Abstract
Spermatogenesis is a complex multi-step process involving intricate interactions between different cell types in the male testis. Disruption of these interactions results in infertility. Combination of shotgun tissue proteomics with MALDI imaging mass spectrometry is markedly potent in revealing topological maps of molecular processes within tissues. Here, we use a combinatorial approach on a characterized mouse model of hormone induced male infertility to uncover misregulated pathways. Comparative testicular proteome of wild-type and mice overexpressing human P450 aromatase (AROM+) with pathologically increased estrogen levels unravels gross dysregulation of spermatogenesis and emergence of pro-inflammatory pathways in AROM+ testis. In situ MS allowed us to localize misregulated proteins/peptides to defined regions within the testis. Results suggest that infertility is associated with substantial loss of proteomic heterogeneity, which define distinct stages of seminiferous tubuli in healthy animals. Importantly, considerable loss of mitochondrial factors, proteins associated with late stages of spermatogenesis and steroidogenic factors characterize AROM+ mice. Thus, the novel proteomic approach pinpoints in unprecedented ways the disruption of normal processes in testis and provides a signature for male infertility.
Highlights
Infertility is a major health condition that affects around 15% of couples of reproductive age worldwide
As the processes dysregulated in these animals are not entirely clear, we performed an extensive proteomic analysis of testis tissues from WT and AROM+ mice (Fig 1A) at the age of 11 mo
We find a number of biological processes (BPs) upregulated in the testes of AROM+ animals
Summary
Infertility is a major health condition that affects around 15% of couples of reproductive age worldwide. Male reproductive health has declined in many parts of the world contributing, cumulatively, to about 65% of all infertility cases worldwide (Li et al, 2006; Singh & Singh, 2017). Apart from these, a number of anatomical and physiological features have been associated with infertility in men, but precise causative molecular mechanisms has remained elusive so far. This has resulted in a substantial percentage of male infertility cases to be classified as idiopathic (Singh & Singh, 2017) and, subject to only empirical treatments. Systematic understanding of spermatogenesis at the molecular level is imperative in attempts to tackle the aforesaid condition
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