Zinc (Zn) is an essential trace element; it exhibits a plethora of physiological properties and biochemical functions. It plays a pivotal role in regulating the cell cycle, apoptosis, and DNA organization, as well as in protein, lipid, and carbohydrate metabolism. Among other important processes, Zn plays an essential role in reproductive health. The ZIP and ZnT proteins are responsible for the mobilization of Zn within the cell. Zn is an inert antioxidant through its interaction with a variety of proteins and enzymes to regulate the redox system, including metallothioneins (MTs), metalloenzymes, and gene regulatory proteins. The role of Zn in the reproductive system is of great importance; processes, such as spermatogenesis and sperm maturation that occur in the testicle and epididymis, respectively, depend on this element for their development and function. Zn modulates the synthesis of androgens, such as testosterone, for these reproductive processes, so Zn deficiency is related to alterations in sperm parameters that lead to male infertility.

The FA/BRCA pathway repairs DNA interstrand crosslinks. Mutations in this pathway cause Fanconi anemia (FA), a chromosome instability syndrome with bone marrow failure and cancer predisposition. Upon DNA damage, normal and FA cells inhibit the cell cycle progression, until the G2/M checkpoint is turned off by the checkpoint recovery, which becomes activated when the DNA damage has been repaired. Interestingly, highly damaged FA cells seem to override the G2/M checkpoint. In this study we explored with a Boolean network model and key experiments whether checkpoint recovery activation occurs in FA cells with extensive unrepaired DNA damage. We performed synchronous/asynchronous simulations of the FA/BRCA pathway Boolean network model. FA-A and normal lymphoblastoid cell lines were used to study checkpoint and checkpoint recovery activation after DNA damage induction. The experimental approach included flow cytometry cell cycle analysis, cell division tracking, chromosome aberration analysis and gene expression analysis through qRT-PCR and western blot. Computational simulations suggested that in FA mutants checkpoint recovery activity inhibits the checkpoint components despite unrepaired DNA damage, a behavior that we did not observed in wild-type simulations. This result implies that FA cells would eventually reenter the cell cycle after a DNA damage induced G2/M checkpoint arrest, but before the damage has been fixed. We observed that FA-A cells activate the G2/M checkpoint and arrest in G2 phase, but eventually reach mitosis and divide with unrepaired DNA damage, thus resolving the initial checkpoint arrest. Based on our model result we look for ectopic activity of checkpoint recovery components. We found that checkpoint recovery components, such as PLK1, are expressed to a similar extent as normal undamaged cells do, even though FA-A cells harbor highly damaged DNA. Our results show that FA cells, despite extensive DNA damage, do not loss the capacity to express the transcriptional and protein components of checkpoint recovery that might eventually allow their division with unrepaired DNA damage. This might allow cell survival but increases the genomic instability inherent to FA individuals and promotes cancer.

Infertility is increasingly recognized as being closely linked to obesity in humans. The successful production of fertile spermatozoa requires adequate spermatogenesis within the testis and proper spermatozoa maturation through the epididymis. This study aimed to evaluate the impact of body adiposity on male fertility, focusing on sperm parameters, epididymal sperm maturation, and sperm capacitation in Wistar rats. Male rats were randomized into three dietary groups over four weeks: a control group receiving less than 4% lard, regular chow, a 10% lard group, and a 60% lard group. Following dietary interventions, fertility tests were conducted across the groups. The epididymis was dissected into caput, corpus, and cauda regions to assess sperm concentration, vitality capacitation, carbohydrate distribution, tyrosine phosphorylation, and phosphatidylserine levels. Additionally, serum testosterone levels were measured to evaluate hormonal influences on fertility. The rats subjected to high-fat diets leading to overweight and obesity exhibited significant alterations in fertility. These changes were characterized by impaired epididymal sperm maturation, as evidenced by lower testosterone levels, decreased sperm viability, and capacitation. Furthermore, increased adiposity was associated with a lack of asymmetry in the plasma membrane, alteration in carbohydrate distribution, and changes in tyrosine phosphorylation. This study underscores the adverse effects of high-fat diets on male fertility, particularly through mechanisms affecting sperm maturation in the epididymis. The evidence suggests that obesity-induced alterations in sperm parameters and hormonal profiles may contribute to reduced fertility in male rats, which could have implications for understanding similar human processes.