Nef, S, T Shipman and LF Parada. 2000. A molecular basis for estrogen-induced cryptorchidism. Developmental Biology 224:354-361.

New epidemiological links between
estrogenic contaminants
and cryptorchidism in people

Nef et al. demonstrate that maternal exposure to estrogens affects a key part of the genetic control of testicular development, in a way that would lead to impaired testicular descent for fetal males exposed in the womb. This result provides a molecular mechanism through which exposure to compounds with estrogenic properties would lead to cryptorchidism.

Background
Cryptorchidism, or failure of one or both testes to descend into the scrotum around birth, is a common birth defect in infant boys, affecting about 3% of newborn males. It can result in infertility and is associated with a pattern of other testicular maladies (testicular dysgenesis syndrome).

Experiments with laboratory animals shows that cryptorchidism can be induced readily through in utero exposure to anti-androgenic and estrogenic contaminants.

Testicular descent is regulated in two phases of fetal development. One of these phases is controlled by androgens, the other by a hormone recently identified as insulin-3. Male fetal mice developing without the insulin-3 gene (also called Insl3) have undescended testes.

What did they do?
Nef et al. exposed pregnant mice to one of 3 different estrogenic substances, 17a-estradiol, 17ß-estradiol or DES. At several pre- and post-natal stages, embryos/pups were sacrificed and examined to assess developmental condition and to determine whether the treatments interfered with insulin-3 action.

What did they find?
Male mice exposed in utero to the estrogenic substances developed undescended testes. Molecular testing of the exposed vs. untreated mice then confirmed that although the testes had differentiated normally and that general patterns of DNA transcription were normal, insulin-3 transcription "was severely altered." Further analysis indicated that insulin-3 gene expression was blocked in a key set of cells (Leydig cells) involved in sending the hormonal signal controlling the second phase of testicular descent. Thus the estrogenic substances blocked the expression of a specific gene necessary for normal testicular descent.

This study is important because it provides a molecular mechanism for the impact of estrogenic compounds in producing cryptorchidism.