Abstract
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.
Introduction
Gram-negative bacteria protect themselves using two phospholipid membranes. The outermost facing membrane contains glucosamine-based phospholipid known as lipopolysaccharide (LPS), which is a recognized endotoxin, meaning it has toxic effects to the host after being shed from lysed bacteria (Raetz 1990, Rietschel et al. 1994). Endotoxin elicits a well-characterized robust immune response in animals, but there is recent appreciation for its marked alteration of host metabolism (independent of overt immune modulation) in multiple laboratory models and humans.
LPS consists of a core oligosaccharide, O-antigens and a lipid A moiety (depicted in Fig. 1). The lipid A moiety portion of LPS is responsible for inducing the cellular response (Loppnow et al. 1989). Systemic endotoxemia (increased circulating LPS) reflects either bacterial infection or compromised epithelial (skin, lung, gastrointestinal tract, uterine and mammary) barrier function. Metabolic endotoxemia is described as the physiological state when circulating LPS is 10–50 times lower than that observed during septic shock (Cani et al. 2007).
Unsurprisingly, endotoxemia is a consequence of infection by LPS-producing bacteria. There are also a myriad of environmental exposures that can cause endotoxemia and these include non-steroidal anti-inflammatory drugs (Arakawa et al. 2012, Van Wijck et al. 2012), mycotoxins (Alizadeh et al. 2015, Marin et al. 2015, Assuncao et al. 2016) and alcohol (Hartmann et al. 2012, 2015). Indeed ‘leaky gut’, and resultant metabolic endotoxemia, has been associated with many pathologies such as inflammatory bowel syndrome (Michielan & D’Inca 2015), cirrhosis (Fukui 2015, Lutz et al. 2015) and cancer (Saggioro 2014). In addition, evidence that gut barrier function becomes compromised during obesity, resulting in metabolic endotoxemia, is firmly established (Amar et al. 2008, Al-Attas et al. 2009, Hawkesworth et al. 2013). Although the etiology is not clear, low-grade, chronic inflammation caused by obesity-induced endotoxemia is thought to play a key role in the development of obesity-related disorders (Cani et al. 2007, Hawkesworth et al. 2013) including female reproductive dysfunction.
Heat stress is an abiotic stress that also induces endotoxemia. In an attempt to maximize radiant heat dissipation, heat-stressed animals redistribute blood to the periphery, and in order to maintain blood pressure, blood flow to the splanchnic tissues, including the gastrointestinal tract, is markedly reduced. The intestinal epithelial cells are extremely sensitive to oxygen and nutrient restriction (Rollwagen et al. 2006). Heat stress thus causes marked hypoxic-induced conformational changes, which ultimately reduces intestinal barrier integrity. Depending upon the severity and magnitude, heat stress can cause intestinally derived endotoxemia (Pearce et al. 2012, 2013a , b , c , Sanz Fernandez et al. 2014). The duration of leaky gut is variable and transitory, for example, intestinal integrity is reduced as early as two hours after the onset of heat stress in pigs (Pearce et al. 2014) and with removal of heat stress, intestinal integrity returned within days. Additionally, leaky gut can be caused by reduced nutrient intake, and this has been demonstrated in multiple models (Rodriguez et al. 1996, Kvidera et al. 2017). Further, psychological and emotional stress also increases gastrointestinal tract barrier permeability (Vanuytsel et al. 2014). Thus, endotoxemia is relatively common and arises due to a variety of frequent initiators, but the severity of it depends on the source (epithelial barrier endotoxin infiltration vs bacterial infection) and duration of the inducing agent(s).
The major purpose of this review is to collectively describe experiments that have either directly tested the female reproductive effects of endotoxemia through in vitro culture models or in vivo experiments in which animals are administered LPS. Additionally, we will highlight research that has identified associations between physiological scenarios that compromise intestinal integrity (and concomitantly increase circulating endotoxin) with detrimental impacts on female reproduction. Studies evaluating the impact of metabolic and acute endotoxemia are included. Typically, controlled experiments to evaluate endotoxemia’s impact on female reproduction have utilized the acute approach (i.e. an I.V. or I.M. LPS bolus). Further, we will describe how specific cells recognize and respond to LPS, characterize the systemic response to endotoxemia and the reproductive outcomes of LPS exposure, which have been examined in both traditional rodent and large animal models.
The systemic response to endotoxemia
Lipopolysaccharide-binding protein
Hepatic acute phase proteins (APP), which are produced as a secondary (non-local) response to a toxic stimuli, have been widely utilized as indicators of systemic and metabolic inflammation, including metabolic endotoxemia (Ceciliani et al. 2012). Lipopolysaccharide-binding protein (LBP) is an APP, primarily produced in hepatocytes (Grube et al. 1994, Kirschning et al. 1997), that interacts directly with the lipid A moiety of LPS (Tobias et al. 1986, 1989, Schumann 2011). Interaction between LBP and LPS results in an LBP conformational change promoting recognition and transfer of LPS to macrophages (Wright et al. 1989). Interleukin (IL)-6 (Grube et al. 1994, Kirschning et al. 1997), IL-1β and dexamethasone (Schumann et al. 1996) stimulate hepatic LBP production but LBP can also be produced in lung epithelial cells (Klein et al. 1998, Dentener et al. 2000), gastrointestinal tract cells (Vreugdenhil et al. 1999), kidney (Wang et al. 1998) and the epididymis (Malm et al. 2005). LBP acts as a soluble receptor and transports LPS to the appropriate toll-like receptor (TLR) to initiate intracellular signal cascades to elicit an immunological response (Schumann 2011). In humans, circulating LBP and plasma C-reactive protein (another broad biomarker of inflammation) are positively correlated (Tremellen et al. 2015), thus providing rationale for using LBP as an inflammatory biomarker (Opal et al. 1999).
The cellular response to endotoxemia
The lipid A moiety of LPS is highly conserved among species, and it stimulates an inflammatory response because it is recognized by membrane-bound TLR4 (Tobias et al. 1989, Raetz & Whitfield 2008, Schumann 2011). Utilizing TLR4-deficient mice, it has been shown that TLR4 is required for LPS recognition and the subsequent cellular response (Hoshino et al. 1999). However, other TLRs can also mediate a cellular response to LPS, dependent on the bacterial strain of origin. As an example, the LPS produced by Leptospirosis can instigate an intracellular response via TLR2, TLR4 or TLR5 (Goris et al. 2011, Faisal et al. 2016). In addition, host species can also differ in their response to LPS with some having variable sensitivity to a specific LPS, which impacts both the physiological response and development of mitigation strategies such as vaccine production (Werling et al. 2009).
Toll-like receptor 4
TLR4 is a membrane spanning protein bearing similarity to the interleukin 1 (IL1) receptor (Greenfeder et al. 1995, Aderem & Ulevitch 2000, Medzhitov & Janeway 2000). LPS binds to cluster of differentiation 14 (CD14) and is then transferred to a complex between TLR4 and myeloid differentiation factor 2 (MD-2) to initiate a cellular response (da Silva Correia et al. 2001, Triantafilou & Triantafilou 2002). The MD-2 protein is a crucial component of LPS recognition as an extracellular piece of the TLR4 complex (Shimazu et al. 1999). Soluble CD14 (sCD14) is integral for serum- and cell-mediated responses to LPS (Wright et al. 1989, 1990, Pugin et al. 1993) while the membrane-bound from (mCD14) is a glycosylphosphatidyl-inositol anchored protein (Haziot et al. 1988, Simmons et al. 1989) and works with TLR4 to transmit the LPS signal across the lipid bilayer to initiate a cellular response (Poltorak et al. 1998). LBP was originally thought to be necessary for CD14 to bind LPS (Wright et al. 1992), however, other studies suggest LPS directly activates CD14 or the MD-2-TLR4 complex (Dentener et al. 2000, da Silva Correia et al. 2001, Triantafilou & Triantafilou 2002), and LBP increases the rate of LPS binding to CD14 (Hailman et al. 1994).
Following LPS recognition, TLR4 recruits proteins including TIR domain-containing adaptor protein (TIRAP), myeloid differentiation primary response gene 88 (MyD88), TIR domain-containing adaptor-inducing interferon beta (TRIF) and TRIF-related adaptor molecule (TRAM) via its Toll-interleukin-1 receptor (TIR) domain causing downstream pathway activation. TIRAP and MyD88 mediate MyD88-dependent signaling, whereas TRIF and TRAM mediate MyD88-independent signaling. Both pathways involve phosphorylation of the REL-associated protein (RELA) subunit of nuclear factor kappa B (NFκB) although the MyD88-dependent pathway activates pro-inflammatory cytokine genes while the MyD88-independent signaling activates type I interferon genes (Kawai et al. 1999, Shimazu et al. 1999). Phosphorylated RELA increases concomitant with increased LPS exposure demonstrating the ability of LPS to drive TLR4-mediated NFKB activation (Chow et al. 1999). Interestingly, single-nucleotide polymorphisms (SNPs) in the TLR4 gene affects immune function and reproductive ability in dairy cows (Shimizu et al. 2017), though the importance of Tlr4 SNPs in humans remains vague (Gowin et al. 2017, Hajjar et al. 2017) and is an area of future interest regarding the biological response(s) to endotoxemia.
Detoxification of LPS by acyloxyacyl hydrolase
Acyloxyacyl hydrolase (AOAH) is a lipase that deacylates and detoxifies LPS within cells and (Hall & Munford 1983). AOAH releases secondary acyl chains from LPS regardless of the acyl chain structure or location on the diglucosamine backbone of LPS (Erwin & Munford 1990). AOAH is primarily produced in macrophages, neutrophils and dendritic cells (Ojogun et al. 2009) and converts hexaacylated LPS to pentaacylated or tetraacylated LPS rendering it unable to stimulate a response through TLR4 complex formation (Teghanemt et al. 2005). AOAH activity increased in murine serum and hepatocytes following a 25 μg bolus of LPS (Ojogun et al. 2009). In these mice, AOAH activity peaked after three days and returned to normal levels by day nine post LPS injection (Ojogun et al. 2009). Deacylated LPS (dLPS) can compete with LPS for LBP or CD14 binding (Kitchens & Munford 1995a , b ); however, binding of dLPS does not stimulate a cellular response (Kitchens et al. 1992). Interestingly, LBP alone or in coordination with CD14 increases the susceptibility of LPS to AOAH detoxification (Gioannini et al. 2007). Aoah-deficient mice have increased pulmonary damage in response to intranasal LPS exposure corroborating AOAH’s protective role against LPS (Zou et al. 2017). Thus, the chemical modification of LPS by AOAH partly regulates the immune response by decreasing the capacity of LPS to stimulate an intracellular signal cascade (Lu et al. 2005).
AOAH cannot act on LPS when the fatty acyl chains are orientated to the inside of LPS aggregates or when LPS is anchored on the outer membrane of bacteria (Gioannini et al. 2007). AOAH can act on LPS-LBP complexes as well as monomeric LPS-sCD14 complexes, suggesting a model where LBP and sCD14 transfer of LPS exposes fatty acyl chains to AOAH (Gioannini et al. 2007). However, when LPS is transferred and bound to MD-2, the fatty acyl chains are less accessible, decreasing AOAH’s ability to deacylate LPS and reduce TLR4 activation (Gioannini et al. 2007). Whether the female reproductive tract has the capacity to locally detoxify LPS remains unknown though recently, the importance of AOAH in the lung (Zou et al. 2017), urinary tract (Yang et al. 2017) and colonic dendritic (Janelsins et al. 2014) cells has been demonstrated.
Effects of LPS on female reproduction and fertility
Understanding the effects of LPS exposure on ovarian function is of interest in humans and production livestock species, since increased circulating LPS is associated with heat stress (Pearce et al. 2012, 2013a , b , 2014, Sanz Fernandez et al. 2014), obesity (Cani et al. 2007) and bacterial infection. Uterine infections have been associated with various negative impacts on bovine fertility, including cystic ovaries (Bosu & Peter 1987, Peter et al. 1989a , b ), abnormal or delayed folliculogenesis after parturition (Huszenicza et al. 1999), a longer postpartum anestrus period (Bosu & Peter 1987) and a lengthened luteal phase (Peter & Bosu 1988). Interestingly, follicular fluid that surrounds and nourishes the maturing oocyte contains LPS levels reflective of the systemic circulation (Herath et al. 2007). An accumulation of IL6 and IL8 in media collected after bovine granulosa cell or ovarian cortical strip culture was observed following LPS incubation, similar to the responsiveness of human immune cells (Dentener et al. 1993, Bromfield & Sheldon 2013). Plasma LBP and follicular fluid IL6 concentrations were also positively correlated, suggesting that systemic endotoxemia is associated with ovarian inflammation (Tremellen et al. 2015). Thus, LPS can locate the ovary and potentially interact directly with the oocyte, though it remains to be determined.
Impacts of endotoxemia on folliculogenesis
Bovine ovarian cortical explants exposed to LPS had reduced number of primordial follicles due to hyperactivation (Bromfield & Sheldon 2013). Similarly, mice exposed to LPS in vivo had reduced primordial follicle number, which was described as TLR4 mediated, since Tlr4 −/− mice are refractory to LPS-mediated primordial follicle depletion (Bromfield & Sheldon 2013) suggesting TLR4 in part regulates the ovarian LPS response. Phosphatase and tensin homolog (PTEN) and Forkhead box O3 (FOXO3), both proteins involved in regulating primordial follicle activation, were translocated out of the oocyte nucleus of primordial and primary follicles in cultured bovine cortical strips after LPS exposure (Bromfield & Sheldon 2013). The aforementioned indicate premature primordial follicle activation, potentially leading to depletion of the ovarian follicular reserve. In rodent studies, altered protein abundance due to LPS exposure in neonatal rodents has been observed (Sominsky et al. 2013). Furthermore, a diminished follicular reserve and earlier onset of ovarian senescence occurs in female rats neonatally exposed to LPS, raising concern about reproductive outcomes of bacterial infections early in life (Sominsky et al. 2012).
Effects on the follicular stage of the estrous cycle, including ovulation
Immune challenges can disrupt the follicular phase in multiple species (Kalra et al. 1990, Peter et al. 1990, Battaglia et al. 2000). LPS suppresses the hypothalamic-pituitary-gonadal axis by decreasing pulsatile gonadotrophin-releasing hormone (GnRH) secretion (Hoshino et al. 1999). LPS also blunts the 17β-estradiol (E2) increase during the preovulatory phase, thus delaying subsequent luteinizing hormone (LH) and follicle-stimulating hormone (FSH) surges, culminating in delayed or inhibited ovulation (Peter et al. 1989a , 1990, Battaglia et al. 2000, Suzuki et al. 2001). Using gonadectomized animals, it has been demonstrated that LPS suppresses GnRH release, thus disrupting the LH surge amplitude, frequency and concentration (Feng et al. 1991, Ebisui et al. 1992, Coleman et al. 1993, Kujjo et al. 1995). In agreement with reduced E2 compromising ovulation, when LPS was infused into the uterine lumen, the preovulatory LH surge was attenuated (Peter et al. 1989a ). Furthermore, LPS-treated females had delays in the time to the LH surge (Fergani et al. 2012) and lower ovulation rates (Williams et al. 2008). Recently, ovine kisspeptin/neurokinin B/dynorphin (KNDy) neuron activation has been demonstrated to be disrupted by LPS exposure, thus altering the hypothalamic-pituitary-ovarian axis (Fergani et al. 2017).
LPS alters anterior pituitary hormones in circulation, through direct or indirect mechanisms. LPS infusion decreased LH but stimulated systemic prolactin (PRL) and cortisol levels in anestrous ewes and reduced mRNA abundance of LH (LHβ) and luteinizing hormone/choriogonadotropin receptor (LHCGR) (Herman et al. 2010). Further, mRNA-encoding FSH and the FSH receptor (FSHR), PRL and the PRL receptor were increased by LPS infusion (Herman et al. 2010). Granulosa cells exposed to high levels of LPS had reduced mRNA expression of LHCGR, FSHR and cytochrome P450 (CYP) 19A1 (CYP19A1) (Magata et al. 2014a ). Theca cells isolated from follicles exposed to high levels of LPS also had decreased mRNA abundance of LHCGR, CYP17 and CYP11A1, but no difference in steroidogenic acute regulatory protein (STAR) or 3β-hydroxysteroid dehydrogenase (HSD3B1) levels compared to theca cells from follicles exposed to low levels of LPS (Magata et al. 2014b ). LPS exposure did not impact cell number or androstenedione production from cultured theca cells from small, medium or large ovarian follicles, but it did reduce E2 production from cultured granulosa cells isolated from all three follicular sizes (Williams et al. 2008). In addition, bovine follicles with high levels of LPS (>0.5 EU/mL) had lower E2 but elevated progesterone (P4) levels, relative to follicles with lower LPS concentrations (Magata et al. 2014a ). In an in vitro system where bovine granulosa cells were cultured with LPS and provided with FSH and androstenedione, E2 and P4 conversion were reduced potentially due to decreased expression of Cyp19a mRNA and protein (Herath et al. 2007). During the in vivo LH surge, a threshold of E2 is needed to induce behavioral display of estrus; however, the amount of E2 actually required for the behavioral estrus is thought to be at lower level than that required to induce ovulation (Saifullizam et al. 2010) and LPS negatively impacts female estrus behavior and frequency (Battaglia et al. 2000).
Post-ovulation impacts of LPS have also been demonstrated. Bovine oocytes subjected to in vitro maturation with LPS were less likely to successfully complete meiosis with intact meiotic structures (Bromfield & Sheldon 2011). In addition, increased levels of reactive oxygen species and apoptotic genes and altered methylation patterns were observed in bovine oocytes as a result of LPS (Zhao et al. 2017). Further, LPS negatively affected bovine oocyte nuclear maturation by compromising meiotic progression, mitochondrial membrane potential and mitochondrial cytoplasmic redistribution (Magata & Shimizu 2017). LPS also reduced blastocyst development of LPS-exposed oocytes and the trophoblast cell number of blastocysts (Magata & Shimizu 2017). These studies support the potential for LPS to negatively impact oocyte developmental competence.
Impact of LPS on luteal phase of the estrous cycle
Endotoxemia can compromise P4 production and lead to decreased luteal function. Corpus luteum (CL) formation and the expected increase in P4 were delayed in heifers exposed to LPS (Suzuki et al. 2001). During a normal estrous cycle, in the absence of fertilization and pregnancy, prostaglandin F2α (PGF2α) causes CL regression and LPS can cause CL regression by inducing PGF2α production (Moore et al. 1991, Hockett et al. 2000). Not only does LPS administration delay ovulation, it also lengthens the time to luteinization, CL formation and sufficient P4 production (Suzuki et al. 2001, Lavon et al. 2011); thus, LPS has numerous targets within the luteal phase. Additionally, CL size is reduced by LPS perhaps due to activation of pro-apoptotic pathways (Herzog et al. 2012). The cannabinoid receptor type 1 (eCS) has recently been discovered to be involved in LPS-induced CL regression in mice as wild-type mice had increased uterine prostaglandin-endoperoxide synthase (PTGS2) and PGF2α expression, which resulted in reduced ovarian P4 receptor abundance and regression of the CL, and these observations were absent in eCS-deficient mice (Schander et al. 2016).
Administrating LPS to goats during their luteal phase did not affect steroid hormone concentrations but did increase PGF2α metabolites (Fredriksson & Edqvist 1985), and repeated uterine LPS infusions in dairy cows every 6 h from 12 h prior to ovulation until 9 day post-ovulation resulted in CL regression much sooner than controls (Luttgenau et al. 2016). Culturing bovine luteal tissue in vitro with TNFα increased PGF2α in a dose-dependent manner (Benyo & Pate 1992). Additionally, porcine luteal tissue, when cultured in vitro with PGF2α, exhibits a feedback mechanism in which more PGF2α is produced (Guthrie et al. 1979). Normally, the porcine CL acquires capacity to undergo luteolysis around day 13 of the luteal phase (Guthrie et al. 1979), but multiple administrations of PGF2α can induce luteolysis in the porcine CL at an earlier time (Diaz et al. 2000) suggesting LPS may accelerate luteolysis via TNFα and PGF2α induction in pigs, though this remains to be confirmed.
A temporal pattern of LPS affecting circulating P4 has been demonstrated, whereby P4 is initially increased and then declines in LPS-treated, relative to control females (Herzog et al. 2012). LPS exposure initially decreased but then did not affect P4 production in bovine granulosa cells in culture (Herath et al. 2007). Further, P4 concentrations were increased in large bovine follicles, and it has been proposed that less P4 is being converted to E2 (Magata et al. 2014a , b ). However, others demonstrated that LPS in vitro can inhibit steroid secretion, specifically P4 and androstenedione in thecal-interstitial cells (Taylor & Terranova 1995) suggesting endotoxemia could alter P4 production, representing an endocrine-disrupting effect.
Endotoxemia and pregnancy maintenance
P4 is essential for pregnancy maintenance, and LPS reduces the P4 receptor in uteri of pregnant mice (Agrawal et al. 2013). The effect of LPS on the ability of P4 to sustain gestation could cause spontaneous abortion, a phenotypic event frequently associated with physiological conditions in which LPS is elevated. Infection from gram-negative bacteria or their outer wall components (including LPS) triggers preterm labor in many species (Koga & Mor 2010) and in fact, intraperitoneal LPS injection is an established experimental model for inducing preterm labor (Deb et al. 2004, Elovitz & Mrinalini 2004, Agrawal et al. 2013). In addition, infertility can be the result of reproductive tract infections in humans and production animals (Williams et al. 2008, Price et al. 2013). As mentioned earlier, LPS increases PGF2α release (Roberts et al. 1975) leading to CL regression, a decline in P4 and spontaneous abortion in goats (Fredriksson & Edqvist 1985). LPS and bacterial infection also increase PGF2α in the mare (Fredriksson et al. 1986) and the cow (Fredriksson et al. 1985). Uterine epithelial and stromal cells express TLR4 and both produced PGF2α and prostaglandin E2 (PGE) after LPS exposure, a response abrogated by using a TLR4 antagonist in bovine endometrial explants (Herath et al. 2006). Endometrial epithelial and stromal cells can respond to LPS exposure via the TLR4- and MYD88-dependent pathways (Cronin et al. 2012) and cows experiencing endometritis had increased endometrial expression of TLR4 and pro-inflammatory mediators in the first week post-partum (Herath et al. 2009). TLR4 also mediates the local immune response in human (Hirata et al. 2005, Rashidi et al. 2015), feline (Jursza et al. 2015) and canine (Silva et al. 2012) endometrial cells. Recent evidence supports that metabolic stress, such as negative energy balance in lactating dairy cows, may alter the endometrial response to LPS (Sheldon et al. 2017), a concern for animals experiencing the transition from gestation to lactation or for animals (and humans) who have metabolic perturbations.
Bovine embryos exposed in vitro to both LPS and PGF2α had reduced survival indicating the potential for LPS to alter pregnancy success (Soto et al. 2003). Human trophoblast cells cultured with LPS increase pro-inflammatory macrophage production (Li et al. 2016) and as mentioned earlier, there are fewer trophoblast cells in blastocysts that develop from LPS-exposed oocytes (Magata & Shimizu 2017). Additionally, human decidual cells exposed to LPS produced TNFα and PGF2α, which negatively affected cell growth. Further, when human amniotic fluid from normal relative to preterm labor pregnancies were compared, there were increased amounts of TNFα in the preterm samples, and LPS was detectable in 50% of preterm labor amniotic fluids (Casey et al. 1989). Furthermore, as evidence that LPS can alter the maternal capacity to support pregnancy, LPS-induced changes to human and bovine endometrial epithelial cell protein abundance (which could affect implantation at the critical time of maternal recognition of pregnancy) has been demonstrated (Cronin et al. 2012, Jensen & Collins 2012, Piras et al. 2017).
Additional considerations
Measuring circulating LPS should be interpreted with caution, since the limulus amebocyte lysate assay measures endotoxin biological activity and not LPS that is bound to inflammatory mediators such as soluble CD14 or LBP (Guerville & Boudry 2016). Additionally, the bacterial source of LPS remains undefined in these assays, and there are interactions that can alter the assay interpretation (Guerville & Boudry 2016). Thus, the usefulness of measuring LPS directly has been questioned (Stadlbauer et al. 2007, Gnauck et al. 2015, 2016). Also, most assays do not distinguish between LBP bound to LPS or that which is unbound; thus, LBP data must also be appropriately interpreted and within context. Taken together, a lack of an effective and convenient LPS assay is limiting the immune-reproduction field and a collective approach in defining the physiological endotoxemia response is required.
Of additional interest and concern is that LPS causes hyperinsulinemia, either directly as an insulin secretagogue or indirectly by increasing glucose stimulated insulin secretion (Baumgard et al. 2016). Reasons why a catabolic signal like LPS increases an acutely anabolic hormone like insulin are not clear, but reports suggest that insulin has potent anti-inflammatory effects (Chalmeh et al. 2013) and that immune cells are insulin sensitive (Maratou et al. 2007). Whether the ovary responds to hyperinsulinemia is unclear (Akamine et al. 2010, Brothers et al. 2010, Wu et al. 2012, Nteeba et al. 2013); however, elevated insulin levels have been reported in both serum and follicular fluids of obese females (Robker et al. 2009, Valckx et al. 2012). Primordial follicle hyperactivation (similar to that caused by LPS exposure) has been documented in neonatal rat ovaries due to insulin administration (Kezele et al. 2002). The negative effects of hyperinsulinemia and insulin resistance on female reproduction have been well documented, largely as pertaining to obesity and polycystic ovary syndrome (Goodarzi et al. 2011, Ogden 2015) and while not described herein in the interest of brevity, hyperinsulinemia could be a secondary consequence of endotoxemia with the potential to negatively influence female reproduction, though studies to specifically investigate this have not yet been performed. Hyperinsulinemia is not the sole secondary metabolic alteration observed due to endotoxemia: reduced circulating high-density lipoprotein (HDL) cholesterol was observed in dairy cows subjected to an acute exposure to LPS (De Campos et al. 2017 ) and, as discussed herein, LPS induces an inflammatory response and inflammatory mediators could also impact reproduction as an indirect secondary consequence of elevated LPS.
Conclusion
In summary, endotoxemia negatively affects female fertility and fecundity and has many points of action within the reproductive tract. Endotoxemia originates from a variety of stressors and also during times of bacterial infection. Several studies investigating reproductive impacts of endotoxemia have used acute, bolus exposures, as summarized in Table 1, which may not accurately represent the temporal pattern of bacterial infection, or ‘leaky gut’, thus, more continuous chronic low-level LPS experiments are warranted in order to identify mitigation strategies to protect and/or improve mammalian female reproductive function. In vitro experiments also are largely reflective of acute exposures since these levels are likely to be much higher than those that occur in vivo or those LPS concentrations that reach the follicular fluid and/or the oocyte. Additionally, endotoxemia that results from compromised intestinal integrity is accompanied by systemic exposure to additional intestinal components, many of which have not been characterized and identified and which may also be dynamic in response to the initiating stressor. Thus greater understanding of resident microbial populations and shifts to these populations will ultimately improve our understanding of the gut-hypothalamic-pituitary-ovarian-uterine axis.
Summary of LPS studies with effects on reproductive outcomes.
Species | Route | Duration | Dose | Citation | Findings |
---|---|---|---|---|---|
Ewes | IA | Single injection | 0.1–10 mg | Newnham et al. (2005) | Fetal death |
Single injection | 400 ng/kg | Battaglia et al. (1997) | Ovariectomized, increased P4, decreased LH | ||
IV | 26 h | 300 ng/kg | Battaglia et al. (2000) | Decreased E2 and LH | |
2× (2 week interval) | 40 ng/kg | Herman et al. (2010) | Decreased LH, increased prolactin, no effect on FSH | ||
Rats | S.C. | Daily injections for 2 or 6 day | 2 mg/kg or 20 μg/kg | Shakil et al. (1994) | Decreased P4 and E2, fewer large preovulatory follicles |
Rhesus monkey | IV | 2× daily for 5 day | 150 μg | Xiao et al. (1999) | Decreased P4 |
Trout | IP | Single injection | 3 mg/kg | MacKenzie et al. (2006) | Induced apoptosis, no effects on germinal vesicle break down |
Gilts | PC | Single injection | 0.5, 1, 2, 3 μg/kg | Cort (1986) | Abortions |
Single injection | 0.5, 1, 2, 3 μg/kg | Cort et al. (1986) | No change in cycle length. decreased P4, increased PGF2α | ||
Single injection | 50, 250, or 1250 μg | Tuo et al. (1999) | No effect on P4 plasma, fetal survival or development, increased fetal weight and amniotic fluid volume | ||
IU | Single injection | 36 mg | Wrathall et al. (1978) | Abortions | |
Mixed into ration | Single injection | 40 mg | Cort et al. (1990) | Increased PGF2α, no change in P4 | |
Goats | IU | Injected 1 or 2× | 0.1–5.2 μg/kg | Fredriksson et al. (1985) | No hormonal changes, increased PGF2α, decreased P4, abortions |
Heifers | IU | Every 6 h for 10 trts | 5 μg/kg | Peter et al. (1990) | Decreased E2 production, inhibited LH surge, no change in P4 |
Every 6 h for 10 trts | 5 μg/kg | Peter et al. (1989a) | Inhibited LH surge and ovulation, caused ovarian cysts | ||
Every 6 h for 9 day | 3 μg/kg | Lüttgenau et al. (2016) | Premature CL luteolysis, increased PGF2α metabolites, decreased P4, reduced luteal size and blood flow | ||
IU or IV | Single injection | 5 μg/kg | Gilbert et al. (1990) | Increased P4, PGF metabolites, cycle length was unchanged | |
IV | Single injection | 0.01 μg/kg | Kujjo et al. (1995) | Ovariectomized, increased P4, decreased E2 and LH | |
Lactating cows | IU | 2× @ 5 and 20 DIM | 5 μg/kg | Peter et al. (1990) | Increased PGF2α metabolites |
IV or IM | Single injection | IV: 0.5 μg/kg or IM: 10 μg | Lavon et al. (2008) | No change in E2 yet delayed or inhibited ovulation | |
IM | Single injection | 200 μg | Lüttgenau et al. (2016) | No change in P4, luteal size or luteal blood flow | |
IM | Single injection | 10 μg | Lavon et al. (2011) | Decreased follicular E2, P4 | |
Non-lactating cows | IV | Single injection | 0.5 μg/kg | Herzog et al. (2012) | Decreased luteal size and luteal blood flow, increased P4 and PGE |
IV | 6 h | 1.0 or 2.5 μg/kg | Giri et al. (1990) | Abortions, increased PGF2α, decreased P4 | |
Mice | IP | Single injection | 10 μg | Buhimschi et al. (2003) | Preterm birth, stillborns |
IP | Single injection | 50 μg/mouse | Fidel et al. (1994) | Preterm birth | |
IP | Single injection | 0.5 μg/g BW | Ogando et al. (2003) | Resorptions | |
IP | Single injection | 100 μg/mouse | Bromfield and Sheldon (2013) | Decreased primordial follicle pool, increased follicle atresia | |
IP | Single injection | 1.0 μg/g | Aisemberg et al. (2013) | Resorptions, decreased P4 | |
IP | Single injection | 0.4–2 mg/kg | Salminen et al. (2008) | Preterm birth, stillborns | |
IP | Single injection | 2.4 mg/kg | Rounioja et al. (2005) | Fetal defects | |
Ip | Single or multiple injections at 1–6 h intervals, 12–17 day | 0–100 mg | Kaga et al. (1996) | Preterm birth | |
IP | 2× | 10 μg/kg then 120 μg/kg | Xu et al. (2007) | Pre-treatment of LPS saved embryonic resorption | |
IV | Single injection | 10 μg | Harper and Skarnes (1972) | Abortions | |
IV | Single injection | 7.5 × 106 E.coli | Coid et al. (1978) | Resorptions | |
IV | Single injection | 1.5–20 μg | Skarnes and Harper (1972) | Abortions | |
IV | Single injection | 2–5 μg | Rioux-Darrieulat et al. (1978) | Abortions | |
IV | Single injection | 0.1 μg | Zhong et al. (2008) | Abortions | |
IA | Single injection | 0.25 μg | Rounioja et al. (2003) | Fetal defects | |
IC | Single injection | Reznikov et al. (1999) | Resorptions | ||
IU | Single injection | 250 μg | Elovitz et al. (2003) | Preterm birth | |
SC | Single injection | 0.5 mg/kg | Chua et al. (2006) | Resorptions, lower fetal weight | |
SC | Single injection | 0.25 mg or 0.147 mg | Coid (1976) | Resorptions, lower fetal weight |
E2, 17β-estradiol; FSH, follicle stimulating hormone; IA, intramniotic; IC, intracervical; IM, intramuscular; IP, intraperitoneal; IV, intravenous; LH, luteinizing hormone; LPS, lipopolysaccharide; P4, progesterone; PC, permanent cannulas; PGE, prostaglandin E; PGF2α, prostaglandin F2α; SC, subcutaneous.
Numerous questions remain to be clarified in our understanding of the impacts of endotoxemia on female fertility include but are certainly not limited to: (1) the level and/or duration required to impact fertility; the initiating insult to the reproductive tract, (2) the immune response within the reproductive tract that responds to endotoxemia, (3) the potential for tolerance to elevated LPS to develop, (4) the actual impact of LPS on the quality of the germ line, (5) potential effects on offspring (trans- and multi-generational) exposed to endotoxemia in utero and (6) the contribution or lack thereof of LBP on data derived from in vitro experiments. In addition, it is difficult to surmise the duration of metabolic endotoxemia, which is likely to vary dependent on the physiological situation, but which ultimately has a potential to impact physiological outcomes. Each of these areas are worthy of investigation with relevance to many facets of public health and production animal agriculture.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by the Iowa Pork Producers Association grant number NPB #16-265 to J W R, L H B and A F K.
References
Aderem A & Ulevitch RJ 2000 Toll-like receptors in the induction of the innate immune response. Nature 406 782–787. (https://doi.org/10.1038/35021228)
Agrawal V, Jaiswal MK & Jaiswal YK 2013 Lipopolysaccharide-induced modulation in the expression of progesterone receptor and estradiol receptor leads to early pregnancy loss in mouse. Zygote 21 337–344. (https://doi.org/10.1017/S0967199412000330)
Aisemberg J, Vercelli CA, Bariani MV, Billi SC, Wolfson ML & Franchi AM 2013 Progesterone is essential for protecting against LPS-induced pregnancy loss. LIF as a potential mediator of the anti-inflammatory effect of progesterone. PloS ONE 8 e56161. (https://doi.org/10.1371/journal.pone.0056161)
Akamine EH, Marcal AC, Camporez JP, Hoshida MS, Caperuto LC, Bevilacqua E & Carvalho CR 2010 Obesity induced by high-fat diet promotes insulin resistance in the ovary. Journal of Endocrinology 206 65–74. (https://doi.org/10.1677/JOE-09-0461)
Al-Attas OS, Al-Daghri NM, Al-Rubeaan K, da Silva NF, Sabico SL, Kumar S, McTernan PG & Harte AL 2009 Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies. Cardiovascular Diabetology 8 20. (https://doi.org/10.1186/1475-2840-8-20)
Alizadeh A, Braber S, Akbari P, Garssen J & Fink-Gremmels J 2015 Deoxynivalenol impairs weight gain and affects markers of gut health after low-dose, short-term exposure of growing pigs. Toxins 7 2071–2095. (https://doi.org/10.3390/toxins7062071)
Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC, Chamontin B & Ferrieres J 2008 Energy intake is associated with endotoxemia in apparently healthy men. American Journal of Clinical Nutrition 87 1219–1223.
Arakawa T, Watanabe T, Tanigawa T, Tominaga K, Otani K, Nadatani Y & Fujiwara Y 2012 Small intestinal injury caused by NSAIDs/aspirin: finding new from old. Current Medicinal Chemistry 19 77–81. (https://doi.org/10.2174/092986712803414105)
Assuncao R, Alvito P, Kleiveland CR & Lea TE 2016 Characterization of in vitro effects of patulin on intestinal epithelial and immune cells. Toxicology Letters 251 47–56. (https://doi.org/10.1016/j.toxlet.2016.04.007)
Battaglia DF, Bowen JM, Krasa HB, Thrun LA, Viguié C & Karsch FJ 1997 Endotoxin inhibits the reproductive neuroendocrine axis while stimulating adrenal steroids: a simultaneous view from hypophyseal portal and peripheral blood. Endocrinology 138 4273–4281. (https://doi.org/10.1210/endo.138.10.5449)
Battaglia DF, Krasa HB, Padmanabhan V, Viguie C & Karsch FJ 2000 Endocrine alterations that underlie endotoxin-induced disruption of the follicular phase in ewes. Biology of Reproduction 62 45–53. (https://doi.org/10.1095/biolreprod62.1.45)
Baumgard LH, Hausman GJ & Sanz Fernandez MV 2016 Insulin: pancreatic secretion and adipocyte regulation. Domestic Animal Endocrinology 54 76–84. (https://doi.org/10.1016/j.domaniend.2015.07.001)
Benyo DF & Pate JL 1992 Tumor necrosis factor-alpha alters bovine luteal cell synthetic capacity and viability. Endocrinology 130 854–860.
Bosu WT & Peter AT 1987 Evidence for a role of intrauterine infections in the pathogenesis of cystic ovaries in postpartum dairy cows. Theriogenology 28 725–736. (https://doi.org/10.1016/0093-691X(87)90289-5)
Bromfield JJ & Sheldon IM 2011 Lipopolysaccharide initiates inflammation in bovine granulosa cells via the TLR4 pathway and perturbs oocyte meiotic progression in vitro. Endocrinology 152 5029–5040. (https://doi.org/10.1210/en.2011-1124)
Bromfield JJ & Sheldon IM 2013 Lipopolysaccharide reduces the primordial follicle pool in the bovine ovarian cortex ex vivo and in the murine ovary in vivo. Biology of Reproduction 88 98.
Brothers KJ, Wu S, DiVall SA, Messmer MR, Kahn CR, Miller RS, Radovick S, Wondisford FE & Wolfe A 2010 Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metabolism 12 295–305. (https://doi.org/10.1016/j.cmet.2010.06.010)
Buhimschi IA, Buhimschi CS & Weiner CP 2003 Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation. American Journal of Obstetrics and Gynecology 188 203–208. (https://doi.org/10.1067/mob.2003.112)
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM & Chabo C et al.2007 Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56 1761–1772. (https://doi.org/10.2337/db06-1491)
Casey ML, Cox SM, Beutler B, Milewich L & MacDonald PC 1989 Cachectin/tumor necrosis factor-alpha formation in human decidua potential role of cytokines in infection-induced preterm labor. Journal of Clinical Investigation 83 430–436. (https://doi.org/10.1172/JCI113901)
Ceciliani F, Ceron JJ, Eckersall PD & Sauerwein H 2012 Acute phase proteins in ruminants. Journal of Proteomics 75 4207–4231. (https://doi.org/10.1016/j.jprot.2012.04.004)
Chalmeh A, Badiei K, Pourjafar M & Nazifi S 2013 Anti-inflammatory effects of insulin regular and flunixin meglumin on endotoxemia experimentally induced by Escherichia coli serotype O55:B5 in an ovine model. Inflammation Research 62 61–67. (https://doi.org/10.1007/s00011-012-0551-6)
Chow JC, Young DW, Golenbock DT, Christ WJ & Gusovsky F 1999 Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. Journal of Biological Chemistry 274 10689–10692. (https://doi.org/10.1074/jbc.274.16.10689)
Chua JSC, Rofe AM & Coyle P 2006 Dietary zinc supplementation ameliorates LPS-induced teratogenicity in mice. Pediatric Research 59 355–358. (https://doi.org/10.1203/01.pdr.0000199906.37619.9c)
Coid CR 1976 Bacterial endotoxin and impaired fetal development. Experientia 32 735–736. (https://doi.org/10.1007/BF01919861)
Coid CR, Sandison H, Slavin S & Altman DG 1978 Escherichia coli infection in mice and impaired fetal development. British Journal of Experimental Pathology 59 292–297.
Coleman ES, Elsasser TH, Kemppainen RJ, Coleman DA & Sartin JL 1993 Effect of endotoxin on pituitary hormone secretion in sheep. Neuroendocrinology 58 111–122. (https://doi.org/10.1159/000126520)
Cort N, Fredriksson G, Kindahl H, Edqvist LE & Rylander R 1990 A clinical and endocrine study on the effect of orally administered bacterial endotoxin in adult pigs and goats. Journal of Veterinary Medicine 37 130–137. (https://doi.org/10.1111/j.1439-0442.1990.tb00884.x)
Cort N 1986 A clinical study on the effect of a gram-negative bacterial endotoxin and cloprostenol in non-pregnant and 60-day pregnant gilts. Animal Reproduction Science 10 133–145. (https://doi.org/10.1016/0378-4320(86)90025-4)
Cort N, Kindahl H & Einarsson S 1986 The effect of a gram-negative bacterial endotoxin and cloprostenol on the plasma levels of 15-keto-13,14-dihydro-PGF2alpha, progesterone, oestradiol-17beta, oestrone sulphate and luteinizing hormone in non-pregnant and 60-day-pregnant gilts. Animal Reproduction Science 10 147–162. (https://doi.org/10.1016/0378-4320(86)90026-6)
Cronin JG, Turner ML, Goetze L, Bryant CE & Sheldon IM 2012 Toll-like receptor 4 and MyD88 dependent signaling mechanisms of the innate immune system are essential for the response to lipopolysaccharide by epithelial and stromal cells of the bovine endometrium. Biology of Reproduction 86 51–51. (https://doi.org/10.1095/biolreprod.111.092718)
da Silva Correia J, Soldau K, Christen U, Tobias PS & Ulevitch RJ 2001 Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex transfer from CD14 to TLR4 and MD-2. Journal of Biological Chemistry 276 21129–21135. (https://doi.org/10.1074/jbc.M009164200)
De Campos FT, Rincon JAA, Rincon DAV, Silveira PAS, Pradieé J, Corrêa MN, Gasperin BG, Pfeifer LFM, Barros CC & Pegoraro LMC et al. 2017 The acute effect of intravenous lipopolysaccharide injection on serum and intrafollicular HDL components and gene expression in granulosa cells of the bovine dominant follicle. Theriogenology 89 244–249. (https://doi.org/10.1016/j.theriogenology.2016.11.013)
Deb K, Chaturvedi MM & Jaiswal YK 2004 A ‘minimum dose’ of lipopolysaccharide required for implantation failure: assessment of its effect on the maternal reproductive organs and interleukin-1alpha expression in the mouse. Reproduction 128 87–97. (https://doi.org/10.1530/rep.1.00110)
Dentener MA, Bazil V, Von Asmuth EJ, Ceska M & Buurman WA 1993 Involvement of CD14 in lipopolysaccharide-induced tumor necrosis factor-alpha, IL-6 and IL-8 release by human monocytes and alveolar macrophages. Journal of Immunology 150 2885–2891.
Dentener MA, Vreugdenhil AC, Hoet PH, Vernooy JH, Nieman FH, Heumann D, Janssen YM, Buurman WA & Wouters EF 2000 Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications for local defense to bacterial endotoxins. American Journal of Respiratory Cell and Molecular Biology 23 146–153. (https://doi.org/10.1165/ajrcmb.23.2.3855)
Diaz FJ, Crenshaw TD & Wiltbank MC 2000 Prostaglandin f(2alpha) induces distinct physiological responses in porcine corpora lutea after acquisition of luteolytic capacity. Biology of Reproduction 63 1504–1512. (https://doi.org/10.1095/biolreprod63.5.1504)
Ebisui O, Fukata J, Tominaga T, Murakami N, Kobayashi H, Segawa H, Muro S, Naito Y, Nakai Y & Masui Y et al.1992 Roles of interleukin-1 alpha and -1 beta in endotoxin-induced suppression of plasma gonadotropin levels in rats. Endocrinology 130 3307–3313. (https://doi.org/10.1210/endo.130.6.1597143)
Elovitz MA & Mrinalini C 2004 Animal models of preterm birth. Trends in Endocrinology and Metabolism 15 479–487. (https://doi.org/10.1016/j.tem.2004.10.009)
Elovitz MA, Wang Z, Chien EK, Rychlik DF & Phillippe M 2003 A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. American Journal of Pathology 163 2103–2111. (https://doi.org/10.1016/S0002-9440(10)63567-5)
Erwin AL & Munford RS 1990 Deacylation of structurally diverse lipopolysaccharides by human acyloxyacyl hydrolase. Journal of Biological Chemistry 265 16444–16449.
Feng YJ, Shalts E, Xia LN, Rivier J, Rivier C, Vale W & Ferin M 1991 An inhibitory effects of interleukin-1a on basal gonadotropin release in the ovariectomized rhesus monkey: reversal by a corticotropin-releasing factor antagonist. Endocrinology 128 2077–2082. (https://doi.org/10.1210/endo-128-4-2077)
Faisal SM, Varma VP, Subathra M, Azam S, Sunkara AK, Akif M, Baig MS & Chang YF 2016 Leptospira surface adhesin (Lsa21) induces Toll like receptor 2 and 4 mediated inflammatory responses in macrophages. Scientific Reports 6 39530. (https://doi.org/10.1038/srep39530)
Fergani C, Saifullizam AK, Routly JE, Smith RF & Dobson H 2012 Estrous behavior, luteinizing hormone and estradiol profiles of intact ewes treated with insulin or endotoxin. Physiology and Behavior 105 757–765. (https://doi.org/10.1016/j.physbeh.2011.09.025)
Fergani C, Routly J, Jones D, Pickavance L, Smith RF & Dobson H 2017 KNDy neurone activation prior to the LH surge of the ewe is disrupted by LPS. Reproduction 154 281–292. (https://doi.org/10.1530/REP-17-0191)
Fidel PL, Romero R, Wolf N, Cutright J, Ramirez M, Araneda H & Cotton DB 1994 Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. American Journal of Obstetrics and Gynecology 170 1467–1475. (https://doi.org/10.1016/S0002-9378(94)70180-6)
Fredriksson G & Edqvist L-E 1985 Endotoxin-induced prostaglandin release and corpus luteum function in goats. Animal Reproduction Science 8 109–121. (https://doi.org/10.1016/0378-4320(85)90077-6)
Fredriksson G, Kindahl H, Sandstedt K & Edqvist LE 1985 Intrauterine bacterial findings and release of PGF2 alpha in the postpartum dairy cow. Zentralbl Veterinarmed A 32 368–380. (https://doi.org/10.1111/j.1439-0442.1985.tb01953.x)
Fredriksson G, Kindahl H & Stabenfeldt G 1986 Endotoxin-induced and prostaglandin-mediated effects on corpus luteum function in the mare. Theriogenology 25 309–316. (https://doi.org/10.1016/0093-691X(86)90066-X)
Fukui H 2015 Gut-liver axis in liver cirrhosis: how to manage leaky gut and endotoxemia. World Journal of Gastroenterology 7 425–442. (https://doi.org/10.4254/wjh.v7.i3.425)
Gilbert RO, Bosu WTK & Peter AT 1990 The effect of Excherichia coli endotoxin on luteal function in holstein heifers. Theriogenology 33 645–651. (https://doi.org/10.1016/0093-691X(90)90062-X)
Gioannini TL, Teghanemt A, Zhang D, Prohinar P, Levis EN, Munford RS & Weiss JP 2007 Endotoxin-binding proteins modulate the susceptibility of bacterial endotoxin to deacylation by acyloxyacyl hydrolase. Journal of Biological Chemistry 282 7877–7884. (https://doi.org/10.1074/jbc.M605031200)
Giri SN, Emau P, Cullor JS, Stabenfeldt GH, Bruss ML, Bondurant RH & Osburn BI 1990 Effects of endotoxin infusion on circulating levels of eicosanoids, progesterone, cortisol, glucose and lactic acid, and abortion in pregnant cows. Veterinary Microbiology 21 211–231. (https://doi.org/10.1016/0378-1135(90)90033-R)
Gnauck A, Lentle RG & Kruger MC 2015 The limulus amebocyte lysate assay may be unsuitable for detecting endotoxin in blood of healthy female subjects. Journal of Immunological Methods 416 146–156. (https://doi.org/10.1016/j.jim.2014.11.010)
Gnauck A, Lentle RG & Kruger MC 2016 Chasing a ghost? – issues with the determination of circulating levels of endotoxin in human blood. Critical Reviews in Clinical Laboratory Sciences 53 197–215. (https://doi.org/10.3109/10408363.2015.1123215)
Goodarzi MO, Dumesic DA, Chazenbalk G & Azziz R 2011 Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nature Reviews Endocrinology 7 219–231. (https://doi.org/10.1038/nrendo.2010.217)
Goris MG, Wagenaar JF, Hartskeerl RA, van Gorp EC, Schuller S, Monahan AM, Nally JE, van der Poll T & van ‘t Veer C 2011 Potent innate immune response to pathogenic leptospira in human whole blood. PLoS ONE 6 e18279. (https://doi.org/10.1371/journal.pone.0018279)
Gowin E, Swiatek-Koscielna B, Kaluzna E, Nowak J, Michalak M, Wysocki J & Januszkiewicz-Lewandowska D 2017 Analysis of TLR2, TLR4, and TLR9 single nucleotide polymorphisms in children with bacterial meningitis and their healthy family members. International Journal of Infectious Diseases 60 23–28. (https://doi.org/10.1016/j.ijid.2017.04.024)
Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA & Ju G 1995 Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. Journal of Biological Chemistry 270 13757–13765. (https://doi.org/10.1074/jbc.270.23.13757)
Grube BJ, Cochane CG, Ye RD, Green CE, McPhail ME, Ulevitch RJ & Tobias PS 1994 Lipopolysaccharide binding protein expression in primary human hepatocytes and HepG2 hepatoma cells. Journal of Biological Chemistry 269 8477–8482.
Guerville M & Boudry G 2016 Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. American Journal of Physiology-Gastrointestinal and Liver Physiology 311 G1–G15. (https://doi.org/10.1152/ajpgi.00098.2016)
Guthrie HD, Rexroad CE Jr & Bolt DJ 1979 In vitro release of progesterone and prostaglandins F and E by porcine luteal and endometrial tissue during induced luteolysis. Advances in Experimental Medicine and Biology 112 627–632.
Hailman E, Lichenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M, Busse LA, Zukowski MM & Wright SD 1994 Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. Journal of Experimental Medicine 179 269–277. (https://doi.org/10.1084/jem.179.1.269)
Hajjar AM, Ernst RK, Yi J, Yam CS & Miller SI 2017 Expression level of human TLR4 rather than sequence is the key determinant of LPS responsiveness. PLoS ONE 12 e0186308. (https://doi.org/10.1371/journal.pone.0186308)
Hall CL & Munford RS 1983 Enzymatic deacylation of the lipid A moiety of Salmonella typhimurium lipopolysaccharides by human neutrophils. PNAS 80 6671–6675. (https://doi.org/10.1073/pnas.80.21.6671)
Harper MJK & Skarnes RC 1972 Inhibtion of abortion and fetal death produced by endotoxin or prostaglandin F2 alpha. Prostaglandins 2 295–309. (https://doi.org/10.1016/S0090-6980(72)80017-0)
Hartmann P, Chen WC & Schnabl B 2012 The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. Frontiers in Physiology 3 402. (https:/doi.org/10.3389/fphys.2012.00402)
Hartmann P, Seebauer CT & Schnabl B 2015 Alcoholic liver disease: the gut microbiome and liver cross talk. Alcoholism: Clinical and Experimental Research 39 763–775. (https://doi.org/10.1111/acer.12704)
Hawkesworth S, Moore SE, Fulford AJ, Barclay GR, Darboe AA, Mark H, Nyan OA & Prentice AM 2013 Evidence for metabolic endotoxemia in obese and diabetic Gambian women. Nutrition and Diabetes 3 e83. (https://doi.org/10.1038/nutd.2013.24)
Haziot A, Chen S, Ferrero E, Low MG, Silber R & Goyert SM 1988 The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. Journal of Immunology 141 547–552.
Herath S, Fischer DP, Werling D, Williams EJ, Lilly ST, Dobson H, Bryant CE & Sheldon IM 2006 Expression and function of Toll-like receptor 4 in the endometrial cells of the uterus. Endocrinology 147 562–570. (https://doi.org/10.1210/en.2005-1113)
Herath S, Williams EJ, Lilly ST, Gilbert RO, Dobson H, Bryant CE & Sheldon IM 2007 Ovarian follicular cells have innate immune capabilities that modulate their endocrine function. Reproduction 134 683–693. (https://doi.org/10.1530/REP-07-0229)
Herath S, Lilly ST, Santos NR, Gilbert RO, Goetze L, Bryant CE, White JO, Cronin J & Sheldon IM 2009 Expression of genes associated with immunity in the endometrium of cattle with disparate postpartum uterine disease and fertility. Reproductive Biology and Endocrinology 7 55. (https://doi.org/10.1186/1477-7827-7-55)
Herman AP, Romanowicz K & Tomaszewska-Zaremba D 2010 Effect of LPS on reproductive system at the level of the pituitary of anestrous ewes. Reproduction in Domestic Animals 45 e351–e359. (https://doi.org/10.1111/j.1439-0531.2009.01577.x)
Herzog K, Struve K, Kastelic JP, Piechotta M, Ulbrich SE, Pfarrer C, Shirasuna K, Shimizu T, Miyamoto A & Bollwein H 2012 Escherichia coli lipopolysaccharide administration transiently suppresses luteal structure and function in diestrous cows. Reproduction 144 467–476. (https://doi.org/10.1530/REP-12-0138)
Hirata T, Osuga Y, Hirota Y, Koga K, Yoshino O, Harada M, Morimoto C, Yano T, Nishii O & Tsutsumi O et al.2005 Evidence for the presence of toll-like receptor 4 system in the human endometrium. Journal of Clinical Endocrinology and Metabolism 90 548–556. (https://doi.org/10.1210/jc.2004-0241)
Hockett ME, Hopkins FM, Lewis MJ, Saxton AM, Dowlen HH, Oliver SP & Schrick FN 2000 Endocrine profiles of dairy cows following experimentally induced clinical mastitis during early lactation. Animal Reproduction Science 58 241–251. (https://doi.org/10.1016/S0378-4320(99)00089-5)
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K & Akira S 1999 Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. Journal of Immunology 162 3749–3752.
Huszenicza G, Gacs FM, Kulcsar M, Dohmen M, Vamos M, Porkolab M, Kegl T, Bartyik J, Lohuis JACA & Janosi S et al.1999 Uterine bacteriology, resumption of cyclic ovarian activity and fertility in postpartum cows kept in large-scale dairy herds. Reproduction in Domestic Animals 34 237–245. (https://doi.org/10.1111/j.1439-0531.1999.tb01246.x)
Janelsins BM, Lu M & Datta SK 2014 Altered inactivation of commensal LPS due to acyloxyacyl hydrolase deficiency in colonic dendritic cells impairs mucosal Th17 immunity. PNAS 111 373–378. (https://doi.org/10.1073/pnas.1311987111)
Jensen AL & Collins J 2012 A subset of human uterine endometrial macrophages is alternatively activated. American Journal of Reproductive Immunology 68 374–386. (https://doi.org/10.1111/j.1600-0897.2012.01181.x)
Jursza E, Kowalewski MP, Boos A, Skarzynski DJ, Socha P & Siemieniuch MJ 2015 The role of toll-like receptors 2 and 4 in the pathogenesis of feline pyometra. Theriogenology 83 596–603. (https://doi.org/10.1016/j.theriogenology.2014.10.023)
Kaga N, Katsuki Y, Obata M & Shibutani Y 1996 Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery. American Journal of Obstetrics and Gynecology 174 754–759. (https://doi.org/10.1016/S0002-9378(96)70460-X)
Kalra PS, Sahu A & Kalra SP 1990 Interleukin-1 inhibits the ovarian steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126 2145–2152. (https://doi.org/10.1210/endo-126-4-2145)
Kawai T, Adachi O, Ogawa T, Takeda K & Akira S 1999 Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11 115–122. (https://doi.org/10.1016/S1074-7613(00)80086-2)
Kezele PR, Nilsson EE & Skinner MK 2002 Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition. Molecular and Cellular Endocrinology 192 37–43. (https://doi.org/10.1016/S0303-7207(02)00114-4)
Kirschning CJ, Unbehaun A, Fiedler G, Hallatschek W, Lamping N, Pfeil D & Schumann RR 1997 The transcriptional activation pattern of lipopolysaccharide binding protein (LBP) involving transcription factors AP-1 and C/EBP beta. Immunobiology 198 124–135. (https://doi.org/10.1016/S0171-2985(97)80033-2)
Kitchens RL & Munford RS 1995a Enzymatically deacylated lipopolysaccharide (LPS) can antagonize LPS at multiple sites in the LPS recognition pathway. Journal of Biological Chemistry 270 9904–9910. (https://doi.org/10.1074/jbc.270.17.9904)
Kitchens RL & Munford RS 1995b Modulation of protein tyrosine phosphorylation in human cells by LPS and enzymatically deacylated LPS. Progress in Clinical and Biological Research 392 353–363.
Kitchens RL, Ulevitch RJ & Munford RS 1992 Lipopolysaccharide (LPS) partial structures inhibit responses to LPS in a human macrophage cell line without inhibiting LPS uptake by a CD14-mediated pathway. Journal of Experimental Medicine 176 485–494. (https://doi.org/10.1084/jem.176.2.485)
Klein RD, Su GL, Aminlari A, Alarcon WH & Wang SC 1998 Pulmonary LPS-binding protein (LBP) upregulation following LPS-mediated injury. Journal of Surgical Research 78 42–47. (https://doi.org/10.1006/jsre.1998.5396)
Koga K & Mor G 2010 Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders. American Journal of Reproductive Immunology 63 587–600. (https://doi.org/10.1111/j.1600-0897.2010.00848.x)
Kvidera SK, Dickson MJ, Abuajamieh M, Snider DB, Fernandez MVS, Johnson JS, Keating AF, Gorden PJ, Green HB & Schoenberg KM et al.2017 Intentionally induced intestinal barrier dysfunction causes inflammation, affects metabolism, and reduces productivity in lactating Holstein cows. Journal of Dairy Science 100 4113–4127. (https://doi.org/10.3168/jds.2016-12349)
Kujjo LL, Bosu WT & Perez GI 1995 Opioid peptides involvement in endotoxin-induced suppression of LH secretion in ovariectomized Holstein heifers. Reproductive Toxicology 9 169–174. (https://doi.org/10.1016/0890-6238(94)00068-9)
Lavon Y, Leitner G, Goshen T, Braw-Tal R, Jacoby S & Wolfenson D 2008 Exposure to endotoxin during estrus alters the timing of ovulation and hormonal concentrations in cows. Theriogenology 70 956–967. (https://doi.org/10.1016/j.theriogenology.2008.05.058)
Lavon Y, Leitner G, Moallem U, Klipper E, Voet H, Jacoby S, Glick G, Meidan R & Wolfenson D 2011 Immediate and carryover effects of Gram-negative and Gram-positive toxin-induced mastitis on follicular function in dairy cows. Theriogenology 76 942–953. (https://doi.org/10.1016/j.theriogenology.2011.05.001)
Li L, Tu J, Jiang Y, Zhou J, Yabe S & Schust DJ 2016 Effects of lipopolysaccharide on human first trimester villous cytotrophoblast cell function in vitro. Biology of Reproduction 94 33. (https://doi.org/10.1095/biolreprod.115.134627)
Loppnow H, Brade H, Durrbaum I, Dinarello CA, Kusumoto S, Rietschel ET & Flad HD 1989 IL-1 induction-capacity of defined lipopolysaccharide partial structures. Journal of Immunology 142 3229–3238.
Lu M, Zhang M, Takashima A, Weiss J, Apicella MA, Li XH, Yuan D & Munford RS 2005 Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria. Nature Immunology 6 989–994. (https://doi.org/10.1038/ni1246)
Luttgenau J, Lingemann B, Wellnitz O, Hankele AK, Schmicke M, Ulbrich SE, Bruckmaier RM & Bollwein H 2016 Repeated intrauterine infusions of lipopolysaccharide alter gene expression and lifespan of the bovine corpus luteum. Journal of Dairy Science 99 6639–6653. (https://doi.org/10.3168/jds.2015-10806)
Lutz P, Nischalke HD, Strassburg CP & Spengler U 2015 Spontaneous bacterial peritonitis: the clinical challenge of a leaky gut and a cirrhotic liver. World Journal of Gastroenterology 7 304–314. (https://doi.org/10.4254/wjh.v7.i3.304)
MacKenzie S, Montserrat N, Mas M, Acerete L, Tort L, Krasnov A, Goetz FW & Planas JV 2006 Bacterial lipopolysaccharide induces apoptosis in the trout ovary. Reproductive Biology and Endocrinology 4 46. (https://doi.org/10.1186/1477-7827-4-46)
Magata F & Shimizu T 2017 Effect of lipopolysaccharide on developmental competence of oocytes. Reproductive Toxicology 71 1–7. (https://doi.org/10.1016/j.reprotox.2017.04.001)
Magata F, Horiuchi M, Echizenya R, Miura R, Chiba S, Matsui M, Miyamoto A, Kobayashi Y & Shimizu T 2014a Lipopolysaccharide in ovarian follicular fluid influences the steroid production in large follicles of dairy cows. Animal Reproduction Science 144 6–13. (https://doi.org/10.1016/j.anireprosci.2013.11.005)
Magata F, Horiuchi M, Miyamoto A & Shimizu T 2014b Lipopolysaccharide (LPS) inhibits steroid production in theca cells of bovine follicles in vitro: distinct effect of LPS on theca cell function in pre- and post-selection follicles. Journal of Reproduction and Development 60 280–287. (https://doi.org/10.1262/jrd.2013-124)
Malm J, Nordahl EA, Bjartell A, Sorensen OE, Frohm B, Dentener MA & Egesten A 2005 Lipopolysaccharide-binding protein is produced in the epididymis and associated with spermatozoa and prostasomes. Journal of Reproductive Immunology 66 33–43. (https://doi.org/10.1016/j.jri.2005.01.005)
Maratou E, Dimitriadis G, Kollias A, Boutati E, Lambadiari V, Mitrou P & Raptis SA 2007 Glucose transporter expression on the plasma membrane of resting and activated white blood cells. European Journal of Clinical 37 282–290. (https://doi.org/10.1111/j.1365-2362.2007.01786.x)
Marin DE, Motiu M & Taranu I 2015 Food contaminant zearalenone and its metabolites affect cytokine synthesis and intestinal epithelial integrity of porcine cells. Toxins 7 1979–1988. (https://doi.org/10.3390/toxins7061979)
Medzhitov R & Janeway C Jr 2000 Innate immune recognition: mechanisms and pathways. Immunological Reviews 173 89–97. (https://doi.org/10.1034/j.1600-065X.2000.917309.x)
Michielan A & D’Inca R 2015 Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation and therapy of leaky gut. Mediators of Inflammation 628157 25. (https://doi.org/10.1155/2015/628157)
Moore DA, Cullor JS, Bondurant RH & Sischo WM 1991 Preliminary field evidence for the association of clinical mastitis with altered interestrus intervals in dairy cattle. Theriogenology 36 257–265. (https://doi.org/10.1016/0093-691X(91)90384-P)
Newnham JP, Shub A, Jobe AH, Bird PS, Ikegami M, Nitsos I & Moss TJM 2005 The effects of intra-amniotic injection of periodontopathic lipopolysaccharides in sheep. American Journal of Obstetrics and Gynecology 193 313–321. (https://doi.org/10.1016/j.ajog.2005.03.065)
Nteeba J, Ross JW, Perfield Ii JW & Keating AF 2013 High fat diet induced obesity alters ovarian phosphatidylinositol-3 kinase signaling gene expression. Reproductive Toxicology 42 68–77. (https://doi.org/10.1016/j.reprotox.2013.07.026)
Ogando DG, Paz D, Cella M & Franchi AM 2003 The fundamental role of increased production of nitric oxide in lipopolysaccharide-induced embryonic resorption in mice. Reproduction 125 95–110. (https://doi.org/10.1530/reprod/125.1.95)
Ogden CL, Carroll MD, Fryar CD & Flegal KM 2015 Prevalence of obesity among adults and youth: United States, 2011–2014. In NCHS data brief, No. 219. Hyattsville, MD: National Center for Health Statistics. 2015
Ojogun N, Kuang TY, Shao B, Greaves DR, Munford RS & Varley AW 2009 Overproduction of acyloxyacyl hydrolase by macrophages and dendritic cells prevents prolonged reactions to bacterial lipopolysaccharide in vivo. Journal of Infectious Diseases 200 1685–1693. (https://doi.org/10.1086/646616)
Opal SM, Scannon PJ, Vincent JL, White M, Carroll SF, Palardy JE, Parejo NA, Pribble JP & Lemke JH 1999 Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. Journal of Infectious Diseases 180 1584–1589. (https://doi.org/10.1086/315093)
Pearce SC, Mani V, Boddicker RL, Johnson JS, Weber TE, Ross JW, Baumgard LH & Gabler NK 2012 Heat stress reduces barrier function and alters intestinal metabolism in growing pigs. Journal of Animal Science 90 (Supplement 4) 257–259. (https://doi.org/10.2527/jas.52339)
Pearce SC, Gabler NK, Ross JW, Escobar J, Patience JF, Rhoads RP & Baumgard LH 2013a The effects of heat stress and plane of nutrition on metabolism in growing pigs. Journal of Animal Science 91 2108–2118. (https://doi.org/10.2527/jas.2012-5738)
Pearce SC, Mani V, Boddicker RL, Johnson JS, Weber TE, Ross JW, Rhoads RP, Baumgard LH & Gabler NK 2013b Heat stress reduces intestinal barrier integrity and favors intestinal glucose transport in growing pigs. PLoS ONE 8 e70215. (https://doi.org/10.1371/journal.pone.0070215)
Pearce SC, Mani V, Weber TE, Rhoads RP, Patience JF, Baumgard LH & Gabler NK 2013c Heat stress and reduced plane of nutrition decreases intestinal integrity and function in pigs. Journal of Animal Science 91 5183–5193.
Pearce SC, Sanz-Fernandez MV, Hollis JH, Baumgard LH & Gabler NK 2014 Short-term exposure to heat stress attenuates appetite and intestinal integrity in growing pigs. Journal of Animal Science 92 5444–5454. (https://doi.org/10.2527/jas.2014-8407)
Peter AT & Bosu WT 1988 Relationship of uterine infections and folliculogenesis in dairy cows during early puerperium. Theriogenology 30 1045–1051. (https://doi.org/10.1016/0093-691X(88)90278-6)
Peter AT, Bosu WT & DeDecker RJ 1989a Suppression of preovulatory luteinizing hormone surges in heifers after intrauterine infusions of Escherichia coli endotoxin. American Journal of Veterinary Research 50 368–373.
Peter AT, Bosu WT, Liptrap RM & Cummings E 1989b Temporal changes in serum prostaglandin F2alpha and oxytocin in dairy cows with short luteal phases after the first postpartum ovulation. Theriogenology 32 277–284. (https://doi.org/10.1016/0093-691X(89)90318-X)
Peter AT, Simon JE, Luker CW & Bosu WT 1990 Site of action for endotoxin-induced cortisol release in the suppression of preovulatory luteinizing hormone surges. Theriogenology 33 637–643. (https://doi.org/10.1016/0093-691X(90)90540-A)
Piras C, Guo Y, Soggiu A, Chanrot M, Greco V, Urbani A, Charpigny G, Bonizzi L, Roncada P & Humblot P 2017 Changes in protein expression profiles in bovine endometrial epithelial cells exposed to E. coli LPS challenge. Molecular BioSystems 13 392–405. (https://doi.org/10.1039/C6MB00723F)
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M & Galanos C et al.1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 2085–2088. (https://doi.org/10.1126/science.282.5396.2085)
Price JC, Bromfield JJ & Sheldon IM 2013 Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Endocrinology 154 3377–3386. (https://doi.org/10.1210/en.2013-1102)
Pugin J, Schurer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ & Tobias PS 1993 Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. PNAS 90 2744–2748. (https://doi.org/10.1073/pnas.90.7.2744)
Raetz CRH 1990 Biochemistry of endotoxins. Annual Review of Biochemistry 59 129–170. (https://doi.org/10.1146/annurev.bi.59.070190.001021)
Raetz CRH & Whitfield C 2008 Lipopolysaccharide endotoxins. Annual Review of Biochemistry 71 635–700. (https://doi.org/10.1146/annurev.biochem.71.110601.135414)
Rashidi N, Mirahmadian M, Jeddi-Tehrani M, Rezania S, Ghasemi J, Kazemnejad S, Mirzadegan E, Vafaei S, Kashanian M & Rasoulzadeh Z et al.2015 Lipopolysaccharide- and lipoteichoic acid-mediated pro-inflammatory cytokine production and modulation of TLR2, TLR4 and MyD88 expression in human endometrial cells. Journal of Reproduction and Infertility 16 72–81.
Reznikov LL, Fantuzzi G, Selzman CH, Shames BD, Barton HA, Bell H, McGregor JA & Dinarello CA 1999 Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: role of interleukin 1beta. Biology of Reproduction 60 1231–1238. (https://doi.org/10.1530/reprod/125.1.95)
Rioux-Darrieulat F, Parant M & Chedid L 1978 Prevention of endotoxin-induced abortion by treatment of mice with antisera. Journal of Infectious Diseases 137 7–13. (https://doi.org/10.1093/infdis/137.1.7)
Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer U, Seydel U & Di Padova F et al.1994 Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB Journal 8 217–225. (https://doi.org/10.1096/fasebj.8.2.811492)
Roberts JS, Barcikowski B, Wilson L, Skarnes RC & McCracken JA 1975 Hormonal and related factors affecting the release of prostaglandin F2alpha from the uterus. Journal of Steroid Biochemistry 6 1091–1097. (https://doi.org/10.1016/0022-4731(75)90354-4)
Robker RL, Akison LK, Bennett BD, Thrupp PN, Chura LR, Russell DL, Lane M & Norman RJ 2009 Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. Journal of Clinical Endocrinology and Metabolism 94 1533–1540. (https://doi.org/10.1210/jc.2008-2648)
Rodriguez P, Darmon N, Chappuis P, Candalh C, Blaton MA, Bouchaud C & Heyman M 1996 Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc. Gut 39 416–422. (https://doi.org/10.1136/gut.39.3.416)
Rollwagen FM, Madhavan S, Singh A, Li YY, Wolcott K & Maheshwari R 2006 IL-6 protects enterocytes from hypoxia-induced apoptosis by induction of bcl-2 mRNA and reduction of fas mRNA. Biochemical and Biophysical Research Communications 347 1094–1098. (https://doi.org/10.1016/j.bbrc.2006.07.016)
Rounioja S, Räsänen J, Glumoff V, Ojaniemi M, Mäkikallio K & Hallman M 2003 Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction: a mouse model for fetal inflammatory response. Cardiovascular Research 60 156–164. (https://doi.org/10.1016/S0008-6363(03)00338-9)
Rounioja S, Räsänen J, Ojaniemi M, Glumoff V, Autio-Harmainen H & Hallman M 2005 Mechanism of acute fetal cardiovascular depression after maternal inflammatory challenge in mouse. American Journal of Pathology 166 1585–1592. (https://doi.org/10.1016/S0002-9440(10)62469-8)
Saggioro A 2014 Leaky gut, microbiota, and cancer: an incoming hypothesis. Journal of Clinical Gastroenterology 48 0000000000000255. (https://doi.org/10.1097/MCG.0000000000000255)
Saifullizam AK, Routly JE, Smith RF & Dobson H 2010 Effect of insulin on the relationship of estrous behaviors to estradiol and LH surges in intact ewes. Physiology and Behavior 99 555–561. (https://doi.org/10.1016/j.physbeh.2010.01.019)
Salminen A, Paananen R, Vuolteenaho R, Metsola J, Ojaniemi M, Autio-Harmainen H & Hallman M 2008 Maternal endotoxin-induced preterm birth in mice: fetal responses in toll-like receptors, collectins, and cytokines. Pediatric Research 63 280–286. (https://doi.org/10.1203/PDR.0b013e318163a8b2)
Sanz Fernandez MV, Pearce SC, Gabler NK, Patience JF, Wilson ME, Socha MT, Torrison JL, Rhoads RP & Baumgard LH 2014 Effects of supplemental zinc amino acid complex on gut integrity in heat-stressed growing pigs. Animal 8 43–50. (https://doi.org/10.1017/S1751731113001961)
Schander JA, Correa F, Bariani MV, Blanco J, Cymeryng C, Jensen F, Wolfson ML & Franchi AM 2016 A role for the endocannabinoid system in premature luteal regression and progesterone withdrawal in lipopolysaccharide-induced early pregnancy loss model. Molecular Human Reproduction 22 800–808. (https://doi.org/10.1093/molehr/gaw050)
Schumann RR 2011 Old and new findings on lipopolysaccharide-binding protein: a soluble pattern-recognition molecule. Biochemical Society Transactions 39 989–993. (https://doi.org/10.1042/BSbib390989)
Schumann RR, Kirschning CJ, Unbehaun A, Aberle HP, Knope HP, Lamping N, Ulevitch RJ & Herrmann F 1996 The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. Molecular and Cellular Biology 16 3490–3503. (https://doi.org/10.1128/MCB.16.7.3490)
Shakil T, Snell A & Whitehead SA 1994 Effects of lipopolysaccharide and cyclosporin on the endocrine control on ovarian function. Journal of Reproduction and Fertility 100 57–64. (https://doi.org/10.1530/jrf.0.1000057)
Sheldon IM, Cronin JG, Pospiech M & Turner ML 2017 Mechanisms linking metabolic stress with innate immunity in the endometrium. Journal of Dairy Science pii: S0022-0302(17)30832-9. (https://doi.org/10.3168/jds.2017-13135)
Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K & Kimoto M 1999 MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. Journal of Experimental Medicine 189 1777–1782. (https://doi.org/10.1084/jem.189.11.1777)
Shimizu T, Kawasaki Y, Aoki Y, Magata F, Kawashima C & Miyamoto A 2017 Effect of single nucleotide polymorphisms of Toll-Like receptor 4 (TLR 4) on reproductive performance and immune function in dairy cows. Biochemical Genetics 55 212–222. (https://doi.org/10.1007/s10528-017-9790-0)
Silva E, Henriques S, Brito S, Ferreira-Dias G, Lopes-da-Costa L & Mateus L 2012 Oestrous cycle-related changes in production of Toll-like receptors and prostaglandins in the canine endometrium. Journal of Reproductive Immunology 96 45–57. (https://doi.org/10.1016/j.jri.2012.07.003)
Simmons DL, Tan S, Tenen DG, Nicholson-Weller A & Seed B 1989 Monocyte antigen CD14 is a phospholipid anchored membrane protein. Blood 73 284–289.
Skarnes RC & Harper MJK 1972 Relationship between endotoxin-induced abortion and the synthesis of prostaglandin F. Prostaglandins 1 191–203. (https://doi.org/10.1016/0090-6980(72)90004-4)
Sominsky L, Meehan CL, Walker AK, Bobrovskaya L, McLaughlin EA & Hodgson DM 2012 Neonatal immune challenge alters reproductive development in the female rat. Hormones and Behavior 62 345–355. (https://doi.org/10.1016/j.yhbeh.2012.02.005)
Sominsky L, Sobinoff AP, Jobling MS, Pye V, McLaughlin EA & Hodgson DM 2013 Immune regulation of ovarian development: programming by neonatal immune challenge. Frontiers in Neuroscience 7 100. (https://doi.org/10.3389/fnins.2013.00100)
Soto P, Natzke RP & Hansen PJ 2003 Identification of possible mediators of embryonic mortality caused by mastitis: actions of lipopolysaccharide, prostaglandin F2alpha, and the nitric oxide generator, sodium nitroprusside dihydrate, on oocyte maturation and embryonic development in cattle. American Journal of Reproductive Immunology 50 263–272. (https://doi.org/10.1034/j.1600-0897.2003.00085.x)
Stadlbauer V, Davies NA, Wright G & Jalan R 2007 Endotoxin measures in patients’ sample: how valid are the results? Journal of Hepatology 47 726–727. (https://doi.org/10.1016/j.jhep.2007.08.001)
Suzuki C, Yoshioka K, Iwamura S & Hirose H 2001 Endotoxin induces delayed ovulation following endocrine aberration during the proestrous phase in Holstein heifers. Domestic Animal Endocrinology 20 267–278. (https://doi.org/10.1016/S0739-7240(01)00098-4)
Taylor CC & Terranova PF 1995 Lipopolysaccharide inhibits rat ovarian thecal-interstitial cell steroid secretion in vitro. Endocrinology 136 5527–5532. (https://doi.org/10.1210/endo.136.12.7588304)
Teghanemt A, Zhang D, Levis EN, Weiss JP & Gioannini TL 2005 Molecular basis of reduced potency of underacylated endotoxins. Journal of Immunology 175 4669–4676. (https://doi.org/10.4049/jimmunol.175.7.4669)
Tobias PS, Soldau K & Ulevitch RJ 1986 Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. Journal of Experimental Medicine 164 777–793. (https://doi.org/10.1084/jem.164.3.777)
Tobias PS, Soldau K & Ulevitch RJ 1989 Identification of a lipid a binding site in the acute phase reactant lipopolysaccharide binding protein. Journal of Biological Chemistry 264 10867–10871.
Tremellen K, Syedi N, Tan S & Pearce K 2015 Metabolic endotoxaemia – a potential novel link between ovarian inflammation and impaired progesterone production. Gynecological Endocrinology 31 309–312. (https://doi.org/10.3109/09513590.2014.994602)
Triantafilou M & Triantafilou K 2002 Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends in Immunology 23 301–304. (https://doi.org/10.1016/S1471-4906(02)02233-0)
Tuo W, Ott TL, Liu S-H & Bazer FW 1999 Intrauterine infusion of bacterial lipopolysaccharide (LPS) prior to mating has no adverse effect on fertility, fetal survival and fetal development. Journal of Reproductive Immunology 42 31–39. (https://doi.org/10.1016/S0165-0378(98)00078-3)
Van Wijck K, Lenaerts K, Van Bijnen AA, Boonen B, Van Loon LJ, Dejong CH & Buurman WA 2012 Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes. Medicine and Science in Sports and Exercise 44 2257–2262. (https://doi.org/10.1249/MSS.0b013e318265dd3d)
Valckx SDM, De Pauw I, De Neubourg D, Inion I, Berth M, Fransen E, Bols PEJ & Leroy JLMR 2012 BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality. Human Reproduction 27 3531–3539. (https://doi.org/10.1093/humrep/des350)
Vanuytsel T, van Wanrooy S, Vanheel