Copper deposition in Wilson disease leads to injury due to oxidative stress, mitochondrial damage, and apoptosis in the testes, according to a new study that used a mouse model of the disease. These changes, in turn, led to the impairment of spermatogenesis.

The study also showed that treatment with glutathione could reduce these changes caused by the deposition of copper and thereby improve spermatogenesis.

The study is published in Biomedicine & Pharmacotherapy.

Read more about the complications of Wilson disease

“This study clarified the mechanism by which glutathione improves spermatogenesis,” the study authors wrote, adding that it also “provides a theoretical basis for the clinical application of glutathione in Wilson disease.”

It is known that Wilson disease is associated with fertility decline in men. 

To clarify the mechanism by which copper deposition may lead to subfertility, a team of researchers from China used a mouse model of the disease.

The researchers divided the mice into 3 groups: those that did not receive any treatment, those treated with penicillamine, and those treated with glutathione. The researchers compared these animals with healthy control animals.

The results showed that the testicular coefficient (ie, the weight of the testes relative to the weight of the animal) was the same in control animals and animals with Wilson disease.

However, the tissue structure of the testes was different, with the seminiferous tubules being damaged in animals with Wilson disease. Moreover, the number of spermatozoa was significantly reduced in these animals. 

The rate of apoptosis was also significantly increased in the testes of animals with Wilson disease, as was the expression of the proapoptotic proteins Bax and caspase-3. On the contrary, the expression of the antiapoptotic protein Bcl-2 was significantly decreased. 

Moreover, the levels of reactive oxygen species and malondialdehyde, one of the final products of polyunsaturated fatty acid peroxidation, significantly increased in animals with Wilson disease, while the levels of catalase and glutathione significantly decreased. 

Finally, mitochondria with abnormal ultrastructure and damage were significantly increased in the mice with Wilson disease. 

Penicillamine treatment significantly improved the structure of the testicular seminiferous tubules and the number of spermatozoa, and it significantly reduced the number of apoptotic cells. It also decreased the levels of Bax and caspase-3 and increased the expression of Bcl-2; penicillamine is a chelating agent for copper.

The treatment also increased catalase and glutathione content and significantly decreased levels of reactive oxygen species and malondialdehyde as well as damaged mitochondria. 

Similarly, treatment with glutathione significantly improved the histomorphology of the seminiferous tubules, mitochondrial damage,spermatogenic function, apoptosis-related proteins, apoptosis rate, and oxidative stress in animals with Wilson disease.

Reference

Chen K, Wu L, Liu Q, et al. Glutathione improves testicular spermatogenesis through inhibiting oxidative stress, mitochondrial damage, and apoptosis induced by copper deposition in mice with Wilson disease. Biomed Pharmacother. Published online December 8, 2022. doi:10.1016/j.biopha.2022.114107