Testosterone-Induced Metabolic Changes in Seminal Vesicle Epithelial cells Alter Plasma Components to Enhance Sperm Fertility
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Curated by eLife
eLife assessment
This study reports a potentially important discovery that testosterone-induced metabolic changes in seminal vesicle epithelial cells lead to the production of oleic acids in seminal plasma to enhance sperm fertility. The evidence to support metabolic changes in seminal vesicles and the identification of oleic acid as a key factor in seminal plasma is solid. However, the evidence for how oleic acids support enhanced sperm fertility in vivo is not well supported, thus currently remains incomplete, and requires further study.
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Abstract
Male infertility depends on both sperm and seminal plasma and is induced by aging. In this study, male infertility was examined with seminal plasma and its synthesis mechanism. The factors ensuring in vivo fertilization potential was secreted from seminal vesicle where the factors were synthesized in an androgen-dependent manner. Androgen increased glucose uptake and glycolytic capacity in seminal vesicles, which caused activation of oleic acid synthesis rather than mitochondrial ATP synthesis. ACLY was identified as a key player in this metabolic mechanism for producing oleic acid that was incorporated into the sperm and enhanced fertilization potential in vivo . In conclusion, an important role of testosterone-induced metabolic pathways in the seminal vesicle was to ensure the synthesis of oleic acid, which is essential for sperm fertilization in vivo . These results provide new perspectives for the development of biochemical markers of semen to assess male fertility and for artificial insemination techniques. Testosterone induces ACLY expression in seminal vesicle, a key factor of forming seminal plasma to acquire in vivo fertilization ability of sperm.
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eLife assessment
This study reports a potentially important discovery that testosterone-induced metabolic changes in seminal vesicle epithelial cells lead to the production of oleic acids in seminal plasma to enhance sperm fertility. The evidence to support metabolic changes in seminal vesicles and the identification of oleic acid as a key factor in seminal plasma is solid. However, the evidence for how oleic acids support enhanced sperm fertility in vivo is not well supported, thus currently remains incomplete, and requires further study.
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Reviewer #1 (Public Review):
Summary:
In this report, the authors investigated the effects of reproductive secretions on sperm function in mice. The authors attempt to weave together an interesting mechanism whereby a testosterone-dependent shift in metabolic flux patterns in the seminal vesicle epithelium supports fatty acid synthesis, which they suggest is an essential component of seminal plasma that modulates sperm function by supporting linear motility patterns.
Strengths:
The topic is interesting and of general interest to the field. The study employs an impressive array of approaches to explore the relationship between mouse endocrine physiology and sperm function mediated by seminal components from various glandular secretions of the male reproductive tract.
Weaknesses:
Unfortunately, support for the proposed mechanism is not …
Reviewer #1 (Public Review):
Summary:
In this report, the authors investigated the effects of reproductive secretions on sperm function in mice. The authors attempt to weave together an interesting mechanism whereby a testosterone-dependent shift in metabolic flux patterns in the seminal vesicle epithelium supports fatty acid synthesis, which they suggest is an essential component of seminal plasma that modulates sperm function by supporting linear motility patterns.
Strengths:
The topic is interesting and of general interest to the field. The study employs an impressive array of approaches to explore the relationship between mouse endocrine physiology and sperm function mediated by seminal components from various glandular secretions of the male reproductive tract.
Weaknesses:
Unfortunately, support for the proposed mechanism is not convincingly supported by the data, and the experimental design and methodology need more rigor and details, and the presence of numerous (uncontrolled) confounding variables in almost every experimental group significantly reduce confidence in the overall conclusions of the study.
The methodological detail as described is insufficient to support replication of the work. Many of the statistical analyses are not appropriate for the apparent designs (e.g. t-tests without corrections for multiple comparisons). This is important because the notion that different seminal secretions will affect sperm function would likely have a different conclusion if the correct controls were selected for post hoc comparison. In addition, the HTF condition was not adjusted to match the protein concentrations of the secretion-containing media, likely resulting in viscosity differences as a major confounding factor on sperm motility patterns.
There is ambiguity in many of the measurements due to the lack of normalization (e.g. all Seahorse Analyzer measurements are unnormalized, making cell mass and uniformity a major confounder in these measurements). This would be less of a concern if basal respiration rates were consistently similar across conditions and there were sufficient independent samples, but this was not the case in most of the experiments.
The observation that oleic acid is physiologically relevant to sperm function is not strongly supported. The cellular uptake of 10-100uM labeled oleic acid is presumably due to the detergent effects of the oleic acid, and the authors only show functional data for nM concentrations of exogenous oleic acid. In addition, the effect sizes in the supporting data were not large enough to provide a high degree of confidence given the small sample sizes and ambiguity of the design regarding the number of biological and technical replicates in the extracellular flux analysis experiments.
Overall, the most confident conclusion of the study was that testosterone affects the distribution of metabolic fluxes in a cultured human seminal vesicle epithelial cell line, although the physiological relevance of this observation is not clear.
In the introduction, the authors suggest that their analyses "reveal the pathways by which seminal vesicles synthesize seminal plasma, ensure sperm fertility, and provide new therapeutic and preventive strategies for male infertility." These conclusions need stronger or more complete data to support them.
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Reviewer #2 (Public Review):
Summary:
Using a combination of in vivo studies with testosterone-inhibited and aged mice with lower testosterone levels, as well as isolated mouse and human seminal vesicle epithelial cells, the authors show that testosterone induces an increase in glucose uptake. They find that testosterone induces differential gene expression with a focus on metabolic enzymes. Specifically, they identify increased expression of enzymes that regulate cholesterol and fatty acid synthesis, leading to increased production of 18:1 oleic acid.
Strength:
Oleic acid is secreted by seminal vesicle epithelial cells and taken up by sperm, inducing an increase in mitochondrial respiration. The difference in sperm motility and in vivo fertilization in the presence of 18:1 oleic acid and the absence of testosterone is small but …
Reviewer #2 (Public Review):
Summary:
Using a combination of in vivo studies with testosterone-inhibited and aged mice with lower testosterone levels, as well as isolated mouse and human seminal vesicle epithelial cells, the authors show that testosterone induces an increase in glucose uptake. They find that testosterone induces differential gene expression with a focus on metabolic enzymes. Specifically, they identify increased expression of enzymes that regulate cholesterol and fatty acid synthesis, leading to increased production of 18:1 oleic acid.
Strength:
Oleic acid is secreted by seminal vesicle epithelial cells and taken up by sperm, inducing an increase in mitochondrial respiration. The difference in sperm motility and in vivo fertilization in the presence of 18:1 oleic acid and the absence of testosterone is small but significant, suggesting that the authors have identified one of the fertilization-supporting factors in seminal plasma.
Weaknesses:
Further studies are required to investigate the effect of other seminal vesicle components on sperm capacitation to support the author's conclusions. The author's experiments focused on potential testosterone-induced changes in the rate of seminal vesicle epithelial cell glycolysis and oxphos, however, provide conflicting results and a potential correlation with seminal vesicle epithelial cell proliferation should be confirmed by additional experiments.
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Reviewer #3 (Public Review):
Summary:
Male fertility depends on both sperm and seminal plasma, but the functional effect of seminal plasma on sperm has been relatively understudied. The authors investigate the testosterone-dependent synthesis of seminal plasma and identify oleic acid as a key factor in enhancing sperm fertility.
Strengths:
The evidence for changes in cell proliferation and metabolism of seminal vesicle epithelial cells and the identification of oleic acid as a key factor in seminal plasma is solid.
Weaknesses:
The evidence that oleic acids enhance sperm fertility in vivo needs more experimental support, as the main phenotypic effect in vitro provided by the authors remains simply as an increase in the linearity of sperm motility, which does not necessarily correlate with enhanced sperm fertility.
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