Intrauterine Hyponutrition Reduces Fetal Testosterone Production and Postnatal Sperm Count in the Mouse

Yasuko Fujisawa; Hiroyuki Ono; Alu Konno; Ikuko Yao; Hiroaki Itoh; Takashi Baba; Kenichirou Morohashi; Yuko Katoh-Fukui; Mami Miyado; Maki Fukami; Tsutomu Ogata

doi:10.1210/jendso/bvac022

Intrauterine Hyponutrition Reduces Fetal Testosterone Production and Postnatal Sperm Count in the Mouse

J Endocr Soc. 2022 Feb 15;6(4):bvac022. doi: 10.1210/jendso/bvac022. eCollection 2022 Apr 1.

Authors

Yasuko Fujisawa¹, Hiroyuki Ono¹, Alu Konno², Ikuko Yao³, Hiroaki Itoh⁴, Takashi Baba⁵, Kenichirou Morohashi⁵, Yuko Katoh-Fukui⁶, Mami Miyado⁶, Maki Fukami⁶, Tsutomu Ogata^{1

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Affiliations

¹ Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
² Department of Medical Spectroscopy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
³ Department of Optical Imaging, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁴ Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁵ Department of Molecular Biology, Kyushu University, Fukuoka, Japan.
⁶ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁷ Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁸ Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan.

Abstract

Background: Although intrauterine hyponutrition is regarded as a risk factor for the development of "testicular dysgenesis syndrome" (TDS) in the human, underlying mechanism(s) remain largely unknown.

Methods: To clarify the underlying mechanism(s), we fed vaginal plug-positive C57BL/6N female mice with regular food ad libitum throughout the pregnant course (control females) (C-females) or with 50% of the mean daily intake of the C-females from 6.5 dpc (calorie-restricted females) (R-females), and compared male reproductive findings between 17.5-dpc-old male mice delivered from C-females (C-fetuses) and those delivered from R-females (R-fetuses) and between 6-week-old male mice born to C-females (C-offspring) and those born to R-females (R-offspring).

Results: Compared with the C-fetuses, the R-fetuses had (1) morphologically normal external genitalia with significantly reduced anogenital distance index, (2) normal numbers of testicular component cells, and (3) significantly low intratesticular testosterone, in association with significantly reduced expressions of steroidogenic genes. Furthermore, compared with the C-offspring, the R-offspring had (1) significantly increased TUNEL-positive cells and normal numbers of other testicular component cells, (2) normal intratesticular testosterone, in association with normal expressions of steroidogenic genes, (3) significantly reduced sperm count, and normal testis weight and sperm motility, and (4) significantly altered expressions of oxidation stress-related, apoptosis-related, and spermatogenesis-related genes.

Conclusions: The results, together with the previous data including the association between testosterone deprivation and oxidative stress-evoked apoptotic activation, imply that reduced fetal testosterone production is the primary underlying factor for the development of TDS in intrauterine hyponutrition, and that TDS is included in the clinical spectrum of Developmental Origins of Health and Disease.

Keywords: apoptosis; gene expression; intrauterine hyponutrition; spermatogenesis; testosterone production.