Early Exposure of Mice to DES Causes Developmental and Sperm Function Deficits

Robert G. Halgren
Michigan State University
T32ES07255

Background: Diethylstilbestrol (DES) is a non-steroidal synthetic estrogen that was once used to prevent miscarriages in pregnant women. Tragically, DES was shown to cause cervical clear cell adenocarcinoma, a very rare form of cancer, in the female offspring of women who took it. DES has also been implicated as a cause of several adverse reproductive outcomes in male offspring such as anatomical malformations, testicular cancer, reduced sperm count, and impaired fertility. Estrogen-like compounds in the environment have been purported to cause similar effects in wildlife populations, and human epidemiologic studies suggest that sperm counts are declining and that testicular cancer and reproductive malformations are increasing. These studies have raised the concern that exposure to synthetic and natural endocrine disrupting chemicals has the potential for causing adverse effects on human reproductive health.

The molecular mechanisms responsible for the adverse effects of DES are unclear, although there is evidence that the initiating events involve changes in gene expression. While there is much literature describing the adverse effects of DES, very little is known about its effects at low doses on gene expression. To test the hypothesis that the long-term effects of DES on the male reproductive system are result of lasting changes in testicular gene expression and to potentially identify early biomarkers of adverse effects at later stages of life, these investigators employed a DNA microarray to identify gene expression changes in the testes of affected mice.

Advance: This study demonstrated a long-term decrease in the number of Sertoli cells, epididymal sperm count, and in vitro fertilizing ability in mice after gestational and lactational exposure to DES. Additionally, a number of changes in gene expression were observed including genes involved in steroidogenesis, lysosomal function, and testicular development. Notably, Hoxa10 expression was depressed. Hoxa10 knockout mice manifest bilateral cryptorchidism which ultimately results in defects in spermatogenesis and sterility. Estrogen receptor expression was also significantly depressed.

Implication: This study demonstrates the potential for developmental exposure to DES, and possibly other estrogenic chemicals, to irreversibly alter testicular growth, sperm function, and testicular gene expression. Comparisons of the effects of other estrogenic chemicals to those observed after DES exposure will allow for the development of biomarkers for estrogenic effects on testicular development and sperm function, and add to the knowledge base of the effects of environmental estrogens on male reproductive function.

Citation: Fielden MR, Halgren RG, Fong CJ, Staub C, Johnson L, Chou K, Zacharewski TR. Gestational and lactational exposure of male mice to diethylstilbestrol causes long-term effects on the testis, sperm fertilizing ability in vitro, and testicular gene expression. Endocrinology. 2002 Aug;143(8):3044-59.