A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the Developing Mammary Gland of Rats in the CLARITY-BPA Study

Autor: Ana M. Soto, Manushree Bharadwaj, Cheryl M. Schaeberle, Suzanne E. Fenton, Maël Montévil, Nicole Acevedo
Přispěvatelé: Institut de Recherche et d'Innovation (IRI), Centre Pompidou, La République des savoirs : Lettres, Sciences, Philosophie, Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Département de Philosophie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Rok vydání: 2020
Předmět:
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT]
endocrine system
Software tool
Health
Toxicology and Mutagenesis
Mammary gland
Physiology
Positive control
Computational biology
010501 environmental sciences
Biology
Ethinyl Estradiol
01 natural sciences
Hazardous Substances
[SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
law.invention
Rats
Sprague-Dawley
03 medical and health sciences
Mammary Glands
Animal
0302 clinical medicine
Phenols
Pregnancy
law
Sprague dawley rats
medicine
Animals
030212 general & internal medicine
Benzhydryl Compounds
030304 developmental biology
0105 earth and related environmental sciences
Estrous cycle
0303 health sciences
business.industry
urogenital system
Research
Breaking point
Public Health
Environmental and Occupational Health
[SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis
Rat Mammary Gland
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Rats
[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
medicine.anatomical_structure
CLARITY
Gestation
Female
business
[STAT.ME]Statistics [stat]/Methodology [stat.ME]
hormones
hormone substitutes
and hormone antagonists
Zdroj: Environmental Health Perspectives
Environmental Health Perspectives, National Institute of Environmental Health Sciences, 2020, 128 (5), pp.057001. ⟨10.1289/EHP6301⟩
ISSN: 1552-9924
0091-6765
DOI: 10.1289/ehp6301
Popis: BackgroundCLARITY-BPA is a rare collaboration of guideline-compliant (core) studies and academic hypothesis-based studies to assess the effects of bisphenol A (BPA).Objectives1) determine BPA’s effects on the developing rat mammary gland using new quantitative and established semi-quantitative methods in two labs, 2) develop a software tool for semi-automatic evaluation of quantifiable aspects of the mammary ductal tree, and 3) compare those methods.MethodsSprague Dawley rats were exposed to BPA, vehicle, or positive control (ethinyl estradiol, EE2) by oral gavage beginning on gestational day 6 and continuing with direct dosing of the pups after birth. There were two studies; sub-chronic and chronic. The latter used two exposure regimes, one stopping at PND21 the other continuing until tissue harvest. Glands were harvested at multiple time points; whole mounts and histological specimens were analyzed blinded to treatment.ResultsThe subchronic study’s semiquantitative analysis revealed no significant differences between control and BPA dose groups at PND21; whereas at PND90 there were significant differences between control and the lowest BPA dose and between control and the lowest EE2 dose in animals in estrus. Quantitative, automatized analysis of the chronic PND21 specimens displayed non-monotonic BPA effects with a breaking point between the 25 and 250μg/kg/day doses. This breaking point was confirmed by a global statistical analysis of chronic study animals at PND90 and 6 months analyzed by the quantitative method. The BPA response was different from the EE2 effect for many features.ConclusionsBoth the semiquantitative and the quantitative methods revealed non-monotonic effects of BPA. The quantitative unsupervised analysis used 91 measurements and produced the most striking non-monotonic dose-response curves. At all-time points, lower doses resulted in larger effects, consistent with the core study which revealed a significant increase of mammary adenocarcinoma incidence in the stop-dose animals at the lowest BPA dose tested.
Databáze: OpenAIRE
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