title: Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals.
abstract: Common environmental contaminants such as bisphenols and phthalates and persistent contaminants such as polychlorinated biphenyls are thought to influence tissue homeostasis and carcinogenesis by acting as disrupters of endocrine function. In this study we investigated the direct effects of exposure to bisphenol A (BPA), mono-n-butyl phthalate (Pht), and polychlorinated biphenyl 153 (PCB153) on the proteome of primary organotypic cultures of the mouse mammary gland. At low-nanomolar doses each of these agents induced distinct effects on the proteomes of these cultures. Although BPA treatment produced effects that were similar to those induced by estradiol, there were some notable differences, including a reduction in the abundance of retinoblastoma-associated protein and increases in the Rho GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle protein CDC42. Both Pht and PCB153 induced changes that were distinct from those induced by estrogen, including decreased levels of the transcriptional corepressor C-terminal binding protein 1. Interestingly, the three chemicals appeared to alter the abundance of distinct splice forms of many proteins as well as the abundance of several proteins that regulate RNA splicing. Our combined results indicate that the three classes of chemical have distinct effects on the proteome of normal mouse mammary cultures, some estrogen-like but most estrogen independent, that influence diverse biological processes including apoptosis, cell adhesion, and proliferation.
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, CA 94143;
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Williams
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143;
authors.forename: George A
authors.initials: GA
authors.lastname: Lemieux
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, CA 94143;
authors.forename: Maria E
authors.initials: ME
authors.lastname: Hassis
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.affiliation: Department of Obstetrics and Gynecology, University of California, San Francisco, CA 94143;
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Fisher
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143; zena.werb@ucsf.edu.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D016000:Cluster Analysis; D004785:Environmental Pollutants / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D009940:Organoids / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000633:toxicity; D010795:Phthalic Acids / Q000633:toxicity; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D020543:Proteome / Q000145:classification / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D004785:Environmental Pollutants; D004968:Estrogens, Non-Steroidal; D010636:Phenols; D010795:Phthalic Acids; D011078:Polychlorinated Biphenyls; D020543:Proteome; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C028577:monobutyl phthalate
keywords: environmental chemicals; estrogen; mammary epithelium; organotypic culture; proteomics