Vitamin A Deprivation Affects the Progression of the Spermatogenic Wave and Initial Formation of the Blood-testis Barrier, Resulting in Irreversible Testicular Degeneration in Mice

Abstract

The blood testis-barrier (BTB) is essential for maintaining homeostasis in the seminiferous epithelium. Although many studies have reported that vitamin A (VA) is required for the maintenance of spermatogenesis, the relationships between the BTB, spermatogenesis and VA have not been elucidated. In this study, we analyzed BTB assembly and spermatogenesis in the testes of mice fed the VA-deficient (VAD) diet from the prepubertal period to adulthood. During the prepubertal period, no changes were observed in the initiation and progression of the first spermatogenic wave in mice fed the VAD diet. However, the numbers of preleptotene/leptotene spermatocytes derived from the second spermatogenic wave onwards were decreased, and initial BTB formation was also delayed, as evidenced by the decreased expression of mRNAs encoding BTB components and VA signaling molecules. From 60 days postpartum, mice fed the VAD diet exhibited apoptosis of germ cells, arrest of meiosis, disruption of the BTB, and dramatically decreased testis size. Furthermore, vacuolization and calcification were observed in the seminiferous epithelium of adult mice fed the VAD diet. Re-initiation of spermatogenesis by VA replenishment in adult mice fed the VAD diet rescued BTB assembly after when the second spermatogenic wave initiated from the arrested spermatogonia reached the preleptotene/leptotene spermatocytes. These results suggested that BTB integrity was regulated by VA metabolism with meiotic progression and that the impermeable BTB was required for persistent spermatogenesis rather than meiotic initiation. In conclusion, consumption of the VAD diet led to critical defects in spermatogenesis progression and altered the dynamics of BTB assembly.

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid

“…Besides systemic oxidative stress, conditions correlated with advanced liver diseases, such as portal systemic shunting, dyslipidemia, protein deficiency and micronutrient malabsorption, could also provoke testicular alterations similar to those observed herein [44,[57][58][59][60][61][62][63].…”

Comparison of endpoints relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient diets with varying soy protein and isoflavone contents

“…It must also be noted that, while the low measured thiamine levels are possibly involved in the observed effect, other micronutrients that were lower in the AIN-93-related diets may have also played a role. For example, as noted previously, vitamin A levels were lower in these diets than in the natural ingredient diets and vitamin A also plays a critical role in the development of the testis and the maintenance of spermatogenesis (Chihara et al, 2013; Hogarth and Griswold, 2010). …”

Ursodeoxycholic acid alleviates cholestasis-induced histophysiological alterations in the male reproductive system of bile duct-ligated rats

“…However, other evidence indicates that cholestasis effects on fertility could be more complex than an oxidative stress-mediated action. Conditions correlated with cholestasis, such as the malabsorption of essential micronutrients and deficiency of proteins, are well-known causes of gonadal dysfunction [59][60][61][62][63][64]. Cholestasis-associated dyslipidemia was also reported to have a major role for in inducing testicular dysfunction, since lipid metabolism disorders are associated with impaired fertility [65] and altered sperm parameters [66].…”