ 20.63万 - 项目类别:
Mechanism of developmental toxicity of Bisphenol-A
双酚A的发育毒性机制
- 批准号:
7211253 - 财政年份:2006
- 资助金额:
$ 20.63万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 20.63万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 20.63万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 20.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 20.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 20.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)