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Diet-induced obesity in male C57BL/6 mice decreases fertility as a consequence of disrupted blood-testis barrier.

Fan Y, Liu Y, Xue K, Gu G, Fan W, Xu Y, Ding Z - PLoS ONE (2015)

Bottom Line: The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls.Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice.Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy, Histology and Embryology, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Reproductive Medicine, Shanghai, China.

ABSTRACT
Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD) for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB) integrity may be one of the crucial underlying factors accounting for this change.

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Model accounting for declines in male fertility in mice fed HFD.However, in mice on HFD, what is the impact of BTB integrity disruption on spermatogensis or subsequent sperm maturation? We found that these mice generally have decreased sperm motility and progressive motility, increased rate of teratozoospermia and even lowering of the sperm fertility index. Undoubtedly, the disruption of BTB integrity is one of the crucial factors for this pathogenesis. A possible reason accounting for why mice on a HFD have a disrupted BTB, but without any sperm concentration alteration is that preleptotene/leptotene spermatocytes merely traverse the BTB in advance of BTB integrity disruption rather than later at spermatogenic arrest prior to meiosis onset. Therefore, spermatozoa of HFD mice within the cauda epididymides may be immature eventually, and sperm abnormality rates will also dramatically increase more in the HFD group than in the CD group [16, 18].
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pone.0120775.g007: Model accounting for declines in male fertility in mice fed HFD.However, in mice on HFD, what is the impact of BTB integrity disruption on spermatogensis or subsequent sperm maturation? We found that these mice generally have decreased sperm motility and progressive motility, increased rate of teratozoospermia and even lowering of the sperm fertility index. Undoubtedly, the disruption of BTB integrity is one of the crucial factors for this pathogenesis. A possible reason accounting for why mice on a HFD have a disrupted BTB, but without any sperm concentration alteration is that preleptotene/leptotene spermatocytes merely traverse the BTB in advance of BTB integrity disruption rather than later at spermatogenic arrest prior to meiosis onset. Therefore, spermatozoa of HFD mice within the cauda epididymides may be immature eventually, and sperm abnormality rates will also dramatically increase more in the HFD group than in the CD group [16, 18].

Mentions: The migration of preleptotene/leptotene spermatocytes across the BTB is an important cellular event that occurs during stage Ⅷ of the seminiferous epithelial cycle of spermatogenesis [38]. This event involves intermittent phases of junction disassembly and reassembly between neighboring Sertoli cells to facilitate their transit [39]. On the other hand, the maintenance of BTB integrity at stage Ⅷ of the seminiferous epithelial cycle especially depends on the balance between endocytic vesicle-mediated tight junction proteins (e.g., occludin, ZO-1) transcytosis, recycling and degradation [40, 41]. Previous studies validated that testosterone can regulate BTB integrity through its effects on clathrin-mediated tight junction proteins endocytosis, transcytosis and recycling [42, 43]. Besides,estradiol also has instead negative effects on BTB integrity [40, 44]. Thus, as HFD mice have lower testosterone levels whereas clathrin levels rose, the balance between the tight junction proteins endocytosis, transcytosis, recycling and degradation broke, and much more endosome-mediated tight proteins appeared to be degraded. Therefore, it can be deduced that increased endosome-mediated tight junction proteins degradation is another pathway by which the BTB integrity is disrupted (a diagram shown in Fig 7).


Diet-induced obesity in male C57BL/6 mice decreases fertility as a consequence of disrupted blood-testis barrier.

Fan Y, Liu Y, Xue K, Gu G, Fan W, Xu Y, Ding Z - PLoS ONE (2015)

Model accounting for declines in male fertility in mice fed HFD.However, in mice on HFD, what is the impact of BTB integrity disruption on spermatogensis or subsequent sperm maturation? We found that these mice generally have decreased sperm motility and progressive motility, increased rate of teratozoospermia and even lowering of the sperm fertility index. Undoubtedly, the disruption of BTB integrity is one of the crucial factors for this pathogenesis. A possible reason accounting for why mice on a HFD have a disrupted BTB, but without any sperm concentration alteration is that preleptotene/leptotene spermatocytes merely traverse the BTB in advance of BTB integrity disruption rather than later at spermatogenic arrest prior to meiosis onset. Therefore, spermatozoa of HFD mice within the cauda epididymides may be immature eventually, and sperm abnormality rates will also dramatically increase more in the HFD group than in the CD group [16, 18].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401673&req=5

pone.0120775.g007: Model accounting for declines in male fertility in mice fed HFD.However, in mice on HFD, what is the impact of BTB integrity disruption on spermatogensis or subsequent sperm maturation? We found that these mice generally have decreased sperm motility and progressive motility, increased rate of teratozoospermia and even lowering of the sperm fertility index. Undoubtedly, the disruption of BTB integrity is one of the crucial factors for this pathogenesis. A possible reason accounting for why mice on a HFD have a disrupted BTB, but without any sperm concentration alteration is that preleptotene/leptotene spermatocytes merely traverse the BTB in advance of BTB integrity disruption rather than later at spermatogenic arrest prior to meiosis onset. Therefore, spermatozoa of HFD mice within the cauda epididymides may be immature eventually, and sperm abnormality rates will also dramatically increase more in the HFD group than in the CD group [16, 18].
Mentions: The migration of preleptotene/leptotene spermatocytes across the BTB is an important cellular event that occurs during stage Ⅷ of the seminiferous epithelial cycle of spermatogenesis [38]. This event involves intermittent phases of junction disassembly and reassembly between neighboring Sertoli cells to facilitate their transit [39]. On the other hand, the maintenance of BTB integrity at stage Ⅷ of the seminiferous epithelial cycle especially depends on the balance between endocytic vesicle-mediated tight junction proteins (e.g., occludin, ZO-1) transcytosis, recycling and degradation [40, 41]. Previous studies validated that testosterone can regulate BTB integrity through its effects on clathrin-mediated tight junction proteins endocytosis, transcytosis and recycling [42, 43]. Besides,estradiol also has instead negative effects on BTB integrity [40, 44]. Thus, as HFD mice have lower testosterone levels whereas clathrin levels rose, the balance between the tight junction proteins endocytosis, transcytosis, recycling and degradation broke, and much more endosome-mediated tight proteins appeared to be degraded. Therefore, it can be deduced that increased endosome-mediated tight junction proteins degradation is another pathway by which the BTB integrity is disrupted (a diagram shown in Fig 7).

Bottom Line: The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls.Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice.Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy, Histology and Embryology, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Reproductive Medicine, Shanghai, China.

ABSTRACT
Obesity is a complex metabolic disease that is a serious detriment to both children and adult health, which induces a variety of diseases, such as cardiovascular disease, type II diabetes, hypertension and cancer. Although adverse effects of obesity on female reproduction or oocyte development have been well recognized, its harmfulness to male fertility is still unclear because of reported conflicting results. The aim of this study was to determine whether diet-induced obesity impairs male fertility and furthermore to uncover its underlying mechanisms. Thus, male C57BL/6 mice fed a high-fat diet (HFD) for 10 weeks served as a model of diet-induced obesity. The results clearly show that the percentage of sperm motility and progressive motility significantly decreased, whereas the proportion of teratozoospermia dramatically increased in HFD mice compared to those in normal diet fed controls. Besides, the sperm acrosome reaction fell accompanied by a decline in testosterone level and an increase in estradiol level in the HFD group. This alteration of sperm function parameters strongly indicated that the fertility of HFD mice was indeed impaired, which was also validated by a low pregnancy rate in their mated normal female. Moreover, testicular morphological analyses revealed that seminiferous epithelia were severely atrophic, and cell adhesions between spermatogenic cells and Sertoli cells were loosely arranged in HFD mice. Meanwhile, the integrity of the blood-testis barrier was severely interrupted consistent with declines in the tight junction related proteins, occludin, ZO-1 and androgen receptor, but instead endocytic vesicle-associated protein, clathrin rose. Taken together, obesity can impair male fertility through declines in the sperm function parameters, sex hormone level, whereas during spermatogenesis damage to the blood-testis barrier (BTB) integrity may be one of the crucial underlying factors accounting for this change.

Show MeSH
Related in: MedlinePlus