ESPE Abstracts

Introduction: Resetting the epigenome in human primordial germ cells is critical for their development. It has been shown that a regulatory network established by SOX17 and PRDM1/BLIMP1 represses DNA methylation pathways and activates TET-mediated hydroxymethylation. (1) Testicular samples from high infertility risk (HIR) cryptorchid boys with defective mini-puberty and impaired differentiation of Ad spermatogonia display altered expression of genes encoding histone methyltransferases. Lacking Ad spermatogonia in testis of HIR patients results in adult infertility. Here, we report expression levels of genes involved in establishing the germ cell epigenome in testicular samples.

Material and Methods: We prospectively selected 15 patients with isolated cryptorchidism and separated them into seven HIR and eight LIR (low infertility risk) patients based on histological data. The median age of the cryptorchid boys was 15 months and they underwent no prior hormonal or surgical treatment. Testicular biopsies obtained during orchidopexy were utilized for histological and transcriptome analyses (RNA sequencing).

Results: We observed that four epigenome establishing genes were expressed at lower levels in HIR testicular samples. (Table 1) This finding is consistent with the notion that cryptorchidism in HIR patients is associated with perturbed establishment of the epigenome and, consequently, abrogated primordial germ cell pluripotency.

Conclusion: We have proposed earlier that hypogonadotropic hypogonadism, cryptorchidism and infertility may be a consequence of elevated fetal estradiol levels during pregnancy. In this context it is noteworthy that the estrogen metabolite 16αOHE negatively regulates the expression of SOX17 which is key regulator of primordial germ cells. (2) This is consistent with evidence that SOX17 and other epigenetic factors are expressed at lower levels in HIR testes. 1983 we reported impaired transformation of primordial germ cells in cryptorchid testes as a possible precursor of seminoma. We hypothesize therefore, that intrauterine perturbance of the primordial germ cell epigenome serve as a template to adult infertility and seminoma development. It is unlikely that such epigenetic alterations can be corrected by early orchidopexy. 1. Tang et al. Cell 2015,161,1453 2. Sangam et al. Am J Respir Crit Care Med. 2023,15;207:1055.