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

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.