ingest cdrApp 2017-07-06T11:53:03.312Z f47fee2b-b335-4530-8fc6-0075e2c9b39d modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-06T12:06:05.255Z Setting exclusive relation modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-06T12:06:06.112Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2017-07-06T12:06:14.396Z Adding technical metadata derived by FITS modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-06T12:06:30.294Z Setting exclusive relation addDatastream MD_FULL_TEXT fedoraAdmin 2017-07-06T12:06:39.302Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-06T12:06:55.634Z Setting exclusive relation modifyDatastreamByValue RELS-EXT cdrApp 2017-07-06T12:27:37.352Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-25T09:49:33.661Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-27T10:06:22.117Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-03-14T06:51:09.476Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-17T18:26:29.420Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T05:19:15.842Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-18T01:33:24.748Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T14:44:42.192Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T01:19:44.094Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-12T01:48:41.162Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T20:02:26.971Z Deirdre Tucker Author Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. Spring 2017 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. Spring 2017 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. Spring 2017 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017-05 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 University of North Carolina at Chapel Hill Degree granting institution Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A; Bisphenol AF; Bisphenol S; mammary gland; Mammary stem cells; pubertal development eng Doctor of Philosophy Dissertation Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 University of North Carolina at Chapel Hill Degree granting institution Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Morphological, Cellular and Molecular Effects of Bisphenol A (BPA) and Bisphenol Alternatives in the Mouse Mammary Gland Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A, Bisphenol AF, Bisphenol S, mammary gland, Mammary stem cells, pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Toxicology Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 Deirdre Tucker Creator Curriculum in Toxicology School of Medicine Bisphenol A (BPA) is an industrial chemical used in manufacturing of epoxy resins and polycarbonate plastics that are in many consumer products, including canned foods, plastic bottles, and water supply pipes, thus increasing human exposure. The effects of early life exposure to BPA have been extensively documented in several tissues of multiple species. Animal studies have been critical in identifying morphological and transcriptional changes in the mammary gland, at human relevant BPA exposures (≤0.05 μg/kg bw/d). These studies have prompted increasing public concerns surrounding the use of BPA in consumer products and have warranted the implementation of alternative analogues, including the fluorinated and sulfonated derivatives, BPAF and BPS. Estrogenicity screenings of these analogues have revealed either enhanced or comparable properties to BPA, indicating their endocrine potential which may impact the mammary gland. This research investigates the potential effects of early life exposure to the bisphenol analogues, BPAF, BPS, and BPA on pubertal development and adult mammary gland alterations, as well as cellular and molecular pathways that are associated with these changes. Disposition studies were performed in pregnant CD-1 dams exposed once to BPA (50 mg/kg), BPAF (5 mg/kg), or BPS (5 mg/kg) to confirm transplacental transfer and to determine serum and urinary pharmacokinetics. This information was used to establish a proper dosing schedule for future developmental exposures. Dams had similar serum, urinary and fecal half-lives that were all ≤ 8 hr for all analogues. Urinary recovery was greatest for BPS whereas BPAF recovery was greater in the feces. All chemicals were confirmed to cross the placenta. Pregnant mice were then exposed to BPA (0.5-50 mg/kg) or BPAF and BPS (0.05-5 mg/kg) during the fetal period when rudimentary mammary placodes are forming (GD 10-17). Pubertal mammary glands from offspring exposed to every chemical exhibited accelerated development that included increased terminal end buds, branching density and longitudinal growth. The incidence of inflammation and proliferative epithelial lesions significantly increased in adult glands and produced adenocarcinomas at less than 12 mos. in chemically treated groups, with the highest occurrence in BPAF 5 mg/kg and BPS 0.5 mg/kg. Mammary transplants from digested FACS sorted mammary glands (PND 19-56) prenatally exposed to these two chemicals/concentrations revealed that neither BPAF nor BPS increased mammary repopulating unit frequency, changed expression of stem cell maintenance and differentiation genes, or altered total epithelial cell counts from pubertal mammary glands even though morphological changes at these time-points suggested that they would. Genome-wide analysis and RT-PCR validation of RNA from pubertal mammary glands revealed BPAF altered immune pathways, whereas BPS altered circadian rhythm and mitochondrial dysfunction pathways. Many gene changes occurred during early puberty (PND 20) and others continued into late puberty (PND 55). Neither chemical altered genes associated with apoptosis or from the nuclear receptor estrogen family except Errg (BPAF), but they did cause changes in Evi5 and Tsc22d1, two genes that are influential in epithelial cancers and adenocarcinomas. Together these data suggest that prenatal exposure to BPAF and BPS can morphologically alter the pubertal mammary gland in ways that persist into adulthood and encourage neoplasia formation. These early changes are associated with gene changes in cell metabolism, circadian clock, and endocrine disruption, all of which are reported to influence breast cancer risk. 2017 Toxicology Bisphenol A; Bisphenol AF; Bisphenol S; mammary gland; Mammary stem cells; pubertal development eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Suzanne Fenton Thesis advisor William Coleman Thesis advisor Lola Reid Thesis advisor Charles Perou Thesis advisor John Rogers Thesis advisor text 2017-05 Tucker_unc_0153D_16958.pdf uuid:f94131ff-b275-4c23-8089-378d2999d53f 2019-07-06T00:00:00 2017-04-19T21:29:44Z proquest application/pdf 4713867 yes