Testicular Development in Growth-Retarded Mice

Kobayashi, Kenichi; Kubota, Hisayo; Saegusa, Junzo

doi:10.1538/expanim.56.393

Cited by 4 publications

(6 citation statements)

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“…Fertility is reduced in male grt mice and is associated with delayed testicular development 20 . In the present study, grt mice possessed fewer PRL cells and exhibited lower plasma PRL levels than normal mice (Figs.…”

Section: Discussionsupporting

confidence: 52%

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Impaired Development of Somatotropes, Lactotropes and Thyrotropes in Growth-Retarded (grt) Mice

et al. 2009

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Congenitally primary hypothyroid growth-retarded (grt) mice exhibit a characteristic growth pause followed by delayed onset of pubertal growth. We characterized the developmental pattern of somatotropes, lactotropes and thyrotropes in the anterior pituitary, as well as plasma levels of their secretory hormones, in grt mice. Compared with normal mice, the weight of grt pituitary gland was similar at 8 weeks of age but significantly heavier after 12 weeks of age. Compared with normal mice, there were significantly fewer somatotropes in the grt pituitary until 8 weeks of age, but the number gradually increased up to 48 weeks. The number of lactotropes in grt mice was consistently lower than that in normal mice from 2 through 48 weeks, whereas the number of thyrotropes in the grt pituitary was consistently higher than in the normal pituitary. Thyrotropes in the grt pituitary exhibited hypertrophy and hyperplasia with less intensive thyroid-stimulating hormone (TSH) immunoreactivity than normal thyrotropes. In normal mice, the sum of the relative proportions of these cells plateaued at 8 weeks, where it remained up to 48 weeks of age. In grt mice, these proportions almost reached normal levels at 12 weeks of age but gradually declined after 24 weeks. Plasma growth hormone concentrations did not differ between grt and normal mice until 24 weeks of age. Compared with normal mice, grt mice exhibited significantly lower plasma prolactin and thyroxine levels but higher TSH levels. These findings indicate that development of somatotropes, lactotropes and thyrotropes in grt mice is impaired, being followed by altered hormone secretion.

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Section: Discussionsupporting

confidence: 52%

“…Severe postnatal growth retardation and hormonal abnormalities are observed in grt mice 16 . In male grt mice, delayed testicular development is associated with reduced fertility 20 . Ovarian and uterine development is defective in female grt mice, which results in infertility 21,22 .…”

Section: Introductionmentioning

confidence: 99%

Impaired Development of Somatotropes, Lactotropes and Thyrotropes in Growth-Retarded (grt) Mice

et al. 2009

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“…In rats, T 3 regulates testicular development and function, Sertoli cells, Leydig cells, and germ cell maturation (Wagner et al, 2008). Neonatal thyroid deficiency impairs reproductive development and function in drug-induced or congenitally hypothyroid rodent models (Kimura and Furudate, 1996;Kobayashi et al, 2007;Sakai et al, 2004). Several industrial chemicals also affect the thyroid system (Howdeshell, 2002).…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent effects of perinatal hypothyroidism on postnatal testicular development in rat offspring

et al. 2014

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-The role of thyroid hormones in gonad development remains incompletely understood. We examined the dose-related effects of perinatal hypothyroidism induced by a reversible goitrogen, 6-propyl-2-thiouracil (PTU), on reproductive development in male rat offspring. Timed-pregnant SpragueDawley rats were orally administered PTU (0, 0.5, 1.0, or 2.0 mg/kg/day) by gavage from gestational day 15 through postnatal day 20. We observed a significant dose-dependent decrease in body weight in offspring with PTU exposure up to 13 weeks of age, but body weight became comparable among groups by 26 weeks of age. Testicular weight tended to be lower up to 7 weeks but was higher after 13 weeks of age. Epididymis weight was not different among the groups at any age. Plasma concentrations of thyroxine and triiodothyronine in the PTU groups were significantly lower at 3 weeks of age but recovered to normal levels by 26 weeks of age. No dose-related trend in plasma testosterone concentrations was found. Seminiferous tubules were larger at 13 and 26 weeks of age with PTU exposure. The number of Sertoli cells was significantly higher from 3 through 26 weeks of age. The number of Leydig cells was significantly lower up to 7 weeks of age but was comparable among groups from 13 weeks of age onwards. Thus, transient gestational and lactational thyroid hormone suppression induced small testes in early life but led to paradoxical dose-dependent testicular enlargement in adults as indicated partly by larger seminiferous tubules with numerous Sertoli cells in male rat offspring.

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“…Tpst2 KO mutant females are fertile, whereas males are infertile, although spermatogenesis and mating are normal. In contrast, female grt/grt mice are infertile throughout life, whereas grt/grt males gradually acquire fertility, although their pubertal growth is markedly delayed [19]. In humans, hypothyroidism is associated with a broad spec- Further, congenital hypothyroidism with thyroid dysgenesis is a genetically heterogeneous disease [2].…”

Section: Discussionmentioning

confidence: 99%

“…The grt males demonstrate severely decreased testicular weight and number of Leydig cells until 5-8 weeks age, then gradually acquire normal structure and function of the testis, finally become fertile at about 6 months [19,36]. However, the reason for the lifelong infertility of grt females has not yet been determined.…”

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confidence: 99%

Female Infertility in grt Mice is Caused by Thyroid Hormone Deficiency, not by Insufficient TPST2 Activity in the Reproductive Organs

Hosoda

Sasaki

Agui

2008

The Journal of Veterinary Medical Science

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ABSTRACT. The growth-retarded (grt) mouse has an autosomal recessive hypothyroidism and the female shows lifelong infertility. We previously reported that these mutant phenotypes are caused by a deficiency in the enzymatic activity of tyrosylprotein sulfotransferase-2 (TPST2), and severe thyroid hypogenesis and consequent dwarfism are mainly due to the impairment of the tyrosine sulfation of thyroid-stimulating hormone receptor (TSHR) by TPST2. Although TPST2 is ubiquitously expressed and many proteins are predicted to be tyrosine sulfated and involved in many biological processes, the functional roles of tyrosine sulfation in the reproductive organs remain unclear. These findings tempted us to hypothesize two possible mechanisms underlying the infertility; a deficiency in TPST2 activity in the reproductive organs might cause the infertility in grt mice, or a significant decrease in serum thyroid hormones might impair the normal development of reproductive organs. When mutant female mice were fed a diet supplemented with sufficient thyroid powder to correct their growth retardation, the rate of copulation, pregnancy, and parturition was completely restored. Therefore, we concluded that the infertility in grt female is due to a thyroid hormone deficiency. The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid dysgenesis related to thyroid-stimulating hormone (TSH) hyporesponsiveness [20,41]. We identified that the grt phenotype is caused by a single misssense mutation in the tyrosylprotein sulfotransferase 2 (TPST2) gene with a C-to-G transition at nucleotide 798, leading to the replacement of a highly conserved histidine with glutamine at codon 266 in the sulfotransferase domain by positional cloning [36].TPST catalyzes the transfer of a sulfuryl group from the universal sulfation substrate, 3'-phosphoadenosine 5'-phosphosulfate, to a tyrosyl residue within the acidic motifs of proteins that transit the Golgi apparatus [28]. In mammals, two isozymes, TPST1 and 2, catalyze the tyrosine sulfation of proteins. Although TPST1 and 2 in mammals have 65~67% identical amino acid sequences [28], they seem to have different acceptor preferences [31,37]. Evidence indicates that the posttranslational modification by tyrosine sulfation regulates many important protein-protein interactions and modulates binding affinity and specificity [8,10,11,18,24,26,29,[33][34][35][36]. We previously showed that the sulfation of the tyrosine 385 of TSHR by TPST2 is indispensable for the activation of TSH signaling, and grt mice develop hypothyroidism and dwarfism since they are unable to fully respond to TSH. However, since many proteins besides TSHR are likely to be the substrates of TPST2, severe growth retardation of grt mice might conceal a defect in other proteins that act as substrates of TPST2 [36].

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Testicular Development in Growth-Retarded Mice

Cited by 4 publications

References 16 publications

Impaired Development of Somatotropes, Lactotropes and Thyrotropes in Growth-Retarded (grt) Mice

Impaired Development of Somatotropes, Lactotropes and Thyrotropes in Growth-Retarded (grt) Mice

Dose-dependent effects of perinatal hypothyroidism on postnatal testicular development in rat offspring

Female Infertility in grt Mice is Caused by Thyroid Hormone Deficiency, not by Insufficient TPST2 Activity in the Reproductive Organs

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