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Exposure of neonatal mice to Sevoflurane may induce male germ cell apoptosis in testicular tissue after puberty.

ABSTRACT: BACKGROUND:common use of sevoflurane in congenital defects during repeated surgeries may have detrimental effects on spermatogenesis after puberty. OBJECTIVE:This study investigated sevoflurane effects on spermatogenesis process in male mature mice after exposure in prepubertal time. MATERIALS AND METHODS:24 neonatal NMRI male mice were randomly classified in three groups. Experimental 1 and 2 groups (exposure to 1 minimum alveolar concentration (MAC) and 2 MAC sevoflurane, respectively in 2 lit/min oxygen (O2) for 7 days (30 min, daily) and control. All groups were sacrificed after 2 months. Histological assessment, immunohistochemistry and apoptosis process was done. Bax and Bcl2 expression was evaluated in the testicular tissue by real time Poly Chain Reaction. RESULTS:Our results showed that the integrity of testicular tissue was preserved in both experimental groups. Count of spermatogonial cells had significant decrease in group 2 compared to others. The rate of apoptosis in spermatogonial cells was 15±3% and 9±2% in the group 2 and 1, respectively. Also, Bax/Bcl2 ratio was 0.2615, 1.0070 and 9.3657 in control, experimental group 1 and 2, respectively. This result was significant (p?0.002) between groups 2 with other groups. CONCLUSION:Continuous exposure of 2 MAC sevoflurane in 2 lit/min O2 simultaneous during prepubertal may create more testicular tissue damage in terms of cellular and molecular function compared to continuous exposure to lower level of sevoflurane by increase in ratio of Bax/Bcl2 and apoptosis in germ cells after puberty.

SUBMITTER: Nezhad Sistani M

PROVIDER: S-EPMC5653908 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Exposure of neonatal mice to Sevoflurane may induce male germ cell apoptosis in testicular tissue after puberty.

Nezhad Sistani Maryam M Maleki Anahid A Salimi Maryam M Ghaffari Novin Marefat M Nazarian Hamid H

International journal of reproductive biomedicine 20170801 8

<h4>Background</h4>common use of sevoflurane in congenital defects during repeated surgeries may have detrimental effects on spermatogenesis after puberty.<h4>Objective</h4>This study investigated sevoflurane effects on spermatogenesis process in male mature mice after exposure in prepubertal time.<h4>Materials and methods</h4>24 neonatal NMRI male mice were randomly classified in three groups. Experimental 1 and 2 groups (exposure to 1 minimum alveolar concentration (MAC) and 2 MAC sevoflurane, ...[more]

PMID: 29082365

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Project description:Background: Testicular germ cell tumor (TGCT) incidence has increased over the last 40 years in the United States. In contrast to TGCT among infants, it is hypothesized that TGCT in adolescents and young men is the result of sex steroid hormone imbalance during early fetal development. However, little is known about the neonatal period when abrupt hormonal changes occur, and direct supporting evidence is scarce due to the difficulties in obtaining prediagnostic specimens.Methods: We conducted a population-based case-control study examining hormone levels at birth among 91 infants (0-4 years) and 276 adolescents (15-19 years) diagnosed with TGCT, and 344 matched controls. Estrogen and androgen levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from archived newborn dried blood spots. Logistic regression models were used to estimate the association between each hormone level and TGCT risk.Results: Higher levels of androstenedione were associated with increased TGCT risk among adolescents [odds ratio (OR): 2.33, 95% confidence interval (CI): 1.37-3.97 for highest vs. lowest quartile; P trend = 0.003] but not among infants (OR: 0.70, 95% CI: 0.28-1.77). A similar pattern was observed for testosterone (OR: 1.73, 95% CI: 1.00-3.00,) although the trend was not significant (P trend = 0.12). Associations were stronger among non-Hispanic white subjects, relative to Hispanics. There was no difference by tumor histologic subtype. Estriol (the only detectable estrogen) was not associated with TGCT risk in either age group.Conclusions: Higher levels of neonatal androgens were associated with increased risk of TGCT among adolescents, suggesting that early life hormone levels are related to the later development of TGCT.Impact: This is the first study with direct measures of sex steroid hormones to examine the relationship between estrogens and androgens at birth and risk of adolescent TGCT. Cancer Epidemiol Biomarkers Prev; 27(4); 488-95. ©2018 AACR.

Project description:Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ER?) and beta (ER?) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ER? expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ER? expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ER? expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKO?, ERKO?, and ERKO??) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.

Project description:While in mice various studies have described the completion of spermatogenesis in vitro using either organotypic culture of prepubertal testicular tissue or 3D culture of isolated cells, in humans it has not been possible to achieve germ cell differentiation from immature testicular tissue (ITT). In our study, we evaluated the ability of human ITT to differentiate via a long-term organotypic culture of frozen-thawed 1 mm3 testicular fragments from five prepubertal boys in two different culture media. Tissue and supernatants were analyzed at regular intervals up to day 139. Sertoli cell (SC) viability and maturation was evaluated using immunohistochemistry (IHC) for SOX9, GDNF, anti-Mullerian hormone (AMH) and androgen receptor (AR), and AMH concentration in supernatants. Spermatogonia (SG) and proliferating cells were identified by MAGE-A4 (for SG) and Ki67 (for proliferating cells) via immunohistochemistry (IHC). Apoptotic cells were studied by active caspase 3. To evaluate Leydig cell (LC) functionality testosterone was measured in the supernatants and steroidogenic acute regulatory protein (STAR) IHC was performed. Germ cell differentiation was evaluated on Hematoxylin-Eosin histological sections, via IHC for synaptonemal complex 3 (SYCP3) for spermatocytes, Protein boule-like (BOLL) for spermatocytes and round spermatids, angiotensin-converting enzyme (ACE), protamine 2 and transition protein 1 (for elongated spermatids) and via chromogenic in situ hybridization (CISH). We reported the generation of meiotic and postmeiotic cells after 16 days of culture, as shown by the histological analyses, the presence of differentiation markers and the increase of haploid germ cells. We showed SC viability and maturation by a decrease of AMH secretion in the supernatants (p ? 0.001) while the number of SOX9 positive cells did not show any variation. A decrease of spermatogonia (p ? 0.001) was observed. The number of apoptotic cells did not vary. LC functionality was shown by the increase in STAR expression (p ? 0.007) and a peak in testosterone secretion, followed by a reduction (p ? 0.001) with stabilization. According to our knowledge, this is the first report of generation of haploid cells in human ITT. Differentiating germ cells have to be further evaluated for their ability to complete differentiation, their fecundability and epigenetic characteristics.

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Exposure of neonatal mice to Sevoflurane may induce male germ cell apoptosis in testicular tissue after puberty.

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Exposure of neonatal mice to Sevoflurane may induce male germ cell apoptosis in testicular tissue after puberty.

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