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21 September 2018 Sources of all-trans retinal oxidation independent of the aldehyde dehydrogenase 1A isozymes exist in the postnatal testis
My-Thanh Beedle, Faith Stevison, Guo Zhong, Traci Topping, Cathryn Hogarth, Nina Isoherranen, Michael D. Griswold
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Abstract

Despite the essential role of the active metabolite of vitamin A, all-trans retinoic acid (atRA) in spermatogenesis, the enzymes, and cellular populations responsible for its synthesis in the postnatal testis remain largely unknown. The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes residing within Sertoli cells is responsible for the synthesis of atRA, driving the first round of spermatogenesis. Those studies also revealed that the atRA required to drive subsequent rounds of spermatogenesis is possibly derived from the ALDH1A enzymes residing within the meiotic and post-meiotic germ cells. Three ALDH1A isozymes (ALDH1A1, ALDH1A2, and ALDH1A3) are present in the testis. Although, ALDH1A1 is expressed in adult Sertoli cells and is suggested to contribute to the atRA required for the pre-meiotic transitions, ALDH1A2 is proposed to be the essential isomer involved in testicular atRA biosynthesis. In this report, we first examine the requirement for ALDH1A2 via the generation and analysis of a conditional Aldh1a2 germ cell knockout and a tamoxifen-induced Aldh1a2 knockout model. We then utilized the pan-ALDH1A inhibitor (WIN 18446) to test the collective contribution of the ALDH1A enzymes to atRA biosynthesis following the first round of spermatogenesis. Collectively, our data provide the first in vivo evidence demonstrating that animals severely deficient in ALDH1A2 postnatally proceed normally through spermatogenesis. Our studies with a pan-ALDH1A inhibitor (WIN 18446) also suggest that an alternative source of atRA biosynthesis independent of the ALDH1A enzymes becomes available to maintain atRA levels for several spermatogenic cycles following an initial atRA injection.

Summary Sentence

Elimination of ALDH1A enzymatic activity following a single pulse of retinoic acid does not immediately ablate spermatogenesis due to the presence of an additional source of atRetinal oxidation.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
My-Thanh Beedle, Faith Stevison, Guo Zhong, Traci Topping, Cathryn Hogarth, Nina Isoherranen, and Michael D. Griswold "Sources of all-trans retinal oxidation independent of the aldehyde dehydrogenase 1A isozymes exist in the postnatal testis," Biology of Reproduction 100(2), 547-560, (21 September 2018). https://doi.org/10.1093/biolre/ioy200
Received: 23 May 2018; Accepted: 11 September 2018; Published: 21 September 2018
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KEYWORDS
Aldh1A
Aldh1a2
retinoic acid
spermatogenesis
spermatogonia
testis
WIN 18,446
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