Hi all,
The article below describes the effects of infertility in rats, over
four generations, when the original rat was exposed to two endocrine
disrupting pesticides, vinclozolin and methoxychlor. Vinclozolin, in
particular, has long been recognized as a problematic pesticide, but the
EPA approved "special use" permits in Oregon and elsewhere for more than
a decade.

Jun. 6, 2005 The Scientist DAILY NEWS

Toxins harm descendant fertility

Epigenetic effects of endocrine disruptors pass down four generations in
rats
By Philip Hunter

US researchers have reported firm evidence that damage to mammalian male
fertility caused by transient exposure of embryos to endocrine-disrupting
environmental toxins can be passed down to subsequent generations. Their
finding is published this week by Science.

<<tox transgen Science june05.pdf>>
Investigators from Washington State University, Pullman, exposed female rats
in mid gestation to two endocrine disruptors, the anti-androgenic
vinclozolin and the estrogenic methoxychlor, both at higher doses than
normally encountered in the environment.

More than 90% of male offspring had low sperm counts and abnormal sperm
production, with 10% being completely infertile. An almost identical pattern
of male fertility impairment was passed down to second-, third-, and
fourth-generation males whose parents were not exposed to the toxins.

The critical process causing the loss of fertility was the DNA remethylation
that always occurs at the time of gonadal sex determination shaping the
patterns of gene expression in the offspring, said Michael Skinner, senior
author and director of the Center for Reproductive Biology at Washington
State University. "The endocrine disruptors appear to have altered the
remethylation and permanently reprogrammed the germ line, that is sperm," he
told The Scientist.

The results are significant, said Marcus Pembrey, professor of Paediatric
Genetics at the Institute of Child Health, University College London, who
wasn't involved in the study. "Yes, it looks convincing for both the
evidence for the transgenerational adverse effect on spermatogenesis down
the male line and the associated methylation changes in sperm," he told The
Scientist.

It has been known for at least a decade that some mammal genes are imprinted
with specific DNA methylation patterns that are passed on to subsequent
generations. More recently, there have been several demonstrations of
epigenetic inheritance in mammals. "There are a number of reports on
transgeneration epigenetic inheritance when mice are exposed during
gestation to nutritional methyl donating supplements, various chemical
agents, and ionizing radiation," said Randy Jirtle, a radiation oncologist
at Duke University Medical Center, Durham, NC.

The novel aspect of the latest study, he said, was the demonstration that
epigenetic changes caused by endocrine disrupters rather than other factors,
such as radiation exposure, can be inherited by future generations beyond
the immediate offspring.

Skinner said the possibility that the changes in phenotype in male rats were
caused by mutations in DNA rather than methylation changes could be
discounted because if that were the case, the incidence of transmission to
subsequent generations would then be much less, generally under 1%.

Also, the investigators used polymerase chain reaction to identify changes
in the methylation patterns of two genes in rats exposed to vinclozolin,
using methylation-sensitive restriction enzymes. The two affected genes were
lysophospholipase (LPLase), critical in the synthesis of bioactive lipids
and associated signalling, and SH2, involved in fertility.

An important follow-up will be to assess whether inheritable decline in
fertility shown by the Washington group can be caused by exposure to
endocrine-disrupting toxins at the levels actually prevailing in the
environment, Skinner said. This could be crucial in determining whether the
steep decline in human male sperm counts observed in some countries, such as
the United Kingdom, has been caused by environmental toxins.

Skinner also indicated that males descended from females exposed to the
toxins are more susceptible to other diseases besides impaired fertility.
"Preliminary evidence suggests other diseases develop as the animals get
older," Skinner said. "Examples are prostate disease, kidney disease, and
tumor development. However, these are preliminary results, and we need to
further studies to confirm this."

The work raises the interesting question of whether evolution has provided a
transgenerational mechanism for responding specifically to potentially
damaging environmental factors by reducing but not completely shutting down
male fertility, according to Pembrey. "But it could also be just a poison
that lasts a few generations and then dies out as eventually selection for
precursor cells that don't have the methylation gets rid of it." Extension
of the study over a further few generations could resolve this, he said.
Links for this article

Anway et al., "Epigenetic transgenerational actions of endocrine disruptors
and male fertility," Science, 308:1466-9, June 6, 2005.
http://www.sciencemag.org
Michael K. Skinner http://www.skinner.wsu.edu/
Marcus Edred Pembrey
http://www.ich.ucl.ac.uk/ich/html/academicunits/clin_mol_gen/c_m_g_staff.htmHi