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Low NAD + Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice.

Authors :
Meyer-Ficca ML
Zwerdling AE
Swanson CA
Tucker AG
Lopez SA
Wandersee MK
Warner GM
Thompson KL
Chini CCS
Chen H
Chini EN
Meyer RG
Source :
Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2022 May 06; Vol. 13, pp. 896356. Date of Electronic Publication: 2022 May 06 (Print Publication: 2022).
Publication Year :
2022

Abstract

Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD <superscript>+</superscript> levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD <superscript>+</superscript> decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD <superscript>+</superscript> levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD <superscript>+</superscript> levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD <superscript>+</superscript> levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD <superscript>+</superscript> decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD <superscript>+</superscript> synthesis, similar to humans. NAD <superscript>+</superscript> -deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD <superscript>+</superscript> -depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD <superscript>+</superscript> is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD <superscript>+</superscript> in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD <superscript>+</superscript> -deficient mice.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2022 Meyer-Ficca, Zwerdling, Swanson, Tucker, Lopez, Wandersee, Warner, Thompson, Chini, Chen, Chini and Meyer.)

Details

Language :
English
ISSN :
1664-2392
Volume :
13
Database :
MEDLINE
Journal :
Frontiers in endocrinology
Publication Type :
Academic Journal
Accession number :
35600581
Full Text :
https://doi.org/10.3389/fendo.2022.896356