bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/783019

A combined morphometric and statistical approach to assess non-monotonicity in the developing mammary gland of rats in the CLARITY-BPA study

Montevil, M.·Acevedo, N.·Schaeberle, C.·Bharadwaj, M.·Fenton, S.·Soto, A. M.
View original source ↗Export metadata ↓

Abstract

BackgroundCLARITY-BPA is a rare collaboration of guideline-compliant (core) studies and academic hypothesis-based studies to assess the effects of bisphenol A (BPA).\n\nObjectives1) determine BPAs 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.\n\nMethodsSprague 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.\n\nResultsThe subchronic studys 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 250g/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.\n\nConclusionsBoth 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.

Source connections

Explore related subjects

developmental biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Montevil, M., Acevedo, N., Schaeberle, C., Bharadwaj, M., Fenton, S., Soto, A. M.. 2019-09-30. A combined morphometric and statistical approach to assess non-monotonicity in the developing mammary gland of rats in the CLARITY-BPA study. https://doi.org/10.1101/783019

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Alveolar and airway progenitors converge on an epigenetically encoded profibrotic state

During organ regeneration, epithelial transitional states arise from progenitors and instruct the mesenchyme to remodel the extracellular matrix. However, the identity of the progenitors, the mechanisms underlying this transition, and why these states persist in tissue fibrosis often remain elusive. Here, using lineage tracing in mice, we show that the profibrotic KRT5-/KRT17+ state in pulmonary fibrosis arises convergently from alveolar type (AT) 2 and airway secretory cells. AT1 cells generate neither KRT5-/KRT17+ nor AT2 cells. TGF-{beta}/SMAD3 acts through KMT2A and p300 to epigenetically reprogram human AT2 cells into the KRT5-/KRT17+ state. In human pulmonary fibrosis, KRT5-/KRT17+ cells slough off, and transitional cells re-epithelialize the denuded basement membrane. Transcriptionally convergent states arise in injured kidney, skin, and intestine. This work reframes fibrogenesis as the accumulation of a conserved profibrotic transitional state via ongoing turnover, not persistence alone, and nominates the state transition and its epigenetic regulators as therapeutic targets.

developmental biology↗
bioRxiv2026

Dynamic mechanical sorting biases niche occupancy and lineage outcome during development of bilayered glandular epithelia

Tissue compartmentalization into basal and luminal domains is a hallmark of glandular epithelia, yet how fate boundaries are established and stabilized during dynamic morphogenesis remains a major unresolved question. Here, using mouse embryonic explants, organoids, quantitative live imaging and genetic perturbations, we show that basal-luminal compartmentalization is not maintained by fixed boundaries, but through continuous positional corrections. We show that differences in cellular adhesion and actomyosin contractility drive these positional corrections by promoting active cell sorting. We further find that these mechanical differences influence lineage specification by controlling cell positioning rather than directly instructing cell fate. Before commitment, mosaic, but not uniform, perturbation of cell mechanics alters niche occupancy and biases lineage outcome, indicating that relative mechanical properties determine access to fate-instructive niches. Conversely, perturbation of Notch and YAP remodels compartment-specific mechanical properties and cell-positioning dynamics, revealing a reciprocal coupling between lineage state and mechanical sorting. Conservation of this mechanism across four glandular epithelia of distinct origins and functions identifies dynamic mechanical sorting as a general strategy for maintaining robust tissue compartmentalization during the extensive growth and cellular rearrangements of branching morphogenesis.

developmental biology↗
bioRxiv2026

Unbiased lineage tracing across the adipose organ decouples developmental origin from anatomical and transcriptomic identities

The developmental origins of individual adipose depots and whether embryonic lineage dictates adult function remain unresolved. Here, we apply in utero CRISPR-mediated barcoding lineage tracing to construct the first unbiased clonal map of adipose organ development in mice. The developmental hierarchy we uncover challenges several conventions. Remarkably, interscapular brown fat, used as the prototypical brown fat, is the most developmentally isolated brown fat; depots sharing Myf5/Pax3 lineage markers fail to cluster together; mesenteric white fat shares unexpected high clonal ancestry with brown fats despite a radically divergent transcriptome; and subcutaneous white adipose tissues converge transcriptomically despite distant developmental origins. These findings call for a reinterpretation of single-marker lineage tracing data across the adipose organ and propose that adipose depot identity is not solely encoded by embryonic lineage but is substantially shaped by the anatomical niche.

developmental biology↗