pesticide-induced infertility

[Guest guest]

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 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

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