2007 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE (PNAS)
PAPER SUMMARY
David Crews, Andrea C. Gore, Timothy S. Hsu, Nygerma L. Dangleben,
Michael Spinetta, Timothy Schallert, Matthew D. Anway, & Michael K. Skinner
(2007) Transgenerational Epigenetic Imprints on Mate Preference.
PNAS (In Press).
David Crews
Professor
Section of Integrative Biology
University of Texas Austin
Austin, TX 78712
Phone: 512-471-1113
Email: crews@mail.utexas.edu
(Expert in Evolutionary Biology and Sexual Selection)
Andrea C. Gore
Associate Professor
Division of Pharmacology & Toxicology
University of Texas Austin
Austin, TX 78712
Phone: 512-471-3669
Email: andrea.gore@mail.utexas.edu
(Expert in Endocrine
Disruptors and Neuroendocrinology)
Michael K. Skinner, Ph.D.
Professor and Director
Center for Reproductive Biology
School of Molecular Biosciences
Washington State University
Pullman, WA 99164-4231
Phone: 509-335-1524
Email: skinner@wsu.edu
(Expert in Epigenetic Transgenerational Phenomena and Reproduction)
Environmental contamination by endocrine-disrupting
chemicals (EDC) can have epigenetic effects (via DNA methylation) on the germ
line and promote disease across subsequent generations. In natural populations
both sexes may encounter affected as well as unaffected individuals during the
breeding season and any diminution in attractiveness could compromise
reproductive success. Here we examine mate preference in male and female rats
whose progenitors had been treated with the anti-androgenic fungicide vinclozolin.
This effect is sex-specific and we demonstrate that females three generations
removed from the exposure discriminate and prefer males who do not have a
history of exposure, while similarly epigenetically imprinted males do not
exhibit such a preference. The observations suggest that the consequences of
EDCs are not just transgenerational but can be ³transpopulational², because in
many mammalian species males are the dispersing sex. This indicates that
epigenetic transgenerational inheritance of EDC action represent an
unappreciated force in sexual selection. Our observations provide direct
experimental evidence for a role of epigenetics as a determinant factor in
evolution.
A pregnant female was exposed to an environmental compound
(i.e. endocrine disruptor) for a short period at a critical period of sex
determination for the embryo. The male progeny later in life developed
breast tumors, prostate disease, kidney disease, testis defects and immune
abnormalities. This phenotype/disease state was passed to all subsequent
generations examined. Only the original F0 generation mother was exposed
to the environmental toxicant. Nearly all males of all generations had
a disease state and passed it on to their progeny. Females developed
disease, but could not pass the phenotype to the next generation. No known
DNA sequence mutation mechanism can cause this type of transgenerational (i.e.
heritable) disease phenotype. An epigenetic mechanism was identified
in that the male germ-line (i.e. sperm) developed abnormal DNA methylation
of specific genes and DNA sequences. The environmental toxicant permanently
reprogrammed the sperm and induced new imprinted-like genes that passed the
disease state on to all subsequent generations. Observations indicate
that epigenetic mechanisms can permanently alter the germ-line and traits
of progeny of an exposed individual and all subsequent generations.
Evolutionary Biology:
Darwinian evolution is based on the appearance of genetic
mutations (i.e. DNA sequence alterations) that promote a natural selection
process and competitive biological advantage. This adaptation evolution
process is the basis for our understanding of biology and the relationship
of ecosystems. The concept that an environmental factor (i.e. toxicant)
could induce an epigenetic effect that could promote a permanent reprogramming
of the germ-line (i.e. sperm), impacts our concept of evolutionary biology.
This suggests environmental impacts and epigenetics may be a critical variable
in evolution. The current observations suggest new variables and factors
in evolution that need to be considered and may explain some unexplained rapid
evolutionary events previously observed.
Indicates that a class of environmental compounds known as
endocrine disruptors can induce a permanent transgenerational effect on an
individual. The exposure your pregnant grandmother had could induce a
disease state in you and you will pass this on to your grandchildren.
Therefore, the potential hazard of environmental toxicants is dramatically
increased, in particular for pregnant women in mid-gestation.
Previously we have realized that fetal and embryonic development
events can impact disease states in the adult. A number of environmental
toxicants have been shown after an embryonic exposure to cause an adult disease.
The concept that these induced disease states could be transgenerational and
permanently inherited has not been appreciated. Observations indicate
that an epigenetic transgenerational mechanism could be involved in some heritable
diseases. Many diseases have increased in frequency of occurrence but
faster than can be explained from normal genetic (i.e. DNA sequence mutation)
mechanisms. This epigenetic transgenerational phenomenon could explain
the rapid onset of these diseases and would suggest an environmental factor
in the process. This information provides new mechanistic insights into
the molecular basis of disease and new therapeutic strategies to potentially
treat the disease states. In addition, other areas of biology such as evolutionary
biology are impacted with such an epigentic transgenerational mechanism.
The transient exposure of a pregnant female at the time of
embryonic sex determination to an environmental toxicant (endocrine disruptor)
can induce an epigenetic transgenerational phenotype in subsequent generations.
This has a significant impact on our understanding of how environmental factors
can influence the genome and alter the potential evolution of the species.
Epigenetics does not involve DNA sequence changes, but factors
around the genome that regulate genomic activity. An example is the chemical
modification of the DNA (DNA Methylation). This can alter gene expression
and determine if genes are turned on or off. A subset of genes called imprinted
genes can transfer their epigenetic pattern, methylation of DNA, to the next
generation and affect activity of DNA. Endocrine disruptors have been shown
to modify a set of new imprinted-like genes. The frequency of an epigenetic
effect is high compared to that of genetic sequence mutations.