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Differences in mouse models of diabetes mellitus in studies of male reproduction
J O'Neill1, A Czerwiec, I Agbaje
1Obstetrics and Gynaecology, Queen's University Belfast, Belfast, UK.
Abstract:
Diabetes Mellitus (DM) has been found to have subtle yet profound effects on the metabolic status of the testis, the expression of numerous spermatogenic genes and is associated with increased numbers of sperm with nuclear DNA damage. The precise mechanism causing these detrimental effects remains unknown. The presence of increased levels of the most prominent member (carboxymethyllysine - CML) of the advanced glycation end product adducts and their receptor (RAGE) in the reproductive tract of DM men has provided a new avenue for research. As there are suspicions that the antibiotic (streptozotocin - STZ) employed to induce DM is also capable of causing oxidative stress and DNA damage, we compared CML and RAGE levels in the reproductive tract and sperm nDNA status of STZ mice with the levels in the Ins(2Akita) mouse to determine which more closely mimics the situation described in the human diabetic. CML was observed in the testes, epididymes and sperm of all animals. Sperm from DM mice showed particularly strong CML immunolocalization in the acrosomal cap, the equatorial region and whenever present, cytoplasmic droplets. Although increased, the level of CML on the sperm of the STZ and Ins(2Akita) DM mice did not reach statistical significance. RAGE was present on the developing acrosome and epididymal sperm of all animals and in discrete regions of the epididymes of the DM models. Only the epididymal sperm of the Ins(2Akita) mice were found to have significantly increased (p < 0.0001) nDNA damage. The Ins(2Akita) mouse therefore appears to more accurately reflect the conditions found in the human and, as such, is a more representative model for the study of diabetes and glycation's influence on male fertility.
Insights
Diabetes Mellitus impacts male fertility by affecting sperm DNA. The Ins(2Akita) mouse model, unlike STZ-induced diabetes, accurately reflects human diabetic conditions and glycation
Area of Science:
- Reproductive Biology
- Endocrinology
- Metabolic Disease Research
Background:
- Diabetes Mellitus (DM) adversely affects testicular function, spermatogenesis, and sperm nuclear DNA integrity.
- Advanced glycation end products (AGEs), particularly carboxymethyllysine (CML) and its receptor (RAGE), are implicated in DM's detrimental effects on the reproductive tract.
- The streptozotocin (STZ) model for inducing DM raises concerns about confounding oxidative stress and DNA damage.
Purpose of the Study:
- To compare CML and RAGE levels and sperm nuclear DNA (nDNA) status in STZ-induced diabetic mice versus Ins(2Akita) diabetic mice.
- To determine which mouse model more accurately reflects the human diabetic condition concerning male reproductive health.
- To investigate the role of CML and RAGE in diabetes-associated male infertility.
Main Methods:
- Induction of diabetes in mice using streptozotocin (STZ) and utilizing the Ins(2Akita) genetic model.
- Immunolocalization of CML and RAGE in testes, epididymes, and sperm.
- Assessment of sperm nuclear DNA damage (nDNA status).
- Statistical analysis of CML, RAGE levels, and nDNA damage.
Main Results:
- CML was detected in the testes, epididymes, and sperm of all studied mice, with notable localization in the acrosomal cap and equatorial region of diabetic sperm.
- Increased CML levels in STZ and Ins(2Akita) mice did not reach statistical significance.
- Significantly increased sperm nDNA damage (p < 0.0001) was exclusively observed in the Ins(2Akita) diabetic mouse model.
- RAGE was present in the reproductive tract and on sperm, with discrete epididymal localization in diabetic models.
Conclusions:
- The Ins(2Akita) mouse model serves as a more accurate representation of human diabetic conditions affecting male fertility compared to the STZ model.
- This study highlights the Ins(2Akita) model's utility for investigating the impact of diabetes and glycation on male reproductive health.
- Further research is warranted to elucidate the precise mechanisms linking CML, RAGE, and DNA damage in diabetic male infertility.
