We can't find the internet
Attempting to reconnect
Something went wrong!
Hang in there while we get back on track
Interplay of Ferroptosis, Cuproptosis, Autophagy and Pyroptosis in Male Infertility: Molecular Crossroads and Therapeutic Opportunities
Summary
This review examines how different types of cell death, including ferroptosis, cuproptosis, pyroptosis, and autophagy, contribute to male infertility by damaging sperm-producing cells. Environmental toxins, including microplastics, can trigger these destructive pathways through oxidative stress and mitochondrial damage. Understanding these mechanisms is important because it helps explain how environmental pollutant exposure could be contributing to declining male fertility worldwide.
Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis-characterized by mitochondrial dysfunction and disulfide stress due to copper overload-exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood-testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy-pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis-cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function.
Sign in to start a discussion.
More Papers Like This
Internalized polystyrene nanoplastics trigger testicular damage and promote ferroptosis via CISD1 downregulation in mouse spermatocyte
Researchers found that polystyrene nanoplastics cause testicular damage in mice through a cell death process called ferroptosis. The nanoplastics triggered the breakdown of iron-storage proteins and reduced levels of a protective mitochondrial protein called CISD1 in sperm cells. The study suggests that nanoplastic exposure may contribute to male reproductive harm by driving excess iron into mitochondria.
Novel insights into male reproductive toxicity: autophagy-dependent ferroptosis triggered by polylactic acid nanoplastics and copper sulfate
Researchers exposed mice to polylactic acid nanoplastics combined with copper sulfate and found that the combination caused significant testicular damage through a process linking autophagy to ferroptosis, a form of iron-dependent cell death. The combined exposure was more damaging than either substance alone, disrupting sperm production and testicular tissue structure. The study suggests that nanoplastics from biodegradable plastics may amplify the reproductive toxicity of environmental heavy metals.
Microplastics: unraveling the signaling pathways involved in reproductive health
This review examines the effects of microplastics on male and female reproductive health, focusing on the metabolic pathways involved in compromised gamete quality, toxicity, apoptosis, and DNA damage. Evidence indicates that microplastics can increase oxidative stress leading to developmental abnormalities, epigenetic changes, and reduced gamete quality, though research on mammalian and human reproductive effects remains limited compared to studies in aquatic organisms.
Microplastics and male reproductive system: A comprehensive review based on cellular and molecular effects
This comprehensive review examines how microplastics affect the male reproductive system at cellular and molecular levels, drawing on studies from multiple scientific databases. Researchers found that microplastics can damage testicular structure and function, impair spermatogenesis, and disrupt sperm parameters through mechanisms including oxidative stress, inflammation, and activation of cell death pathways. The review highlights that microplastics reduce ATP production and trigger signaling cascades that may contribute to male fertility problems.
Research Progress on Micro(nano)plastic-Induced Programmed Cell Death Associated with Disease Risks
This review summarizes how micro and nanoplastics can trigger different types of programmed cell death, including ferroptosis, pyroptosis, and apoptosis, based on recent animal and cell studies. These forms of cell death are linked to inflammation and diseases affecting the gut, liver, lungs, brain, and reproductive system. The findings help explain the biological mechanisms through which microplastic exposure could contribute to chronic disease in humans.