Mammary Gland as a Sensitive End Point to Effects of Endocrine Disruptors

乳腺作为内分泌干扰物影响的敏感终点

• 批准号: 8929805
• 负责人: Suzanne Fenton
• 金额: $ 329.24万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8929805
• 关键词: Acids; Adverse effects; Affect; Alkanesulfonates; Amniotic Fluid; Animal Model; Animals; Asians; Atrazine; Biological Assay; Brain; Breast; Breast Diseases; Camping; Carcinogens; Centers for Disease Control and Prevention (U.S.); Chemical Actions; Chemicals; Collaborations; Collection; Complex; Computers; Contractor; Data; Data Quality; Development; Differentiation and Growth; Discipline of Nursing; Disease; Dose; Drops; Endocrine; Endocrine Disruptors; Endocrine Reproductive Tissue; Epidemic; Epithelial; European; Evaluation; Female; Fetus; Flame Retardants; Friction; Future; Generations; Genes; Gland; Goals; Government; Guidelines; Health; Herbicides; Human; Hyperplasia; Impairment; Industry; Instruction; Investigation; Laboratories; Lead; Life; Liver; Malignant Neoplasms; Malignant neoplasm of male breast; Mammary Gland Parenchyma; Mammary gland; Manufacturer Name; Manuscripts; Measures; Methodology; Military Personnel; Milk; Mission; Molecular; Mus; Neonatal; Outcome Study; PPAR alpha; Paper; Pathology; Pathway interactions; Pattern; Phase; Pilot Projects; Population; Predisposition; Pregnancy; Production; Protocols documentation; Publications; Publishing; Rat Strains; Rattus; Regulation; Reporting; Reproductive Endocrinology; Research; Risk; Risk Assessment; Rodent; Role; Route; Science; Serum; Site; Solvents; Sprague-Dawley Rats; Staining method; Stains; Techniques; Testing; Time; Tissues; Toxicology; Urine; Weight Gain; Woman; Work; base; bisphenol A; breast cancer diagnosis; dosimetry; environmental chemical; fetal; girls; human disease; improved; interest; male; malignant breast neoplasm; mammary gland development; men; mouse model; novel; offspring; pregnant; prenatal exposure; prevent; pup; reproductive; response; signal processing; surfactant; tumor; working group

Our research is focused on understanding the effects of environmental chemicals on mammary gland (MG) development, function, and cancer susceptibility. The use of animal models for human disease allows us to evaluate different routes of exposure, internal dose of the test chemical, as well as a variety of effects in the rodent that are relevant to human health. During the last several years, we have produced numerous important documents that are being used in the risk regulation of brominated flame retardants (DE-71), perfluorooctanoic acid (PFOA) and atrazine (ATR). Flame retardants are currently regulated at the state level, as a federal risk assessment has not been completed yet. Our work on DE-71 in the rat are completed for now, but I continue to advise the ongoing NTP studies regarding the mechanisms of action of these high use and emerging flame retardants. We have also reported mammary gland effects following atrazine exposure during late pregnancy in rats. Atrazine is one of the highest use herbicides in the US. In the female rat offspring, the mammary gland is the most endocrine-sensitive end point evaluated. Our pilot studies, which were evaluated in 2012, suggested that there was a strain difference in atrazine effects at the level of mammary gland development. We have also had a pathology working group evaluation of our preliminary mammary pathology following prenatal exposures and carcinogen challenge. This year, we have undertaken studies to evaluate the potential for tumors in mammary tissue that was developmentally exposed to atrazine. This is along with a more thorough evaluation of the effects of this herbicide on development across strains of rats heavily used in industry and government toxicology testing, including the Harlan Sprague-Dawley rat, the strain of choice for the NTP. These studies will demonstrate normal mammary development patterns so that chemically induced changes will be easier and more consistently determined. We have donated a substantial amount of time to supply our data to the manufacturer of atrazine, as a result of an 8 month FOIA. Our on-going work on this high use herbicide is to understand its mechanism of action, and its metabolites, on the fetal and early neonatal MG development. We aim to identify genes involved in this response and to determine the similarity of these genes with other chemicals that induce a similar delay in morphological development in the rat or mouse. We predict that there are a common set of genes regulating delayed MG development. This year, in particular, we have finished studies on the maternal-fetal disposition on ATR and its metabolites following a late gestation exposure. We are awaiting CDC data for this study. We have published several papers investigating the effects of PFOA in the mouse model over the last year. PFOA is a surfactant used in computers, wiring, and firefighting foam to reduce friction, and in non-stick coating and stain-preventing agents and applications. All US inhabitants have PFOA in their serum. The US population is exposed to it in their everyday life. We have developed techniques for measuring the amount of PFOA in serum, urine, amniotic fluid, brain, MG, and liver. We have characterized the amount of PFOA that gets to the various compartments of the body following a single or multiple exposure scenarios. The mammary gland, again, appears to be a sensitive tissue to the effects of PFOA. The liver is another target site for this compound. PFOA is transferred to the offspring through nursing and the amount that is present in milk vs serum was quantitatively determined in our studies. We have published papers this year that clarified the low dose responsivity of the mammary gland to PFOA exposures in female offspring. The mechanisms underlying this low-dose response in mammary gland development has been the focus of our work this year and we will soonsubmit two other papers on this important compound. We also reported on low dose effects of PFOA on uterine development this year in collaboration with the Dixon lab. We have finalized studies persuing novel mechanisms for PFOA-induced hepatomegally and tumor formation. Our studies will define for the first time a mechanism other than PPAR-alpha. The liver paper and studies on mechinsms for mammary changes are to be submitted for publication soon. These studies are all in line with current efforts on-going in the NTP, as perfluorinated chemicals are under investigation there, in several capacities. PFOA is undergoing risk regulation at the state level at this point, as a federal risk assessment has not taken place. I have donated a substantial amount of time to the NC and NJ state regulators to discuss our PFOA data during their debates on regulation of this compound. Our work has resulted in NC dropping their allowable level to half of the original value. Production and use of this compound is set to be phased out in 2015, however that does not mean that we will not be exposed any further. Other complex flouro-telomer acids can be broken down to PFOA and those compounds will not be regulated. In addition, European and Asian companies are now beginning PFOA production and therefore, exposure will continue. We have made major progress on our work involving investigation of dry cleaning solvents and their developmental exposure effects on the mammary gland, specifically in males. These compounds are theorized to have a role in male breast cancer diagnoses in men who were born or grew up at the Camp Lejeune military base in NC, USA. We have finished dosimetry studies in the pregnant and lactating rat and her offspring in conjunction with our CDC collaborators. We have evaluated mammary gland development and will soon prepare a manuscript on the effects of these compounds on male and female mammary glands. We have also begun studies to look at susceptibility to mammary gland hyperplasia in female mice exposed to bisphenol A (BPA), BPAF and BPAS (fluorinated and sulfonated forms)in early life. These studies are all in line with NTP mission or in collaboration with other Federal agencies. Dispositon studies are underway to understand the transfer of these compounds to the developing fetus and the clearance within the pregnant dam.