Hypospadias in DES GrandSons

Latrogenic legacy from diethylstilbestrol exposure

2002 Study Abstract

In theory, however, birth defects can result not only from direct action on the embryo, but also through genetic damage before conception. Such mechanisms could affect not only the generation exposed to diethylstilbestrol while in utero, but also their own children—ie, transgenerational effects.

Animal studies suggest that diethylstilbestrol might increase transgenerational susceptibility to malignant tumours of the female reproductive tract, presumably from damage to germ cells and abnormal imprinting. In human beings, diethylstilbestrol exposure may lead to permanently altered germ cells and to abnormal semen, but speculation about such transgenerational effects in human beings has been based on animal models.

The report in this issue of The Lancet is the first suggestion of a transgenerational effect of diethylstilbestrol in human beings. Helen Klip and colleagues found an increased prevalence of hypospadias, particularly of severe cases, in the sons of women who were exposed to diethylstilbestrol in utero. Genetic or epigenetic changes in germ or (less likely) somatic cells of these exposed women are suggested as the biological explanation, although physiological changes induced by diethylstilbestrol in uteroplacental functions might also result in impaired male genital development and low birthweight for gestational age.

  • If diethylstilbestrol affects germ cells, transgenerational effects might occur in the descendants of males exposed in utero;
  • if the drug affects uteroplacental functions, only the descendants of exposed females would be affected.



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