Findings of the Independent Academic Prostate Studies in CLARITY-BPA - - PowerPoint PPT Presentation

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Nov 19, 2023 115 likes •214 views

Findings of the Independent Academic Prostate Studies in CLARITY-BPA Gail S. Prins, PhD CLARITY-BPA InvesDgator University of Illinois at Chicago Early-life BPA Exposure Increases Prostate Cancer Susceptibility BPA (10 g/kg BW) No PCa Birth

SLIDE 1

Findings of the Independent Academic Prostate Studies in CLARITY-BPA

Gail S. Prins, PhD CLARITY-BPA InvesDgator University of Illinois at Chicago

SLIDE 2

Birth Puberty

BPA (10 µg/kg BW)

Early-life BPA Exposure Increases Prostate Cancer Susceptibility

No PCa

Ho, et al, Cancer Research, 2006; Prins, et al, Repro Toxicology, 2011; Prins et al, Environ Health Perspec8ves, 2017

Adult Estrogen

↑ E/T in aging men

á PCa incidence

SLIDE 3

CLARITY-BPA: Prostate Independent Study: Prins laboratory

SUMMARY

Repeated previous findings:
Increased prostate cancer risk
Greatest effect at lowest BPA dose

i.e. 2.5 µg/kg BPA Dorsolateral Prostate

SLIDE 4

Dorso-Lateral Prostate Ducts:

Increased multiplicity of ductal adenocarcinoma in 2.5µg BPA (P<0.01 vs Vehicle).

Trending for higher doses; borderline significance in parametric analysis.

Low-dose BPA increased E2-induced adenocarcinoma multiplicity

Tumor Numbers

SLIDE 5

BPA

?

How might early-life BPA exposure affect prostate cancer susceptibility later in life, long after BPA is cleared from the body? Prostate Epithelial Cell Hierarchy

Basal Neuroendocrine Luminal Stem Cell Bipotent Progenitor

unipotent basal progenitor

niche

unipotent luminal progenitor

transit amplification self-renewal differentiation

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Workflow at UIC Animal Tx at FDA-NCTR CLARITY-BPA: Examined the stem and progenitor cells from BPA-exposed rat prostates Prostasphere (PS) Assay and Passage

SLIDE 7

PS number (>40um)/10,000 cells 100 200 300 400 500 600 700

* *

Veh 0.5 2.5 25 250 EE2 BPA (µg/kg BW/day)

Chronic exposure to low-dose BPA increased prostate stem cell numbers and progenitor cell proliferation

Passage 3 – Total PS #

Representative of stem cell number

Symmetric Self-renewal

Representative of progenitor cell proliferation

Symmetric CommiWed division

Passage 3 – PS > 80 µM

PS number (>80um)/10,000 cells 100 300 500 700 200 400 600

† †

Veh 0.5 2.5 25 250 EE2 BPA (µg/kg BW/day)

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Luminal Progenitor Pattern Basal Progenitor Pattern

Chronic low-dose EE and BPA (25 and 250 µg/kg) exposures alter progenitor cell lineage commitment See a shift towards increased basal progenitor lineage at the expense of decreased luminal progenitor lineage

Vehicle EE 2.5 25 250

mRNA Levels (Fold Change)

2 4 6 8 10

CK5 Sox2 Hoxb13 Sox9

‡

†

‡ ‡ ‡

BPA (m g/kg)

Vehicle EE 2.5 25 250

mRNA Levels (Fold Change)

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

CK8 Tbx3 Trop2

BPA (m g/kg)

‡

†

‡ ‡

SLIDE 9

CLARITY-BPA Prostate Study: Summary Model

Ø Propose: Chronic in vivo low-dose BPA exposures ↑ prostate stem cell numbers and altered lineage commitment underpinning an increased carcinogenic risk with aging Ø How might the stem cell changes influence PCa susceptibility?

Cancer risk is highly correlated to # normal stem cell divisions in most tissues, including prostate.

(Tomasetti & Vogelstein, Science, 2015, 2017)

Tumor initiating cells for human PCa are largely localized to basal cell population.

(Goldstein et al, Science, 2010)

Prins et al, Environ Health Perspectives Nov;126(11):117001, 2018