Epigenetics, cryptorchidism, and infertility.

Background: Cryptorchid boys with defective mini-puberty and impaired differentiation of Ad spermatogonia (high infertility risk) have altered expression of several genes encoding histone methyltransferases compared to patients with intact differentiation of gonocytes into Ad spermatogonia (low infertility risk).

Results: High infertility risk cryptorchid boys display hypogonadotropic hypogonadism, which, together with the diminished expression of histone deacetylases and increased expression of HDAC8 decrotonylase, indicates altered histone marks and, thus, a perturbed histone code. Curative GnRHa treatment induces normalization of histone methyltransferase, chromatin remodeling, and histone deacetylase gene expression. As a result, histone changes induce differentiation of Ad spermatogonia from their precursors and, thus, fertility. In this short report, we describe key functions of histone lysine methyltransferases, chromatin remodeling proteins, and long-noncoding RNAs, and discuss their potential roles in processes leading to infertility.

Conclusion: Our findings suggest that epigenetic mechanisms are critical to better understanding the root causes underlying male infertility related to cryptorchidism and its possible transgenerational transmission.