Toxins harm descendant fertility

Epigenetic effects of endocrine disruptors pass down four generations in rats

By | June 6, 2005

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.

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.

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