Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The capacity of testicular somatic cells to promote and sustain germ cell differentiation is largely regulated by sexual steroids and notably androgens. In fish species the importance of androgens is emphasized by their ability to induce sex reversal of the developing fries and to trigger spermatogenesis. Here we studied the influence of androgens on testicular gene expression in trout testis using microarrays. Following treatment of immature males with physiological doses of testosterone or 11-ketotestosterone, 418 genes that exhibit changes in expression were identified. Interestingly, the activity of testosterone appeared stronger than that of 11-ketotestosterone. Expression profiles of responsive genes throughout testis development and in isolated germ cells confirmed androgens to mainly affect gene expression in somatic cells. Furthermore, specific clusters of genes that exhibit regulation coincidently with changes in the natural circulating levels of androgens during the reproductive cycle were highlighted, reinforcing the physiological significance of these data. Among somatic genes, a phylogenetic footprinting study identified putative androgen response elements within the proximal promoter regions of 42 potential direct androgen target genes. Finally, androgens were also found to alter the germ line towards meiotic expression profiles, supporting the hypothesis of a role for the somatic responsive genes in driving germ cell fate. This study significantly increases our understanding of molecular pathways regulated by androgens in vertebrates. The highly cyclic testicular development in trout together with functions associated with regulated genes reveal potential mechanisms for androgen actions in tubule formation, steroid production, germ cell development and sperm secretion.
ISSN: 1932-6203

inserm-00825763
http://www.hal.inserm.fr/inserm-00825763
http://www.hal.inserm.fr/inserm-00825763/document
http://www.hal.inserm.fr/inserm-00825763/file/Rolland_et_al.pdf
DOI : 10.1371/journal.pone.0053302

Éditeur(s) : HAL CCSD BioScientifica
Résumé : International audience
Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDN-POA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women.
ISSN: 1470-1626

hal-01560285
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560285/file/Prenatal%20exposures%20to%20paracetamol-accepted.pdf
DOI : 10.1530/REP-17-0165

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
Are bisphenol A (BPA) and BPA analogs (BPA-A) safe for male human reproductive function? The endocrine function of human testes explants [assessed by measuring testosterone and insulin-like factor 3 (INSL3)] was impacted by exposure of the human adult testis explants to BPA/BPA-A. The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB) and bisphenol A diglycidyl ether (BADGE) at 10(-9)-10(-5) M for 24 or 48 h. Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase three immunohistochemistry), and the levels of testosterone, INSL3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). A significant dose-dependent inhibition was found between testosterone levels measured in the culture medium and concentrations of BPA (P = 0.00778 at 24 h and P = 0.0291 at 48 h), BPE (P = 0.039) and BPF (P = 0.00663). The observed BPA and BPA-A-induced inhibition of testosterone production varied according to duration of exposure and BPA/BPA-A concentrations. BPA (10(-9) M; P < 0.05), BPB (10(-9) M; P < 0.05), BPS (10(-9) and 10(-8) M; P < 0.05) and BADGE (10(-5) M; P < 0.05) increased Leydig cell INSL3 production. By contrast, BPE dose dependently inhibited INSL3 (P = 0.0372). Conversely, Sertoli cell function (inhibin B) and germ cell viability were not significantly affected by either bisphenols. N/A. Environmental compounds cannot be deliberately administered to men, justifying the use of an ex vivo approach. A relatively low number of testes samples were available for analysis (n = 3, except for testosterone secretion with n = 5). The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis.
ISSN: 0268-1161

hal-01578582
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578582
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578582/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578582/file/Parallel%20assessment%20of%20the%20effects%20of%20bisphenol%20A_accepted.pdf
DOI : 10.1093/humrep/dex093

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: Phthalic acid esters are widely used in the manufacture of plastics. Numerous studies have shown that these phthalates impair testicular testosterone production in the rat. However, the scarce and contradictory data concerning humans have cast doubt over whether these compounds are also anti-androgenic in man. We therefore investigated the direct effects of di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) on organo-cultured adult human testis and a human cell line. METHODS: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with DEHP or MEHP. The effects of ketoconazole, used as a reference molecule, were also assessed. RESULTS: In both models, DEHP and MEHP significantly inhibited testosterone production. The effects of both phthalates appeared to be specific for steroidogenesis, as INSL3 production by Leydig cells was not altered. Furthermore, the phthalates of interest had no effect on inhibin B production by Sertoli cells or on germ cell apoptosis. As only a small fraction of the phthalates added was found in the testis explants, and as these compounds were found to be metabolized, we estimate that the anti-androgenic effects observed occurred at concentrations of phthalates that are of the same order of magnitude as exposures reported in the literature for men. CONCLUSIONS: We provide the first evidence that DEHP and MEHP can inhibit testosterone production in the adult human testis. This is consistent with recent epidemiological findings of an inverse correlation between exposure to MEHP and testosterone concentrations.
ISSN: 0268-1161

hal-00876965
https://hal.archives-ouvertes.fr/hal-00876965
DOI : 10.1093/humrep/des069
PUBMED : 22402212

Éditeur(s) : HAL CCSD Oxford University Press (OUP): Policy B1 - Oxford Open Option B Oxford University Press (OUP)
Résumé : International audience
BACKGROUNDA very large proportion of the literature on the endocrine disruptors categorized as anti-androgens deals with phthalates, which are produced in large amounts for use as plastic emollients and additives. In this review, we bring together and analyse work on the effects of phthalates in animals and humans at different stages of their development to assess whether or not their possible anti-androgenic properties represent a significant threat to human health.METHODSThe database PubMed was systematically searched for all English language articles until July 2013 in each subject area discussed.RESULTSWe provide an up-to-date exhaustive, comparative and critical assessment of both in vivo and in vitro studies undertaken to explore the effects of phthalates on the human testis from fetal life to adulthood. These results are compared and discussed in the light of the key data reported in the literature for mice and rats.CONCLUSIONSThe current literature highlights the fact that (i) there is a huge difference between the number of studies performed in animals and in humans, with many fewer for humans; (ii) there are differences in the way rats, mice, primates and humans respond to phthalates, for reasons that need to be further explored; (iii) more work is required to clarify the contradictions, in the few existing human epidemiological studies at all stages of development, which may be partly explained by varying methods of exposure assessment; (iv) in accordance with recent findings in rodents, it cannot be excluded that transgenerational effects of phthalates and/or epigenetic changes exist in humans; (v) a number of methodological limitations need to be solved for the in vitro and xenografting models using human fetal testis to fulfil their 'missing link' role between epidemiological studies in humans and rodent models; and (vi) epidemiological and in vitro studies generally converge sufficiently to conclude that phthalate anti-androgenicity is plausible in adult men.
ISSN: 1355-4786

inserm-00869540
http://www.hal.inserm.fr/inserm-00869540
DOI : 10.1093/humupd/dmt050
PUBMED : 24077978

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
More than half the pregnant women in the Western world report taking mild analgesics. These pharmaceutical compounds have been associated with congenital cryptorchidism in humans, the best-known risk factor for low semen quality and testicular germ cell cancer. Furthermore, some of these mild analgesics exert potent anti-androgenic effects in the male rat and several endocrine-disrupting compounds, known to alter masculinization, have also been shown to be potent inhibitors of prostaglandin (PG) synthesis similar to mild analgesics. Using a 3-day ex vivo organotypic model system based on gestational day 14.5 rat testes, we herein show that testosterone production was inhibited by paracetamol, at doses of 0.1 μm to 100 μm. Similar results were obtained for aspirin (1-100 μm) and indomethacin (10 μm). The production of the other Leydig cell hormone, Insl3, was not disrupted by exposure to paracetamol. Investigations of the gross anatomy of the testis as well as Leydig cells number and rate of gonocyte apoptosis after the 3 days of ex vivo differentiation showed no significant effect of the analgesics tested compared with controls. These data indicate therefore that mild analgesics specifically inhibit testosterone production in rat foetal testes in vitro and that these compounds had no effect on gonocyte survival. Parallel determinations of prostaglandin D2 (PGD2) production indicated that the effects of paracetamol and aspirin on PGD2 and testosterone were not connected, whereas the effects of indomethacin were correlated. We conclude that mild analgesics exert direct and specific anti-androgenic effects in rat foetal testis in our experimental setup and that the mechanism of action is probably uncoupled from the inhibition of PG synthesis.
ISSN: 0105-6263

hal-00876956
https://hal.archives-ouvertes.fr/hal-00876956
DOI : 10.1111/j.1365-2605.2012.01282.x
PUBMED : 22612476

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The tg(cyp19a1b-GFP) transgenic zebrafish expresses GFP (green fluorescent protein) under the control of the cyp19a1b gene, encoding brain aromatase. This gene has two major characteristics: (i) it is only expressed in radial glial progenitors in the brain of fish and (ii) it is exquisitely sensitive to estrogens. Based on these properties, we demonstrate that natural or synthetic hormones (alone or in binary mixture), including androgens or progestagens, and industrial chemicals induce a concentration-dependent GFP expression in radial glial progenitors. As GFP expression can be quantified by in vivo imaging, this model presents a very powerful tool to screen and characterize compounds potentially acting as estrogen mimics either directly or after metabolization by the zebrafish embryo. This study also shows that radial glial cells that act as stem cells are direct targets for a large panel of endocrine disruptors, calling for more attention regarding the impact of environmental estrogens and/or certain pharmaceuticals on brain development. Altogether these data identify this in vivo bioassay as an interesting alternative to detect estrogen mimics in hazard and risk assessment perspective.
ISSN: 1932-6203

hal-00877371
https://hal.archives-ouvertes.fr/hal-00877371
https://hal.archives-ouvertes.fr/hal-00877371/document
https://hal.archives-ouvertes.fr/hal-00877371/file/Screening_Estrogenic_Activities-accepted.pdf
DOI : 10.1371/journal.pone.0036069

Éditeur(s) : HAL CCSD
Résumé : International audience
Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolised to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into anti-androgenic paracetamol, impairs male reproductive development
Toxicological Sciences: An Official Journal of the Society of Toxicology

hal-01187305
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187305
DOI : 10.1093/toxsci/kfv179
PUBMED : 26259604

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5-17.5 days post-coitum) and humans (8-12 gestational weeks) and under different culture conditions. BPA concentrations of 10-8M and 10-5M for 72h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48h in both strains. BPA at 10-7-10-5M for 72h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10-8M, 10-7M, and 10-5M for 72h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.
ISSN: 1932-6203

hal-01121759
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01121759
PUBMED : 25706302
DOI : 10.1371/journal.pone.0117226

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The cyp19a1 gene that encodes aromatase, the only enzyme permitting conversion of C19 aromatizable androgens into estrogens, is present as a single copy in the genome of most vertebrate species, except in teleosts in which it has been duplicated. This study aimed at investigating the brain expression of a cyp19a1 gene expressed in both gonad and brain of Japanese eel, a basal teleost. By means of immunohistochemistry and in situ hybridization, we show that cyp19a1 is expressed only in radial glial cells of the brain and in pituitary cells. Treatments with salmon pituitary homogenates (female) or human chorionic gonadotrophin (male), known to turn on steroid production in immature eels, strongly stimulated cyp19a1 messenger and protein expression in radial glial cells and pituitary cells. Using double staining studies, we also showed that aromatase-expressing radial glial cells exhibit proliferative activity in both the brain and the pituitary. Altogether, these data indicate that brain and pituitary expression of Japanese eel cyp19a1 exhibits characteristics similar to those reported for the brain specific cyp19a1b gene in teleosts having duplicated cyp19a1 genes. This supports the hypothesis that, despite the fact that eels also underwent the teleost specific genome duplication, they have a single cyp19a1 expressed in both brain and gonad. Such data also suggest that the intriguing features of brain aromatase expression in teleost fishes were not gained after the whole genome duplication and may reflect properties of the cyp19a1 gene of ancestral Actinopterygians.
ISSN: 1932-6203

hal-00877375
https://hal.archives-ouvertes.fr/hal-00877375
https://hal.archives-ouvertes.fr/hal-00877375/document
https://hal.archives-ouvertes.fr/hal-00877375/file/Expressionsur Aromatase-accepted.pdf
DOI : 10.1371/journal.pone.0044750

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Androgen signaling, via the androgen receptor (AR), is crucial in mediating prostate cancer (PCa) initiation and progression. Identifying new downstream effectors of the androgens/AR pathway will allow a better understanding of these mechanisms and could reveal novel biomarkers and/or therapeutic agents to improve the rate of patient survival. We compared the microRNA expression profiles in androgen-sensitive LNCaP cells stimulated or not with 1 nM R1881 by performing a high-throughput reverse transcriptase-quantitative PCR and found that miR-135a was upregulated. After androgen stimulation, we showed that AR directly activates the transcription of miR-135a2 gene by binding to an androgen response element in the promoter region. Our findings identify miR-135a as a novel effector in androgens/AR signaling. Using xenograft experiments in chick embryos and adult male mice, we showed that miR-135a overexpression decreases in vivo invasion abilities of prostate PC-3 cells. Through in vitro wound-healing migration and invasion assays, we demonstrated that this effect is mediated through downregulating ROCK1 and ROCK2 expression, two genes that we characterized as miR-135a direct target genes. In human surgical samples from prostatectomy, we observed that miR-135a expression was lower in tumoral compared with paired adjacent normal tissues, mainly in tumors classified with a high Gleason score (⩾8). Moreover, miR-135a expression is lower in invasive tumors, showing extraprostatic extension, as compared with intraprostatic localized tumors. In tumor relative to normal glands, we also showed a more frequently higher ROCK1 protein expression determined using a semi-quantitative immunohistochemistry analysis. Therefore, in tumor cells, the lower miR-135a expression could lead to a higher ROCK1 protein expression, which could explain their invasion abilities. The highlighted relationship between miR-135a expression level and the degree of disease aggressiveness suggests that miR-135a may be considered as a prognostic marker in human PCa.Oncogene advance online publication, 28 July 2014; doi:10.1038/onc.2014.222.
ISSN: 0950-9232

hal-01063902
https://hal.archives-ouvertes.fr/hal-01063902
https://hal.archives-ouvertes.fr/hal-01063902/file/Androgen-regulated%20microRNA-135a.pdf
DOI : 10.1038/onc.2014.222
PUBMED : 25065599

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis? SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.
ISSN: 0268-1161

inserm-00866016
http://www.hal.inserm.fr/inserm-00866016
PUBMED : 23670170
DOI : 10.1093/humrep/det112

Résumé : En Guadeloupe, la prévalence du diabète est deux fois plus élevée qu'en France hexagonale, avec une prédominance féminine. En dehors des facteurs environnementaux, la vitamine D et certains polymorphismes de gènes impliqués dans son métabolisme seraient associés à un risque de pathologies métaboliques. Les androgènes sont également associés aux anomalies du métabolisme glucidique, soit directement, soit via leur transporteur SHBG (Sex Hormone Binding Protein). Nous avons émis les hypothèses de recherche suivantes: 11 le statut en vitamine D et les polymorphismes des gènes impliqués dans son métabolisme pourraient être associés aux paramètres métaboliques chez des sujets Afro-Caribéens (AC). Ils expliqueraient l'importance des pathologies cardiométaboliques en Guadeloupe. 2/ la SHBG pourrait être associée aux anomalies du métabolisme glucidique, indépendamment des stéroïdes sexuels. Nos travaux sont présentés dans 4 études. Nous avons mis en évidence une prévalence élevée du déficit en vitamine D chez les sujets AC diabétiques de type 2. Nous avons trouvé une association significative entre le statut vitaminique D et le risque cardiométabolique chez ces sujets, mais aussi dans une population de sujets en hémodialyse chronique. Les polymorphismes des gènes impliqués dans le métabolisme de la vitamine D sont aussi associés à ce risque. Chez les sujets dysmétaboliques, une relation entre la SHBG, la graisse intra-hépatique, les hépatokines et les paramètres métaboliques a été mise en évidence, indépendamment des stéroïdes sexuels. En conclusion, la vitamine D et la SHBG pourraient être des marqueurs d'intérêt pour le dépistage des sujets à haut risque cardiométabolique.
In Guadeloupe, the prevalence of diabetes is two times higher than in Metropolitan France, with a female predominance. Apart from environmental factors, vitamin D and polymorphisms of genes involved in vitamin D metabolism would be associated with increased risk of metabolic diseases. Androgens are also associated with abnormal glucose metabolism, directly or through the Sex Hormone Binding Protein (SHBG). Our main hypotheses were: 11 Vitamin D status and polymorphisms of genes involved in its metabolism may be associated with metabolic pammeters in Afro-Caribbean (AC). They could explain the importance of cardiometabolic diseases in Guadeloupe. 2/ SHBG may be associated with abnormal glucose metabolism, independently of sex steroids. Our research is presente
http://www.theses.fr/2012AGUY0536/document

Éditeur(s) : HAL CCSD
Résumé : International audience
Estrogens affect brain development of vertebrates, not only by impacting activity and morphology of existing circuits, but also by modulating embryonic and adult neurogenesis. The issue is complex as estrogens can not only originate from peripheral tissues, but also be locally produced within the brain itself due to local aromatization of androgens. In this respect, teleost fishes are quite unique because aromatase is expressed exclusively in radial glial cells, which represent pluripotent cells in the brain of all vertebrates. Expression of aromatase in the brain of fish is also strongly stimulated by estrogens and some androgens. This creates a very intriguing positive auto-regulatory loop leading to dramatic aromatase expression in sexually mature fish with elevated levels of circulating steroids. Looking at the effects of estrogens or anti-estrogens in the brain of adult zebrafish showed that estrogens inhibit rather than stimulate cell proliferation and newborn cell migration. The functional meaning of these observations is still unclear, but these data suggest that the brain of fish is experiencing constant remodeling under the influence of circulating steroids and brain-derived neurosteroids, possibly permitting a diversification of sexual strategies, notably hermaphroditism. Recent data in frogs indicate that aromatase expression is limited to neurons and do not concern radial glial cells. Thus, until now, there is no other example of vertebrates in which radial progenitors express aromatase. This raises the question of when and why these new features were gained and what are their adaptive benefits. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Droits : info:eu-repo/semantics/OpenAccess
hal-01102449
https://hal.archives-ouvertes.fr/hal-01102449
https://hal.archives-ouvertes.fr/hal-01102449/document
https://hal.archives-ouvertes.fr/hal-01102449/file/Coumailleau%20et%20al%20final%20manuscript.pdf
DOI : 10.1016/j.bbagrm.2014.07.002

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: Numerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life. OBJECTIVES: Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals. METHODS: We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10-12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures. RESULTS: We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose-response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight. CONCLUSIONS: Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life. https://doi.org/10.1289/EHP1014.
Environmental Health Perspectives

hal-01579609
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579609
DOI : 10.1289/EHP1014
PUBMED : 28796631

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Estrogens are known as steroid hormones affecting the brain in many different ways and a wealth of data now document effects on neurogenesis. Estrogens are provided by the periphery but can also be locally produced within the brain itself due to local aromatization of circulating androgens. Adult neurogenesis is described in all vertebrate species examined so far, but comparative investigations have brought to light differences between vertebrate groups. In teleost fishes, the neurogenic activity is spectacular and adult stem cells maintain their mitogenic activity in many proliferative areas within the brain. Fish are also quite unique because brain aromatase expression is limited to radial glia cells, the progenitor cells of adult fish brain. The zebrafish has emerged as an interesting vertebrate model to elucidate the cellular and molecular mechanisms of adult neurogenesis, and notably its modulation by steroids. The main objective of this review is to summarize data related to the functional link between estrogens production in the brain and neurogenesis in fish. First, we will demonstrate that the brain of zebrafish is an endogenous source of steroids and is directly targeted by local and/or peripheral steroids. Then, we will present data demonstrating the progenitor nature of radial glial cells in the brain of adult fish. Next, we will emphasize the role of estrogens in constitutive neurogenesis and its potential contribution to the regenerative neurogenesis. Finally, the negative impacts on neurogenesis of synthetic hormones used in contraceptive pills production and released in the aquatic environment will be discussed
ISSN: 0960-0760

hal-01174214
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01174214
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01174214/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01174214/file/Steroid%20modulation%20of%20neurogenesis.pdf
DOI : 10.1016/j.jsbmb.2015.06.011

Éditeur(s) : HAL CCSD Oxford Scholarship Online
Résumé : Brain aromatase in fish is an exciting research topic because of several unconventional features that challenge the established view based on studies in other vertebrates. First, the brain of teleost fish exhibits a high degree of aromatase activity, especially in sexually mature animals. Given the emerging roles of estrogens in neurogenesis, the unique features of the adult fish brain suggest that, in addition to classical functions on brain sexual differentiation and sexual behavior, aromatase expression in radial glial cells could be involved in the modulation of the high proliferative activity in the brain of fish.
Brain Aromatase, Estrogens, and Behavior

ISBN : 9780199841196
hal-00905522
https://hal.archives-ouvertes.fr/hal-00905522
DOI : 10.1093/acprof:oso/9780199841196.003.0007

Éditeur(s) : HAL CCSD BioScientifica
Résumé : International audience
BACKGROUND: Differences in circulating steroid hormone levels have been hypothesized to explain ethnic differences in steroid-related diseases. The aim of this study was to determine the serum levels of a wide panel of steroid hormones, both androgens and estrogens, in healthy middle-aged African-Caribbean and European men. DESIGN AND METHODS: Serum steroid hormone levels were determined in men participating in a systematic public health study funded by the French National Health Insurance system. Blood was collected in the morning from 304 healthy African-Caribbean and European men aged between 40 and 69 years. Serum steroids were measured by mass spectrometry-gas chromatography, except for DHEAS and sex hormone-binding globulin, which were determined by RIA. Data were analyzed in 10-year age intervals by analysis of covariance, with adjustment for age, body mass index, waist-to-hip ratio, tobacco and alcohol consumption, and season of sampling. RESULTS: Compared with Europeans, African-Caribbean men presented significantly higher serum levels of measured bioavailable testosterone, 4-androstenedione (4-dione), and estrone (E1) regardless of the age group, of 5-androstenediol (5-diol) in those aged 40-49 and 50-59 years, and of testosterone (TT) and dihydrotestosterone in those aged 40-49 years. In contrast, European men aged 40-69 years showed significantly higher serum levels of DHEA and DHEAS. CONCLUSIONS: Significant differences in serum steroid hormone levels were observed in middle-aged African-Caribbean and European men. Whether such differences could contribute to ethnic differences in disease risk in adult men remains to be investigated. Some steroids, such as bioavailable TT, 4-dione, 5-diol, and E1, deserve particular attention.
ISSN: 0804-4643

hal-00876034
https://hal.archives-ouvertes.fr/hal-00876034
DOI : 10.1530/EJE-11-0551
PUBMED : 21951700