Diabetes is a chronic metabolic disorder characterized by hyperglycemia and associated with many health complications due to the long-term damage and dysfunction of various organs. A consequential complication of diabetes in men is reproductive dysfunction, reduced fertility, and poor reproductive outcomes. However, the molecular mechanisms responsible for diabetic environment-induced sperm damage and overall decreased reproductive outcomes are not fully established. We evaluated the effects of type 2 diabetes exposure on the reproductive system and the reproductive outcomes of males and their male offspring, using a mouse model. We demonstrate that paternal exposure to type 2 diabetes mediates intergenerational and transgenerational effects on the reproductive health of the offspring, especially on sperm quality, and on metabolic characteristics. Given the transgenerational impairment of reproductive and metabolic parameters through two generations, these changes likely take the form of inherited epigenetic marks through the germline. Our results emphasize the importance of improving metabolic health not only in women of reproductive age, but also in potential fathers, in order to reduce the negative impacts of diabetes on subsequent generations.

• Keywords
• GAPDS, TERA, diabetes, fertility, molecular biomarkers, offspring, sperm, testes,
• MeSH
• Diabetes Mellitus, Type 2 blood   chemically induced   genetics   MeSH
• Diet, High-Fat adverse effects   MeSH
• Diabetes Mellitus, Experimental MeSH
• Phenotype * MeSH
• Infertility blood   chemically induced   genetics   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Paternal Inheritance drug effects   genetics   MeSH
• Spermatozoa drug effects   physiology   MeSH
• Streptozocin toxicity   MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Streptozocin MeSH

Male infertility is a worldwide problem associated with genetic background, environmental factors, and diseases. One of the suspected contributing factors to male infertility is diabetes mellitus. We investigated the molecular and morphological changes in sperms and testicular tissue of diabetic males. The study was performed in streptozotocin-induced type 1 diabetes mouse model. Diabetes decreased sperm concentration and viability and increased sperm apoptosis. Changes in protamine 1/protamine 2 ratio indicated reduced sperm quality. The testicular tissue of diabetic males showed significant tissue damage, disruption of meiotic progression, and changes in the expression of genes encoding proteins important for spermiogenesis. Paternal diabetes altered sperm quality and expression pattern in the testes in offspring of two subsequent generations. Our study revealed that paternal diabetes increased susceptibility to infertility in offspring through gametic alternations. Our data also provide a mechanistic basis for transgenerational inheritance of diabetes-associated pathologies since protamines may be involved in epigenetic regulations.

• MeSH
• Biomarkers MeSH
• Diabetes Mellitus, Type 1 complications   metabolism   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease * MeSH
• Meiosis MeSH
• Infertility, Male etiology   MeSH
• Mice MeSH
• Protamines metabolism   MeSH
• Spermatogenesis MeSH
• Spermatozoa metabolism   MeSH
• Testis metabolism   MeSH
• Inheritance Patterns * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Protamines MeSH

In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs) during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.

• MeSH
• Apoptosis MeSH
• Cell Differentiation MeSH
• Endocrine Disruptors toxicity   MeSH
• Epigenesis, Genetic drug effects   MeSH
• Environmental Pollutants toxicity   MeSH
• DNA Methylation MeSH
• MicroRNAs genetics   metabolism   MeSH
• Mice MeSH
• Oxazoles toxicity   MeSH
• Positive Regulatory Domain I-Binding Factor 1 MeSH
• Pregnancy MeSH
• Testis drug effects   pathology   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Germ Cells drug effects   physiology   MeSH
• Prenatal Exposure Delayed Effects chemically induced   genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Endocrine Disruptors MeSH
• Environmental Pollutants MeSH
• MicroRNAs MeSH
• Oxazoles MeSH
• Prdm1 protein, mouse MeSH Browser
• Positive Regulatory Domain I-Binding Factor 1 MeSH
• Transcription Factors MeSH
• vinclozolin MeSH Browser