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Section E
DES and BPA
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Endocrine Active Chemicals: Natural and Synthetic
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Diethylstilbesterol (DES)
! Clinical use and adverse human health effects
! Initial use: prevention of spontaneous abortion
! desPlex was promoted as agent that would enhance
health of babies
! Adverse effect
• Appearance of clear cell adenocarcinoma of the
vagina and cervix in exposed offspring of mothers
treated during pregnancy
! An initial small case-control study published by Herbst et
al. in 1971
This image
can not be
provided due
to copyright
DES ad from 1957
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DES Case-Control
Study: Summary
of Data
Comparing
Patients with
Matched Controls
Source: Herbst et al. (1971). New Eng. J. Med.,
284, 878-881.
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DES: Incidence by
Age of Clear Cell
Adenocarcinoma
at Diagnosis
among NativeBorn White
Resident Female
Subjects
This image can not be provided due
to copyright
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DES: Effects of in Utero Exposure on Human Female Progeny
! Clear cell adenocarcinoma (malignant)
in young women
! 1.4/1,000–10,000
! Reproductive problems: 18%
! Structural abnormalities of the
cervicovaginal area
! Structural abnormalities of uterus
! Menstrual irregularities
! Possible adverse pregnancy
outcomes
! Spontaneous abortions, ectopic
pregnancies, and premature
delivery
! Possible increased risk for breast
cancer (recent)
! Possible transgenerational effects
(recent)
! http://www.cancer.gov/cancertopics/
factsheet/Risk/DES
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DES: Effects of in Utero Exposure on Human Male Progeny
! Three times normal incidence
! Anatomic abnormalities of the reproductive tract
! Altered semen—including decreased sperm density, count, and motility
• But DES sons do not appear to be at increased risk for infertility (http://
www.cdc.gov/des/consumers/about/effects_sons.html)
! No apparent increased risk for neoplasms of the reproductive tract
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How Does DES Work?
! DES is metabolized to reactive quinone metabolites
! Toxicity
! DNA damage
mutation
! DES is a potent estrogen
! Effects of estrogens are mediated through estrogen receptors (ER)
! DES alters gene expression
! Epigenetic changes that are transgenerational
• Altered DNA methylation (Science, 308, 1466, 2005)
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DES Metabolism
HO
O
OH
O
P450-mediated
Diethylstilbestrol
DES quinone very reactive
Species differences
Tissue differences
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! Two core
estrogen
receptors
! ERα
! ERβ:
expressed in
human fetal
tissues
! ERs control
cellular
response to
estrogens
Estrogen concentration
Binding to Estrogen Receptors
Critical period for
in utero exposure
to DES
Critical period
1
2
3
Pregnancy (trimester)
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ERα- and ERβMediated Effects
Image source: Yager and Davidson. (2006). N Engl J
Med, 354:270–82.
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Bisphenol A (BPA)
This image can not be provided due
to copyright
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BPA Serum Concentrations
! Range of human exposure (US FDA,
2009)—from Rhomberg et al.,
Regulatory Toxicology and
Pharmacology, in press
! Mean dietary intake from foodcontact articles
! Children and adults: 0.1–0.2µg/kg-d
! Infants: 0.2–0.4µg/kg-d
! Human serum levels: 2–3ng/ml range
! FDA 2012 statement: baby bottles and
children’s drinking cups can no longer
contain BPA
! RfD (fact sheet on BPA)
! Oral = 20–50mg/kg-day (20–50ppb)
! Water = 100mg/l (100ppb)—one
teaspoon in an average 16,000gallon residential in-ground
swimming pool
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Estrogen Receptors
! Two core estrogen receptors:
1. ERα
2. ERβ
! BPA binding to ERα is extremely weak: 1/1000–1/10,000 affinity compared to E2
! Estrogen receptor related receptor γ (ERRγ)
! Member of the ER gene family
! Function and natural ligand—unknown
! Does have tissue-specific expression
• Brain during development
• Brain, lung, many other tissues in adults
! BPA has a strong binding affinity for ERRγ
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Mechanisms of BPA Effects: BPA Causes Epigenetic Changes
! Yellow:
agouti gene,
unmethylated
! Pseudoagouti:
agouti gene,
methylated
Source: Dolinoy et al. (2007). PNAS.
This image can
not be provided
due to copyright
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Dietary Modification of BPA-Induced Methylation Pattern
Source: Dolinoy et al. (2007). PNAS.
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BPA Effects on Mammary Gland Development in Rhesus Monkeys
This image can not be provided due
to copyright
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Effects of BPA on
Follicle
Development in
Rhesus Monkeys
This image can not be provided due
to copyright
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