Lipopolysaccharide-Induced Maternal Inflammation Affects the Gonadotropin-Releasing Hormone Neuron Development in Fetal Mice

Abstract

Recent studies provide evidence that prenatal immunological stress may affect the programming of reproductive health and sexual behavior in adult animals. The aim of this study was to investigate the influence of maternal inflammation, induced by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 45 µg/kg) on embryonic day 11.5 (E 11.5), on the development of the gonadotropin-releasing hormone (GnRH) system in mouse fetuses as well as on the proinflammatory cytokine level in pregnant mice and their fetuses. In the fetuses, the GnRH neuron migration from the olfactory pit to the forebrain was estimated on embryonic days 14.5 and 18.5. The levels of the proinflammatory cytokines interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α and leukemia inhibitory factor (LIF) were measured with the cytometric bead and ELISA array method in the maternal and fetal blood, amniotic fluid and fetal cerebrospinal fluid (CSF). According to our data, activation of the immune system by LPS treatment on embryonic day 11.5 leads to an increased quantity of neurons in the nasal and olfactory bulb areas and a decreased quantity in the forebrain area on embryonic day 14.5. There was a slight decrease in the total number of neurons in the forebrain area on embryonic day 18.5. The levels of proinflammatory cytokines were significantly increased within 3 h after LPS treatment in the maternal and fetal blood, amniotic fluid and fetal CSF. IL-6-receptor immunoreactivity was detected on olfactory/vomeronasal axons. Thus, prenatal immunological stress delays the GnRH neuron migration in the nasal compartment of mouse fetuses, which may be mediated by the regulation of IL-6, MCP-1 and LIF secretion in the maternal-fetal system.

Abolition of prenatal lipopolysaccharide-induced reproductive disorders in rat male offspring by fulvestrant

“…LIF receptors (LIFR) are also expressed in primordial germ cells and play an organising role in its migration to the urogenital ridge. Increased LIF secretion in the maternal–foetal mouse system was detected after LPS treatment at 12th day of pregnancy (Sharova et al, ), which could cause disorganising effect on cell proliferation and migration. Both LIF and interleukin‐6 (IL‐6) are expressed in urogenital ridge and involved in prenatal germ cell differentiation in mice (Cheng et al, ; Eddie, Childs, Jabbour, & Anderson, ).…”

“…Previous studies provide evidence that exposure to LPS in perinatal period could account for disrupted development and dysfunction of dopamine (Ling et al, ), serotonin (Wang, Yan, Lo, Carvey, & Ling, ) and GABA‐producing neurons in adult offspring (Nouel, Burt, Zhang, Harvey, & Boksa, ). In previous studies, our attention was paid to disruptions in the hypothalamic–pituitary–gonadal (HPG) system in rat and mouse offspring following prenatal LPS treatment (Izvolskaia, Tillet, Sharova, Voronova, & Zakharova, ; Sharova, Izvolskaia, & Zakharova, ). According to our preliminary data, maternal LPS‐induced immunological stress at day 12 (embryonic day [E] 12) of pregnancy causes a delay in gonadotropin‐releasing hormone (GnRH) neuron migration in mouse and rat foetuses (Sharova, Izvolskaia, & Zakharova, ).…”

“…In previous studies, our attention was paid to disruptions in the hypothalamic–pituitary–gonadal (HPG) system in rat and mouse offspring following prenatal LPS treatment (Izvolskaia, Tillet, Sharova, Voronova, & Zakharova, ; Sharova, Izvolskaia, & Zakharova, ). According to our preliminary data, maternal LPS‐induced immunological stress at day 12 (embryonic day [E] 12) of pregnancy causes a delay in gonadotropin‐releasing hormone (GnRH) neuron migration in mouse and rat foetuses (Sharova, Izvolskaia, & Zakharova, ). Delay in GnRH neuron migration leads to decreased GnRH content in hypothalamus of pre‐pubertal and adult rats.…”

Factors in Early-Life Programming of Reproductive Fitness

“…Prenatal exposure to LPS has been demonstrated to alter foetal GnRH neuronal migration into the forebrain, leading to suppression of GnRH synthesis before and after puberty [63,64]. This effect has been suggested to be mediated via the maternal and foetal inflammatory response to an immune challenge, given the possible regulatory role of pro-inflammatory cytokines in GnRH migration [65].…”

Lipopolysaccharide-Induced Immunological Stress at Early Stages of Pregnancy Affects the Development of Gonadotropin Releasing-Hormone (Gnrh)-Producing System

“…Inflammation is associated with elevated cytokine levels in both mother and fetus, affecting brain development [3]. According to our previous data, LPS E. coli affects development of GnRH neurons [4]; GnRH is an important signal molecule in the neuroendocrine and immune system interactions. GnRH neurons stem from olfactory placodes outside the brain and migrate along growing nerves in hypothalamus.…”