Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility

Abstract

DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions.

Cadmium activates the innate immune system through the AIM2 inflammasome

“…When Cd enters the body primarily through inhalation and ingestion, its biological half-life is 20-40 years [6]. Cd exposure can result in adverse effects in various organs, including male reproductive dysfunction, presenting as male infertility and poor semen quality in humans [7], and testicular toxicity in rodents [8][9][10]. However, further research is needed to explore the mechanism of Cd-induced male reproductive dysfunction and prevent Cd-induced male reproductive toxicity.…”

Optimizing 2-Nitrophenol and Chromium Adsorption from Water with Aluminium Oxide via Response Surface Methodology

“…Toxic substances, often originating from human activities, are contaminating ecosystems and posing risks to life by causing oxidative stress [1], DNA damage [2], and apoptosis [3] in living cells. Substances like chromium (Cr) and 2-nitrophenol (2-NP) particularly are hazardous as they can travel and persist in the environment without degrading [4].…”

“…An adsorption method can be used to remove toxic substances and is widely favored due to its simplicity, renewability, and versatility [2], [3]. Nanoparticles, available in standalone, functionalized, modified, or substrate-incorporated forms, have been demonstrating significant promise in adsorption processes.…”