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R. L. Gendron, F. P. Nestel, W. S. Lapp and M. G. Baines

Summary. Certain strains of mice display an increased frequency of fetal resorption, but little is known about the effector mechanisms involved. We have examined the events associated with lipopolysaccharide (LPS)-induced fetal resorption in mice. Administration of 25 μg LPS on Day 12 of gestation resulted in the appearance of tumour necrosis factor-alpha (TNF-α) in the amniotic fluid and fetal resorption. Levels of LPS-induced TNF-α were reduced by 90% after pretreatment with the TNF-α-suppressing drug pentoxifylline (PXF). Treatment of pregnant mice during early gestation with 0·1 μg LPS resulted in fetoplacental resorption which was maximal when the LPS was given on Day 8. Resorption induced by 0·1 μg LPS on Day 8 of gestation was significantly reduced by pretreatment with PXF. Infiltration of asialo-GM1-positive cells was observed in the decidual–ectoplacental cone area of embryonic units from LPS-treated mice. In addition, treatment with anti-AGM1 antiserum prevented the LPS-induced resorption. Our results suggest that TNF-α and asialo-GM1-positive cells are involved in LPS-induced fetal resorption.

Keywords: abortion; lipopolysaccharide; TNF-α; natural killer cells; pentoxifylline; mouse

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K L Bidne, M J Dickson, J W Ross, L H Baumgard and A F Keating

Endotoxemia can be caused by obesity, environmental chemical exposure, abiotic stressors and bacterial infection. Circumstances that deleteriously impact intestinal barrier integrity can induce endotoxemia, and controlled experiments have identified negative impacts of lipopolysaccharide (LPS; an endotoxin mimetic) on folliculogenesis, puberty onset, estrus behavior, ovulation, meiotic competence, luteal function and ovarian steroidogenesis. In addition, neonatal LPS exposures have transgenerational female reproductive impacts, raising concern about early life contacts to this endogenous reproductive toxicant. Aims of this review are to identify physiological stressors causing endotoxemia, to highlight potential mechanism(s) by which LPS compromises female reproduction and identify knowledge gaps regarding how acute and/or metabolic endotoxemia influence(s) female reproduction.

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J Lüttgenau, B Möller, D Kradolfer, O Wellnitz, R M Bruckmaier, A Miyamoto, S E Ulbrich and H Bollwein

Lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria, has detrimental effects on the structure and function of bovine corpus luteum (CL) in vivo. The objective was to investigate whether these effects were mediated directly by LPS or via LPS-induced release of PGF. Bovine ovaries with a mid-cycle CL were collected immediately after slaughter and isolated perfused for 240 min. After 60 min of equilibration, LPS (0.5 μg/ml) was added to the medium of five ovaries, whereas an additional six ovaries were not treated with LPS (control). After 210 min of perfusion, all ovaries were treated with 500 iu of hCG. In the effluent perfusate, concentrations of progesterone (P4) and PGF were measured every 10 and 30 min, respectively. Punch biopsies of the CL were collected every 60 min and used for RT-qPCR to evaluate mRNA expression of receptors for LPS (TLR2, -4) and LH (LHCGR); the cytokine TNFA; steroidogenic (STAR, HSD3B), angiogenic (VEGFA 121, FGF2), and vasoactive (EDN1) factors; and factors of prostaglandin synthesis (PGES, PGFS, PTGFR) and apoptosis (CASP3, -8, -9). Treatment with LPS abolished the hCG-induced increase in P4 (P≤0.05); however, there was a tendency (P=0.10) for increased release of PGF at 70 min after LPS challenge. Furthermore, mRNA abundance of TLR2, TNFA, CASP3, CASP8, PGES, PGFS, and VEGFA 121 increased (P≤0.05) after LPS treatment, whereas all other factors remained unchanged (P>0.05). In conclusion, reduced P4 responsiveness to hCG in LPS-treated ovaries in vitro was not due to reduced steroidogenesis, but was attributed to enhanced apoptosis. However, an impact of luteal PGF could not be excluded.

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DG Ogando, D Paz, M Cella and AM Franchi

Nitric oxide (NO) fulfils important functions during pregnancy and has a role in implantation, decidualization, vasodilatation and myometrial relaxation. However, at high concentrations, such as those that are produced in sepsis, NO has toxic effects as it is a free radical. The aim of this study was to characterize uterine and decidual NO production in lipopolysaccharide (LPS)-induced embryonic resorption in mice and to determine which isoforms of nitric oxide synthase (NOS) take part. LPS produced 100% embryonic resorption at 24 h, with complete fetus expulsions at 48 h. Decidual and uterine NO production were increased by LPS, with maximum production at 6 h. This increase was due to the induction of expression of inducible nitric oxide synthase (iNOS) isoform in the decidua and uterus, and neuronal nitric oxide synthase (nNOS) isoform in the decidua, as detected by western blot analysis and immunohistochemistry. LPS increased iNOS expression in decidual and myometrial cells and increased nNOS expression in decidual cells. In addition, LPS caused fibrinolysis and infiltration of mesometrial decidua by macrophages positive for iNOS and CD14 (LPS receptor). Endothelial nitric oxide synthase (eNOS) was found in decidual and uterine arteries but LPS did not modify its expression. LPS induced CD14 expression in endometrial glands, and this could have amplified the inflammatory response. Aminoguanidine, an inhibitor of iNOS activity, totally reversed the LPS-induced embryonic resorption. This result could be explained by an inhibition of the increase in NO production but also by an inhibition of the cellular infiltration and fibrinolysis. These results show that NO fulfils a fundamental role in LPS-induced embryonic resorption.

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T. Shakil, A. Snell and S. A. Whitehead

The effects of stimulating the immune system with lipopolysaccharide (LPS) or suppressing the immune system with cyclosporin (CS) on reproductive functions in the female rat were investigated. Animals were either treated acutely with LPS (2 mg kg−1) or cyclosporin (20 mg kg−1) on dioestrus day 1 and 2 or treated chronically over a period of 6 days (on alternate days with LPS, daily with CS). Chronic LPS treatment induced a state of constant dioestrus and decreased circulating concentrations of progesterone and oestradiol. Chronic CS treatment induced some irregularity in the 4-day vaginal smear pattern in a minority of animals and, while it had no effect on circulating concentrations of progesterone, oestradiol concentrations were suppressed compared with those measured in pro-oestrous animals. LH responses to GnRH were reduced in both perifused pituitary fragments and cultured pituitary cells obtained from animals pretreated with either LPS or CS. In contrast, a low dose of LPS (20 μg kg−1) given over 6 days did not disrupt ovarian cycles and reduced, but did not abolish, the second phase primed LH response. Neither drug had a direct effect on the pituitary LH responses to GnRH, except that pituitary cells exposed to high doses of CS for periods greater than 48 h did show attenuated LH responses to GnRH. This finding was not paralleled with high doses of LPS. The differential count of ovarian follicles from histological studies showed that LPS treatment was associated with significantly fewer large preovulatory follicles, whereas animals treated with CS showed a similar distribution of follicular volumes compared with controls. Results suggest that the hypothalamic–pituitary control of ovarian function is impaired by both LPS and CS treatment, and LPS appears to have an additional effect in suppressing ovarian functions, possibly via an inhibitory action on steroidogenesis.

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Kalpana Subedi, Naoki Isobe, Masahide Nishibori and Yukinori Yoshimura

The aim of this study was to identify the types of gallinacin genes (GALs) expressed in ovarian follicles and to determine the changes in their expression during follicular growth and in response to lipopolysaccharide (LPS). Follicles at different stages of growth were collected from laying hens (n = 5) and LPS-injected hens (n = 3). The expression of GALs in the theca and granulosa layers was examined by semi-quantitative RT-PCR. The expression of GAL-1, -2, -7, -8, -10, and -12 in the theca layer and GAL-1, - 8, -10, and -12 in the granulosa layer was identified in white and yellow follicles. The expression of these genes was not changed in the theca and granulosa layers during follicular growth except for a decrease in that of GAL-1 in theca. The expression of GAL-1, -7, and -12 in the theca layer of the third largest follicles was increased in response to LPS at a dose of 1 mg/kg body weight and this increase was induced within 3 h and maintained until 12h postinjection. Granulosa layers did not respond to LPS until 12h injection. These results show that six and four types of GALs are expressed in the theca and granulosa layers of healthy follicles respectively, and their levels do not change with follicular growth except for GAL-1 in theca. Elevated levels of GAL-1, -7, and -12 expression in theca in response to LPS suggest that the theca cells expressing these GALs function to eliminate LPS-containing bacteria.

Open access

Xue-Qing Wu, Xiao-Feng Li, Bilu Ye, Neha Popat, Stuart R Milligan, Stafford L Lightman and Kevin T O'Byrne

Neonatal exposure to an immunological challenge (lipopolysaccharide, LPS) increases the activity of hypothalamo-pituitary–adrenal axis and sensitises the GNRH pulse generator to the inhibitory influence of stress in adult rats. We investigated the effects of neonatal exposure to LPS on various reproductive parameters during puberty and into adulthood in female rats. LPS (50 μg/kg, i.p.) or saline was administered on postnatal days 3 and 5. Vaginal opening was recorded, and oestrous cyclicity was monitored immediately post puberty and again at 8–9 weeks of age. At 10 weeks of age, the ovaries were removed and the number of follicles was counted, together with the thickness of the theca interna of the largest antral follicles. Ovarian sympathetic nerve activity was assessed immunohistochemically by measurement of the levels of ovarian low-affinity receptor of nerve growth factor (p75NGFR). In rats exposed to LPS in early life, there was a significant delay in puberty and disruption of oestrous cyclicity immediately post puberty, which persisted into adulthood. The follicle reserve was decreased, the thickness of the theca interna increased and the expression profile of ovarian p75NGFR increased in the neonatal LPS-treated animals. These data suggest that exposure to LPS during early neonatal life can have long-term dysfunctional effects on the female reproductive system, which might involve, at least in part, increased ovarian sympathetic nerve activity.

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N Shinkai, K Takasuna and S Takayama

Previous studies have demonstrated that formoterol, a beta2-adrenoceptor agonist, has potent tocolytic effects in rats. The aim of the present study was to determine whether formoterol treatment affects proinflammatory cytokine production in a lipopolysaccharide (LPS)-treated premature delivery mouse model. Formoterol was continuously administered by osmotic pump and the number of fetuses in the uteri were counted. Samples of amniotic fluid and plasma were collected 8 and 16 h after systemic administration of LPS. LPS induced premature delivery and an increase in prostaglandin F(2alpha) (PGF(2alpha)), interleukin 1alpha (IL-1alpha), IL-6 and IL-10 in the amniotic fluid, and an increase in IL-6 in plasma. Formoterol blocked all changes except the increase in IL-10. These data indicate that formoterol exerts inhibitory effects on proinflammatory cytokine production, and these effects may play an important role in the prevention of premature delivery.

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Shan Herath, Erin J Williams, Sonia T Lilly, Robert O Gilbert, Hilary Dobson, Clare E Bryant and I Martin Sheldon

Oestrogens are pivotal in ovarian follicular growth, development and function, with fundamental roles in steroidogenesis, nurturing the oocyte and ovulation. Infections with bacteria such as Escherichia coli cause infertility in mammals at least in part by perturbing ovarian follicle function, characterised by suppression of oestradiol production. Ovarian follicle granulosa cells produce oestradiol by aromatisation of androstenedione from the theca cells, under the regulation of gonadotrophins such as FSH. Many of the effects of E. coli are mediated by its surface molecule lipopolysaccharide (LPS) binding to the Toll-like receptor-4 (TLR4), CD14, MD-2 receptor complex on immune cells, but immune cells are not present inside ovarian follicles. The present study tested the hypothesis that granulosa cells express the TLR4 complex and LPS directly perturbs their secretion of oestradiol. Granulosa cells from recruited or dominant follicles are exposed to LPS in vivo and when they were cultured in the absence of immune cell contamination in vitro they produced less oestradiol when challenged with LPS, although theca cell androstenedione production was unchanged. The suppression of oestradiol production by LPS was associated with down-regulation of transcripts for aromatase in granulosa cells, and did not affect cell survival. Furthermore, these cells expressed TLR4, CD14 and MD-2 transcripts throughout the key stages of follicle growth and development. It appears that granulosa cells have an immune capability to detect bacterial infection, which perturbs follicle steroidogenesis, and this is a likely mechanism by which ovarian follicle growth and function is perturbed during bacterial infection.

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Julieta Aisemberg, María V Bariani, Claudia A Vercelli, Manuel L Wolfson and Ana M Franchi

The initial inactivation of prostaglandins (PGs) is mediated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). PGs are potent mediators of several biological processes, including inflammation and reproduction. In uterus, PGs play a key role in infection-induced pregnancy loss, in which concentration of this mediator increased. This process is accompanied with the induction of nitric oxide synthase expression and a marked increase in uterine levels of nitric oxide. There is no information concerning nitric oxide contribution to potential changes in PG catabolism, but experimental evidence suggests that nitric oxide modulates PG pathways. The specific objectives of the study were to evaluate the protein expression of HPGD (15-PGDH) and to characterize the nitric oxide-dependent regulation of this enzyme in a model of lipopolysaccharide (LPS)-induced embryonic resorption. Results show that LPS decreased HPGD protein expression and augmented PGE synthase activity; therefore, PGE2 levels increased in uterus in this inflammatory condition. Just as LPS, the treatment with a nitric oxide donor diminished HPGD protein expression in uterine tissue. In contrast, the inhibition of nitric oxide synthesis both in control and in LPS-treated mice increased 15-PGDH levels. Also, we have found that this enzyme and PGE2 levels are not modulated by peroxynitrite, an oxidant agent derived from nitric oxide. This study suggests that LPS and nitric oxide promote a decrease in the ability of the uterus for PG catabolism during bacterially triggered pregnancy loss in mice.