Epigenetic and experimental modifications in early mammalian development: part I. Preface.

Abstract

IVF was ®rst introduced for the treatment of severe female tubal infertility but was rapidly utilized for treatment of cervical factor infertility, polycystic ovarian disease, endometriosis, immunological infertility, unexplained infertility and male factor infertility. Programmes for sperm donation and/or donation of oocytes were established allowing couples unable (e.g. azoospermic males; females without endogenous ovarian function) or unwilling (e.g. due to hereditary disease carrier status) to use their gametes to become biological parents. Cryopreservation of gametes and embryos has been shown to increase the chances of pregnancy in IVF patients and to reduce their costs. Micromanipulation techniques, e.g. intracytoplasmic sperm injection (ICSI), were subsequently developed which now allow treatment of severe male factor cases not amenable to conventional IVF insemination by recovery of mature spermatozoa from the epididymis or testis. Micromanipulation (to remove polar bodies or cells from the developing embryo) when combined with molecular biological protocols, e.g. reverse transcription±polymerase chain reaction (RT±PCR) and uorescence in-situ hybridization (FISH), also aids in preimplantation genetic diagnosis, thereby preventing transfer of embryos at risk of inheritable genetic disease (e.g. sex-linked or autosomal recessive) or chromosomal anomalies. The increase in recent years in older female partners (>40 years old) and in severe male factor cases seeking infertility treatment has led to the use of immature gametes in assisted reproductive technologies (ART) procedures. Such patients often reject the use of donor gametes both because they desire their own (`genetic') child (Tsai et al., 2000) and because of social issues about whether or not to inform the child about his/her genetic background (e.g. van Berkel et al., 1999). The use of immature gametes has also been spurred by shortage of oocyte, but not semen, donors (Van den Hurk et al., 2000). Genetic history or the results of genetic testing preclude acceptance into an oocyte donor programme of a large fraction of candidate women (Wallerstein et al., 1998). Animal studies ®rst demonstrated that immature haploid male germ cells, such as round and elongating spermatids, could produce normal offspring and therefore could be used as gametes (Ogura and Yanagimachi, 1995). Rodent primary and secondary spermatocyte nuclei are able to complete meiosis after oocyte injection and give rise to live offspring, albeit at lower frequencies than with haploid germ cells (Kimura and Yanagimachi, 1995; Kimura et al., 1998; Sasagawa et al., 1998). Human studies have primarily focused on the use of haploid germ cell precursors. Human pregnancies and live births were produced following ICSI with round or elongating spermatids retrieved from testicular tissue (Tesarik et al., 1995; Tessarik, 1996; Araki et al., 1997; Kahraman et al., 1998; AlHasani et al., 1999; Choavaratana et al., 1999; Schoysman et al., 1999). However, fertilization rates, embryo morphology, implantation and pregnancy rates are lower, blastocyst development is delayed, and spontaneous abortion rates are higher with round spermatids as the male gamete, compared with elongated spermatids or mature spermatozoa (Fishel et al., 1997; Vanderzwalmen et al., 1997, 1998; Kahraman et al., 1998; AlHasani et al., 1999; Ghazzawi et al., 1999; Schoysman et al., 1999; Balaban et al., 2000; Levran et al., 2000). This may be due, at least in part, to dif®culties in accurate identi®cation of round spermatids (Vanderzwalmen et al., 1998; Vereyen et al., 1998; Schoysman et al., 1999). In addition, the reduced fertility potential of round spermatids may be related to the timing of oocyte activating ability (Tesarik et al., 1998), which, though the study of homologous and heterologous spermatid injection into mouse oocytes, is thought to occur between the round and elongating stages of sperm development (Yanagida et al., 2000). Other factors may also come into play. These include nuclear maturity (Antinori et al., 1997), whether the sperm calcium oscillation-promoting activity of round spermatid nuclei (Tesarik et al., 2000), which develops between the secondary spermatocyte and round spermatid stage (Sousa et al., 1996), is suf®cient to induce a rapid inactivation of the oocyte's metaphase-promoting factor (Tesarik, 1998) and whether or not the round spermatids are Human Reproduction Update, Vol.7, No.2 pp. 211±216, 2001