Immune regulation of ovarian development: programming by neonatal immune challenge

Abstract

Neonatal immune challenge by administration of lipopolysaccharide (LPS) produces enduring alterations in the development and activity of neuroendocrine, immune and other physiological systems. We have recently reported that neonatal exposure to an immune challenge by administration of LPS results in altered reproductive development in the female Wistar rat. Specifically, LPS-treated animals exhibited diminished ovarian reserve and altered reproductive lifespan. In the current study, we examined the cellular mechanisms that lead to the previously documented impaired ovulation and reduced follicular pool. Rats were administered intraperitoneally either 0.05 mg/kg of LPS (Salmonella Enteritidis) or an equivalent volume of non-pyrogenic saline on postnatal days (PNDs) 3 and 5, and ovaries were obtained on PND 7. Microarray analysis revealed a significant upregulation in transcript expression (2-fold change; p < 0.05) for a substantial number of genes in the ovaries of LPS-treated animals, implicated in immune cell signaling, inflammatory responses, reproductive system development and disease. Several canonical pathways involved in immune recognition were affected by LPS treatment, such as nuclear factor-κB (NF-κB) activation and LPS-stimulated mitogen-activated protein kinase (MAPK) signaling. Quantitative Real-time PCR analysis supported the microarray results. Protein expression analysis of several components of the MAPK signaling pathway revealed a significant upregulation in the expression of Toll-like receptor 4 (TLR4) in the neonatal ovary of LPS-treated animals. These results indicate that neonatal immune challenge by administration of LPS has a direct effect on the ovary during the sensitive period of follicular formation. Given the pivotal role of inflammatory processes in the regulation of reproductive health, our findings suggest that early life immune activation via TLR signaling may have significant implications for the programming of ovarian development and fertility.

Genome-wide gene expression analysis of amphioxus (Branchiostoma belcheri) following lipopolysaccharide challenge using strand-specific RNA-seq

“…GO and KEGG terms involved in reproductive development and biomacromolecule biogenesis and organization were specifically detected at 0 h. Previous studies have shown that organismal LPS exposure can alter reproductive development in rat. 58 , 59 In addition, DEGs were significantly enriched in GO terms involved in biomacromolecule biogenesis in L. vannamei under nitrite stress. 17 LPS immune challenge thus may affect the reproduction and development of amphioxus.…”

Differential expression of Toll-like receptors in goat dominant and nondominant follicles

“…On one hand, our results suggest that the TLRs do not play a key role in this biological process. On the other hand, the widespread expression of TLRs in different developmental stages of follicles was consistent with the fact that the autoimmune system plays a critical role in the reproductive functioning in both males and females (Sominsky et al, 2013).…”

Factors in Early-Life Programming of Reproductive Fitness

“…A recent study has shown that 2 days after in vivo neonatal LPS challenge, there is a substantial upregulation of inflammatory genes in the neonatal ovary. Specifically, the expression of TLR4 transcript, a major component of the LPS-stimulated mitogen-activated protein kinase signalling pathway, was found to be significantly increased [102]. These data indicate that peripheral administration of LPS during the perinatal period in the rat results in activation of ovarian TLR4 signalling, which may directly intervene with the formation and establishment of the finite primordial follicle pool via activation of inflammatory pathways.…”