Cuttingedge Discoveries: Transforming Lives, Fueling the Economy

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Cutting-edge DiscoveriesTransforming
Lives,Fueling the Economy

• Fall 2006 Series

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• The Innovators
• Epigenetics, Heredity, and the EnvironmentThe
  Ghost in Your Genes

Michael K. Skinner, Ph.D. Director and
Professor, Center for Reproductive BiologyCenter
for Integrated BiotechnologySchool of Molecular
Biosciences
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Overview of Biology
Medicine
Physiology
Expression
Genome(DNA Sequence)
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Overview of Biology
Medicine
Physiology
Expression
Genome(DNA Sequence)
?
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Environmental Impact on Biology

• Regional disease frequencies
• Increases in disease frequencies
• Environmental exposures disease
• Environment and endangered species
• Evolutionary differences

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Embryonic Testis Development
Cord Formation
Growth
Sex Determination
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Effects of Endocrine Disruptorson Testis
Development
Urogenital Ridge
Indifferent Gonad
Sex Determination SRY/SOX9/DMRT/DAX
Endocrine Disruptors
Cord Formation
NT3/trk C
E13.5-14
Cellular Growth
Cellular Apoptosis
TGFb (-) TGFa () NT3/NGF () EGF ()
TGFb1 TGFb2 trk A/NGF
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Endocrine Disruptors

• Environmental compounds that bindto hormone
  receptors and alter hormone actions and the
  endocrine system
• Examples include pesticides, fungicides and
  plastics (i.e. DDT, BPA and phthalates)
• Influence a number of different species from
  frogs to humans
• Promote disease states from reproductive defects
  to tumors

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Model EndocrineDisruptor Vinclozolin

• Vinclozolin is a systemic fungicide (e.g. wine
  industry)
• Two degradation products butenoic acid and
  enanilide
• Vinclozolin and its metabolites are
  anti-androgenic
• Late embryonic/early postnatal exposure causes
  abnormal reproductive tract development
  andgonadal function

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Experimental Protocolfor Embryonic Exposureto
Endocrine Disruptors
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Vinclozolin Effects onSpermatogenic Cell
Apoptosis
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Transgeneration Transmission
Vinclozolin
F0
F1
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Transgeneration Transmission
Vinclozolin
F0
F1
F2
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Transgeneration Transmission
Vinclozolin
F0
F1
F2
F3
F4
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Germ Cell Apoptosis





Plt0.05
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Complete Male Infertility(10-15)
F3 Generation Males
Control
Vinclozolin
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DNA Methylation is the addition of a methyl group
(M) to the DNA base cytosine (C) in a CpG
sequence.
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The Process of Methylation
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The Process of Methylation
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Chromosomal Locations
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Transgenerational Disease States
F1-F4 Generations Combined

• Vinclozolin
• Generations

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Transgenerational Diseasein Female F1-F4
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Transgenerational Disease Etiology - Vinclozolin

• Spermatogenic Defect (gt90)
• Male infertility (complete 10, severe 20)
• Premature aging (30)
• Kidney disease (40)
• Prostate disease (50)
• Increase in tumor formation (20)
• Pre-eclampsia-like during late pregnancy (15)

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Summary

• Transient Embryonic Exposure Effects Adult
• Sex Determination Period
• Fetal Basis of Disease
• Spermatogenic Fertility Defect Other Diseases
• Epigenetic Transgenerational Phenotype
• Toxicology Endocrine Disruptors
• Permanent Re-Program Germ-Line
• Disease Etiology
• Evolutionary Biology

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Medicine
Physiology
Expression
Genome(DNA Sequence)
Epigenetics
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Medicine
Physiology
Expression
Epigenetic Ghosts
Genome(DNA Sequence)
Epigenetics
Environment
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Skinner Laboratory
Selected Past Fellows Mehmet Uzumcu,
Rutgers Andrea Cupp, Nebraska Jeff Parrott,
Kadmus Pharm. Tera Muir Suzy Westfall Jackie
Ague Jaideep Chaudhary
Current Members Matt Anway Jeff Stevens Tracy
Back Hung-shu Chang Eric Nilsson Ingrid
Sadler-Riggleman Mushtaq Memon Nathan Meyer Shane
Rekow Nicole Mills Kalie Dove-McGuire Trevor
Covert Jacob Stanfield Mary Francis Jill Griffin
Support - NIEHS, EPA Star Program
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• Contact Information

Michael K. Skinner, Ph.D. Director and
Professor, Center for Reproductive BiologyCenter
for Integrated BiotechnologySchool of Molecular
Biosciences www.biotechnology.wsu.edu www.skinne
r.wsu.edu
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• Coming Up
• The Innovators lecture series

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• The Innovators March 21, Spokane
• Riverpoint Campus, South Campus Facility

Sylvia Oliver, Ph.D. Assistant Director, Health
Research Education Center Founder and director
of the WSU Spokane CityLab
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• For more information
• wsu.edu/theinnovators
• Toll free 1-877-978-3868