Toward Molecular Medicine in Female Infertility Management: Editorial to the Special Issue “Molecular Mechanisms of Human Oogenesis and Early Embryogenesis”

Female infertility is the main reason for involuntary childlessness nowadays [...]

A pathogenic DMC1 frameshift mutation causes nonobstructive azoospermia but not primary ovarian insufficiency in humans

Nonobstructive azoospermia (NOA) and diminished ovarian reserve (DOR) are two disorders that can lead to infertility in males and females. Genetic factors have been identified to contribute to NOA and DOR. However, the same genetic factor that can cause both NOA and DOR remains largely unknown. To explore the candidate pathogenic gene that causes both NOA and DOR, we conducted whole-exome sequencing (WES) in a non-consanguineous family with two daughters with DOR and a son with NOA. We detected one pathogenic frameshift variant (NM_007068:c.28delG, p. Glu10Asnfs*31) following a recessive inheritance mode in a meiosis gene DMC1 (DNA meiotic recombinase 1). Clinical analysis showed reduced antral follicle number in both daughters with DOR, but metaphase II oocytes could be retrieved from one of them. For the son with NOA, no spermatozoa were found after microsurgical testicular sperm extraction. A further homozygous Dmc1 knockout mice study demonstrated total failure of follicle development and spermatogenesis. These results revealed a discrepancy of DMC1 action between mice and humans. In humans, DMC1 is required for spermatogenesis but is dispensable for oogenesis, although the loss of function of this gene may lead to DOR. To our knowledge, this is the first report on the homozygous frameshift mutation as causative for both NOA and DOR and demonstrating that DMC1 is dispensable in human oogenesis.

Extracellular Vesicles in Human Oogenesis and Implantation

Reproduction, the ability to generate offspring, represents one of the most important biological processes, being essential for the conservation of the species. In mammals, it involves different cell types, tissues and organs, which, by several signaling molecules, coordinate the different events such as gametogenesis, fertilization and embryo development. In the last few years, the role of Extracellular Vesicles, as mediators of cell communication, has been investigated in every phase of these complex processes. Microvesicles and exosomes, identified in the fluid of ovarian follicles during egg maturation, are involved in communication between the developing oocyte and the somatic follicular cells. More recently, it has been demonstrated that, during implantation, Extracellular Vesicles could participate in the complex dialog between the embryo and maternal tissues. In this review, we will focus our attention on extracellular vesicles and their cargo in human female reproduction, mainly underlining the involvement of microRNAs in intercellular communication during the several phases of the reproductive process.

Do Prenatal Exposures Pose a Real Threat to Ovarian Function? BPA as a Case Study

Fetal development represents a time of potential vulnerability due to rapid cell division, organ development, and limited fetal kidney/liver activity for detoxification and metabolism of exposures. Health effects of prenatal toxicant exposure have previously been described, but there is little cohesive evidence surrounding effects on ovarian function. Using bisphenol A (BPA) as a case study, we seek to examine whether a prominent prenatal environmental exposure can pose a real threat to human ovarian function. To do so, we broadly review human oogenesis and menstrual cycle biology. We then present available literature addressing prenatal bisphenol A and diverse outcomes at the level of the ovary. We highlight relevant human cohorts, and mammalian models to review the existing data on prenatal exposures and ovarian disruption. Doing so suggests that while current exposures to BPA have not shown marked or consistent results, there is data sufficient to raise concerns regarding ovarian function. Challenges in the examination of this question suggests the need for additional models and pathways by which to expand these examinations in humans.