PMID- 32438830
OWN - NLM
STAT- MEDLINE
DCOM- 20201210
LR  - 20220708
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 128
IP  - 5
DP  - 2020 May
TI  - A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the 
      Developing Mammary Gland of Rats in the CLARITY-BPA Study.
PG  - 57001
LID - 10.1289/EHP6301 [doi]
LID - 057001
AB  - BACKGROUND: The Consortium Linking Academic and Regulatory Insights on 
      Bisphenol-A (CLARITY-BPA) is a rare collaboration of guideline-compliant (core) 
      studies and academic hypothesis-based studies to assess the effects of bisphenol 
      A (BPA). OBJECTIVES: We aimed to a) determine whether BPA showed effects on the 
      developing rat mammary gland using new quantitative and established 
      semiquantitative methods in two laboratories, b) develop a software tool for 
      automatic evaluation of quantifiable aspects of the mammary ductal tree, and c) 
      compare those methods. METHODS: Sprague-Dawley rats were exposed to BPA, vehicle, 
      or positive control [ethinyl estradiol (EE2)] by oral gavage beginning on 
      gestational day (GD)6 and continuing with direct dosing of the pups after birth. 
      There were two studies: subchronic and chronic. The latter used two exposure 
      regimes, one stopping at postnatal day (PND)21 (stop-dose) the other continuing 
      until tissue harvest (continuous). Glands were harvested at multiple time points; 
      whole mounts and histological specimens were analyzed blinded to treatment. 
      RESULTS: The 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 nonmonotonic BPA effects, with 
      a breaking point between the 25 and 250 mug/kg body weight (BW) per 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. CONCLUSIONS: Both 
      the semiquantitative and the quantitative methods revealed nonmonotonic effects 
      of BPA. The quantitative unsupervised analysis used 91 measurements and produced 
      the most striking nonmonotonic 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. https://doi.org/10.1289/EHP6301.
FAU - Montevil, Mael
AU  - Montevil M
AD  - Department of Integrative Physiology and Pathobiology, Tufts University School of 
      Medicine, Boston Massachusetts, USA.
FAU - Acevedo, Nicole
AU  - Acevedo N
AD  - Department of Integrative Physiology and Pathobiology, Tufts University School of 
      Medicine, Boston Massachusetts, USA.
FAU - Schaeberle, Cheryl M
AU  - Schaeberle CM
AD  - Department of Integrative Physiology and Pathobiology, Tufts University School of 
      Medicine, Boston Massachusetts, USA.
FAU - Bharadwaj, Manushree
AU  - Bharadwaj M
AD  - National Toxicology Program (NTP) Laboratory, Division of the NTP, National 
      Institute of Environmental Health Sciences, National Institutes of Health, 
      Department of Health and Human Services, Research Triangle Park, North Carolina, 
      USA.
FAU - Fenton, Suzanne E
AU  - Fenton SE
AD  - National Toxicology Program (NTP) Laboratory, Division of the NTP, National 
      Institute of Environmental Health Sciences, National Institutes of Health, 
      Department of Health and Human Services, Research Triangle Park, North Carolina, 
      USA.
FAU - Soto, Ana M
AU  - Soto AM
AD  - Department of Integrative Physiology and Pathobiology, Tufts University School of 
      Medicine, Boston Massachusetts, USA.
LA  - eng
GR  - U01 ES020888/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20200520
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Hazardous Substances)
RN  - 0 (Phenols)
RN  - 423D2T571U (Ethinyl Estradiol)
RN  - MLT3645I99 (bisphenol A)
SB  - IM
MH  - Animals
MH  - Benzhydryl Compounds/*toxicity
MH  - Ethinyl Estradiol/toxicity
MH  - Female
MH  - Hazardous Substances/*toxicity
MH  - Mammary Glands, Animal/drug effects/*growth & development
MH  - Phenols/*toxicity
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC7263454
EDAT- 2020/05/23 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/05/20
CRDT- 2020/05/23 06:00
PHST- 2020/05/23 06:00 [entrez]
PHST- 2020/05/23 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/05/20 00:00 [pmc-release]
AID - EHP6301 [pii]
AID - 10.1289/EHP6301 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2020 May;128(5):57001. doi: 10.1289/EHP6301. Epub 2020 
      May 20.