scholarly journals Chronic exposure to perfluorohexane sulfonate leads to a reproduction deficit by suppressing hypothalamic kisspeptin expression in mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiaorui Yin ◽  
Tingting Di ◽  
Xinyuan Cao ◽  
Zhengnan Liu ◽  
Jingyan Xie ◽  
...  

Abstract Background Perfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice. Methods Eight-week-old ICR mice were divided randomly into four groups administered corn oil (vehicle) and PFHxS at doses of 0.5, 5, and 50 mg/kg/day for 42 days by intragastric administration. Body weight, ovarian weight, estrous cycle, follicle counts, and serum sex hormone levels were evaluated. The expression of kisspeptin and gonadotropin releasing hormone (GnRH) in the hypothalamus was also detected. Results Compared to vehicle exposure, 5 mg/kg/day PFHxS treatment prolonged the estrous cycle, especially the duration of diestrus, after 42 days of treatment. The numbers of secondary follicles, antral follicles and corpus lutea were significantly reduced in the PFHxS-treated mice. Moreover, compared with the control mice, the PFHxS-treated mice showed decreases in the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2), and reduced GnRH mRNA levels, along with the lack of an LH surge. Furthermore, the PFHxS-treated mice had lower levels of kisspeptin immunoreactivity and kiss-1 mRNA in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) than the control mice. After intraventricular administration of kisspeptin-10, the numbers of secondary follicles, antral follicles and corpus lutea recovered, along with the levels of GnRH mRNA, FSH, and LH in the mice treated with 5 mg/kg/day PFHxS. Conclusion These results indicate that chronic exposure of mice to 5 mg/kg/day PFHxS affects reproductive functions by inhibiting kisspeptin expression in the ARC and AVPV regions, leading to deficits in follicular development and ovulation.

2021 ◽  
Author(s):  
Xiaorui Yin ◽  
Tingting Di ◽  
Xinyuan Cao ◽  
Zhengnan Liu ◽  
Jingyan Xie ◽  
...  

Abstract BackgroundPerfluorohexane sulfonate (PFHxS) is a six-carbon perfluoroalkyl sulfonic acid found as an environmental contaminant. This study aims to investigate the effects of PFHxS exposure on female reproduction and the underlying mechanism in mice. MethodsEight-week-old ICR mice were divided randomly into four groups: corn oil (vehicle) and PFHxS at doses of 0.5, 5, and 50 mg/kg/day for 42 days by intragastric administration. Body weight, ovarian weight, estrous cycle, follicle counts, and serum sex hormone levels were evaluated. Expression of kisspeptin and gonadotropin releasing hormone (GnRH) in the hypothalamus was also detected. ResultsCompared to vehicle exposure, 5 mg/kg/day PFHxS prolonged the estrous cycle, especially the duration of diestrus, after 42 days of treatment. The numbers of antral follicles and corpus lutea were significantly reduced in PFHxS-treated mice. Moreover, compared with the control group, PFHxS-treated mice showed decreases in serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2), and reduced GnRH mRNA levels, along with the lack of an LH surge. Furthermore, PFHxS-treated mice had lower levels of kisspeptin immunoreactivity and kiss-1 mRNA in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). After intraventricular administration of kisspeptin-10, the numbers of antral follicles and corpus lutea recovered, along with the levels of GnRH mRNA, FSH, and LH in mice treated with 5 mg/kg/day PFHxS. ConclusionThese results indicate that chronic exposure of mice to 5 mg/kg/day PFHxS affects reproductive functions by inhibiting kisspeptin expression in the ARC and AVPV regions, leading to the deficit of follicular development and ovulation.


2002 ◽  
Vol 172 (1) ◽  
pp. 45-59 ◽  
Author(s):  
F Le Bellego ◽  
C Pisselet ◽  
C Huet ◽  
P Monget ◽  
D Monniaux

This study aimed to determine the physiological role of laminin (LN) and its receptor, alpha(6)beta(1) integrin, in controlling the functions of granulosa cells (GC) during follicular development in sheep ovary. Immunohistochemistry experiments showed the presence of increasing levels of LN (P<0.0001), and high levels of mature alpha(6)beta(1) integrin in GC layers of healthy antral follicles during the follicular and the preovulatory phases of the estrous cycle. In vitro, the addition of a function-blocking antibody raised against alpha(6) subunit (anti-alpha(6) IgG) to the medium of ovine GC cultured on LN impaired cell spreading (P<0.0001), decreased the proliferation rate (P<0.05) and increased the apoptosis rate (P<0.05). Furthermore, addition of anti-alpha(6) IgG enhanced estradiol (E2) secretion by GC in the presence or absence of follicle-stimulating hormone (FSH), luteinizing hormone or insulin-like growth factor-I in culture medium (P<0.0001), and inhibited progesterone (P4) secretion in basal conditions or in the presence of low (0.5 ng/ml) FSH concentrations only (P<0.0001). The anti-alpha(6) IgG effect was specific to an interaction of LN with alpha(6)beta(1) integrin since it was ineffective on GC cultured on heat-denatured LN, RGD (arginine-glycine-aspartic acid) peptides and non-coated substratum. Hence, this study established that alpha(6)beta(1) integrin 1) was expressed in GC of antral follicles, 2) mediated the actions of LN on survival, proliferation and steroidogenesis of GC, and 3) was able to dramatically modulate P4 and E2 secretion by GC in vitro. It is suggested that during the follicular and the preovulatory phases of the estrous cycle, the increasing levels of LN in GC of large antral follicles might support their final development to ovulation.


Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2870-2880 ◽  
Author(s):  
Makoto Orisaka ◽  
Katsushige Hattori ◽  
Shin Fukuda ◽  
Tetsuya Mizutani ◽  
Kaoru Miyamoto ◽  
...  

Abstract Several clinical studies have shown a correlation of hypersecretion of LH and polycystic ovary syndrome (PCOS), infertility, and miscarriage in women, suggesting that chronically elevated LH impairs fertility. Growth arrest of small antral follicles in PCOS is also assumed to be associated with an abnormal endocrine environment involving increased LH stimulation, a hyperandrogenic milieu, and subsequent dysregulated FSH action in the ovarian follicles. In this study, we examined whether and how LH modulates follicular development and steroid production during preantral-early antral follicle transition by using a rat preantral follicle culture system. LH augments testosterone and estradiol production in preantral follicles via up-regulating mRNA abundance of CYP17A1 and CYP19A1. LH promotes rat preantral follicle growth, and the follicular size reaches that of early antral follicles in vitro, a response attenuated by the specific androgen receptor antagonist and a targeted disruption of androgen receptor gene. Sustained follicle stimulation by LH, but not by androgen, decreases FSH receptor mRNA levels and FSH receptor signaling and inhibits FSH-induced follicular growth. The data suggest that LH promotes preantral-early antral transition via the increased synthesis and growth-promoting action of androgen. However, chronic LH stimulation impairs FSH-dependent antral follicle growth by suppressing granulosa cell FSHR expression via the modulation of intraovarian regulators, including LH-induced thecal factors.


2004 ◽  
Vol 16 (9) ◽  
pp. 220
Author(s):  
R. L. Robker ◽  
W. V. Ingman ◽  
S. A. Robertson

Transforming Growth Factor β1 (TGFβ1) is essential for normal female reproduction. Mice with a targeted deletion in the TGFβ1 gene (TGFβ1–/–) have severely impaired fertility with pregnancy occurring in <25% of mated females. TGFβ1 is implicated in several aspects of ovarian function, including potentiation of granulosa cell proliferation and suppression of luteal cell apoptosis. Our initial observations indicate that estrous cycling is disrupted in TGFβ1–/– mice and that ovulation rate is reduced. To further investigate how impaired ovarian function contributes to the infertility of TGFβ1–/– mice, ovaries were isolated from TGFβ1+/+ and TGFβ1–/– littermates at proestrus and fixed and sectioned for examination of follicle morphology and growth. BrdU labelling was performed to detect granulosa cell proliferation and blood samples were obtained for analysis of gonadotrophins and ovarian steroid hormones. Histological examination showed that ovaries from TGFβ1–/– mice were smaller than those of TGF–1+/+ mice, however large antral follicles were observed, indicating that TGFβ1 is not essential for granulosa cell proliferation. Compared to TGFβ1+/+ ovaries however, there were fewer antral follicles and only rare corpora lutea. Interestingly, in some cases there were large numbers of macrophages surrounding small follicles suggesting increased follicular atresia and/or altered macrophage activity in the TGFβ1–/– ovaries. Ovaries and serum were also isolated from females at d4 post-coital for assessment of corpora lutea morphology. TGFβ1–/– ovaries weighed less and had fewer corpora lutea than TGFβ1+/+ ovaries. TGFβ1–/– corpora lutea also contained increased numbers of apoptotic cells and infiltrating macrophages indicative of premature luteal regression. Circulating progesterone levels were reduced in TGFβ1–/– females, as was progesterone production per corpus luteum further indicating a functional defect in luteal maintenance. Cumulatively these observations show that TGFβ1 has essential roles in regulation of ovarian macrophage populations, in normal follicular development and in the generation, maintenance and steroidogenic function of corpora lutea.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Enrico Gugliandolo ◽  
Marika Cordaro ◽  
Roberta Fusco ◽  
Alessio Filippo Peritore ◽  
Rosalba Siracusa ◽  
...  

AbstractGastric ulcer or peptic ulcer is a common disease worldwide. Basically, it develops when there is an imbalance between the protective and aggressive factors, especially at the luminal surface of epithelial cells. Thus, there is a constant interest in research new drugs for treatment of gastric ulcer. The snail secretion is a dense mucous, that covers the external surface of the snails, with important functions for the survival of snails. The biological proprieties of snail Helix Aspersa Muller mucus it has been known for centuries to treat human disorders in particular for skin disease. Recently the use of snail mucus has seen a worldwide increase, as a component in cosmetic product and it has been used in particular for the management of wound and skin disorders. In this study we use a murine model of ethanol intragastric administration which has been widely used to test the drugs efficacies and to explore the underlying mechanism for gastric ulcer development. The intragastric ethanol administration causes several mucosal damages and an induction of a severe inflammatory response. Our results show a significant protective effect of snail secretion filtrate in reducing macroscopic and histological lesions, as well the protective effect on mucus content, oxidative stress and inflammatory response. In conclusion this study demonstrate the protective effect of intragastrical snail secretion filtrate, in a model of ethanol-induced gastric ulcer in mice, suggesting its possible useful use in the treatment or prevention of gastric ulcer.


Reproduction ◽  
2006 ◽  
Vol 131 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Kirsty A Walters ◽  
John P Binnie ◽  
Bruce K Campbell ◽  
David G Armstrong ◽  
Evelyn E Telfer

This study aimed to determine the effect of insulin-like growth factor-I (IGF-I) on early antral bovine follicular development, and the expression of insulin-like growth factor-binding protein-2 (IGFBP-2). Antral follicles separated into three different size groups were cultured for 6 days in medium supplemented with either a low (10 ng/ml) or high (1 μg/ml) dose of human recombinant IGF-I. Oestradiol production by follicles in all size ranges, cultured in the presence of the high concentration of IGF-I, significantly increased by day 6 (P < 0.05). Follicles in the smallest size range, 165–215 μm, cultured in a high dose of IGF-I, were found to be significantly increased in size (P < 0.01). Oocyte health of the largest follicles (281–380 μm) was significantly improved by the addition of IGF-I to the culture medium. mRNA expression of IGFBP-2 was decreased in the granulosa cells of follicles, size range 216–280 μm, cultured with a high dose of IGF-I (P < 0.05). Granulosa cells (P < 0.05) and oocytes (P < 0.01) of the largest follicles (281–380 μm) showed a decrease in IGFBP-2 expression (protein) when cultured in the control and low-IGF-I treatment groups. Therefore, the response of a bovine follicle to IGF-I is both dose and stage dependent. This work supports a role for IGF-I in modulating somatic and germ-cell maturation and development in early antral follicles. Furthermore, the inverse relationship between the level of IGF-I stimulation and IGFBP-2 expression suggests a local regulatory system modulating IGF-I availability.


2014 ◽  
Vol 54 (8) ◽  
pp. 992 ◽  
Author(s):  
Yingying Zhang ◽  
Hehe Liu ◽  
Mingjun Yang ◽  
Shengqiang Hu ◽  
Liang Li ◽  
...  

The enzyme 3β-hydroxysteroid dehydrogenase/isomerase1 (3βHSD1) can catalyse the conversion of pregnenolone to progesterone in the △4-3-ketosteroid metabolic pathway. The aim of the present study was to clone 3βHSD1 and to determine whether this enzyme in the follicular wall has an effect on yolk progesterone in geese (Anser cygnoides). A putative coding sequence of 3βHSD1, which was 1134 nucleotides in length, was successfully obtained by using reverse transcription polymerase chain reaction (RT–PCR). A comparison of the deduced amino acid sequence with chicken, quail, zebra finch, cattle, horse, pig, human and mouse 3βHSD1 showed 89.7%, 88.4%, 87.3%, 55.6%, 54.0%, 53.5%, 55.3% and 52.9% similarity, respectively. The detection of 3βHSD1 mRNA levels in several tissues by quantitative real-time PCR showed that the highest level of 3βHSD1 was in the adrenal gland, followed by the ovary, which indicated that the gene we obtained was the adrenal gland/gonad-specific one. We measured the level of 3βHSD1 mRNA in the follicular wall and determined the concentration of progesterone in the yolk of these ovarian follicles; the concentration of progesterone in the yolk had a pattern of expression similar to that of 3βHSD1 in the follicular wall during follicular development. This result suggests that the expression of 3βHSD1 in the follicular wall may be a main factor that contributes to the accumulation of yolk progesterone.


Reproduction ◽  
2005 ◽  
Vol 129 (4) ◽  
pp. 463-472 ◽  
Author(s):  
Takashi Shimizu ◽  
Izumi Ohshima ◽  
Manabu Ozawa ◽  
Satoko Takahashi ◽  
Atsushi Tajima ◽  
...  

Heat stress inhibits ovarian follicular development in mammalian species. We hypothesized that heat stress inhibits the function of follicular granulosa cells and suppresses follicular development. To test this, immature female rats were injected with pregnant mare serum gonadotropin (PMSG) at 48 h after the start of temperature treatment (control: 25 °C, 50% RH; heat stress: 35 °C, 70% Relative Humidity). The ovaries and granulosa cells of follicles at different developmental stages were analyzed for gonadotropin receptor levels and aromatase activity; estradiol levels were measured in follicular fluid. Before injection, heat stress diminished only the amount of FSH receptor on granulosa cells of antral follicles. During PMSG-stimulated follicular development, heat stress strongly inhibited gonadotropin receptor levels and aromatase activity in granulosa cells, and estradiol levels in the follicular fluid of early antral, antral and preovulatory follicles. To examine apoptosis and mRNA levels of bcl-2 and bax in granulosa cells, follicles harvested 48 h after PMSG injection were cultured in serum-free conditions. Heat-stressed granulosa cells showed a time-dependent increase in apoptosis. The bcl-2 mRNA levels were similar in control and heat-stressed granulosa cells; bax mRNA levels were increased in heat-stressed granulosa cells. According to these results, heat stress inhibits expression of gonadotropin receptors in granulosa cells and attenuates estrogenic activity of growing follicles, granulosa cells of heat-stressed follicles are susceptible to apoptosis, and the bcl2/bax system is not associated with heat-stress-induced apoptosis of granulosa cells. Our study suggests that decreased numbers and function of granulosa cells may cause ovarian dysfunction in domestic animals in summer.


Reproduction ◽  
2012 ◽  
Vol 144 (5) ◽  
pp. 557-567 ◽  
Author(s):  
Jia Yi Lin ◽  
Janet L Pitman-Crawford ◽  
Adrian H Bibby ◽  
Norma L Hudson ◽  
C Joy McIntosh ◽  
...  

The aims were to investigate whether oocyte-secreted growth factors from a high (i.e. rat) and low (i.e. sheep) ovulation rate species could stimulate 3H-thymidine incorporation in granulosa cells (GC) from antral follicles from the same or across species. Denuded oocytes (DO) were co-incubated with GC with or without specific antibodies to growth differentiating factor 9 (GDF9) or bone morphogenetic protein 15 (BMP15). Co-incubations of DO-GC from the same or across species significantly increased thymidine incorporation in GC with increasing numbers of DO. GDF9 immuno-neutralisation reduced thymidine incorporation in rat GC co-incubated with either rat or ovine DO and in ovine GC co-incubated with ovine or rat DO. BMP15 immuno-neutralisation only reduced thymidine incorporation when ovine DO were co-incubated with either ovine or rat GC. Western blotting of oocytes co-incubated with GC identified GDF9 and BMP15 proteins for sheep and GDF9 protein for rats in oocyte lysates and incubation media. With respect to rat BMP15, a promature protein was identified in the oocyte lysate but not in media. Expression levels of GDF9 relative to BMP15 mRNA in DO co-incubated with GC were highly correlated (R 2=0.99) within both species. However, the expression ratios were markedly different for the rat and sheep (4.3 vs 1.0 respectively). We conclude that during follicular development, rat oocytes secrete little, if any, BMP15 and that GDF9 without BMP15 can stimulate proliferation of rat and ovine GC. In contrast, ovine oocytes secrete both BMP15 and GDF9, and both were found to stimulate proliferation in ovine and rat GC.


2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hitarthi Vyas ◽  
Ranjitsinh Devkar

Elevated levels of miR34a and its association with macrophage polarization is reported in atherosclerosis but the underlying mechanism that upregulates miR34a lacks clarity. Herein, the mechanism of miR34a elevation in atherogenic human monocyte derived macrophages (MdMs) and subsequent changes in mitochondria were monitored. Further, CO supplementation (via Carbon monoxide Releasing Molecule A1; CORM A1) to atherogenic (OxLDL treated) MdMs was used to achieve downregulation of miR34a. Herein, we also hypothesize that lowering of miR34a in atherogenic MdMs improves the cellular health and mitochondrial function. Transcriptional factors (P53, NF-κb), transcriptional inhibitors (Zeb1, snai1, stat3) and epigenetic modification (methylation) in promoter region of miR34a were evaluated. OxLDL treated MdMs recorded significant decrement in mRNA levels of the said transcription inhibitors whereas; the same were reversed in CORM A1 co-treated group. Further, hypomethylation was recorded in the promotor region of miR34a on oxLDL treatment but methylation status was reverted to the control levels following CORM A1 co-supplementation. The mRNA levels of transcription factors showed non-significant changes in all the experimental groups. In silico docking studies had shown that CO effectively binds to the DNA binding domains of p53 that possibly prevents subsequent binding to their respective miR34a promotor regions. Positive docking of miR34a to 3’UTR of SIRT-1 supported our observation on lowered SIRT-1 and PGC-1α levels in oxLDL group that were found to be restored in CORM A1 co-treated group. Poor indices of mitochondrial biogenesis (SIRT-1, PGC1α, Nrf-1, Drp1, Mito Tracker Red staining), function (ATP assay), mitochondrial membrane potential (JC-1) and mitochondrial antioxidants (SOD2 and TrxR2), cellular ROS (DCFDA) following oxLDL treatment was found to be restored by CORM A1 co-treatment. In conclusion, atherogenic elevation of miR34a is as a result of hypomethylation in its promotor region and lowered mRNA transcripts of its inhibitors (Zeb1, snai1, stat3). Further, lowering of miR34a by CORM A1, improves atherogenic status of MdMs as evidenced by an improved cellular and mitochondrial health.


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