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.
Highlights
Worldwide there is a trend for declining fertility
The current findings report that postnatal LPS challenge results in increased mRNA and protein expression of TLR4 in the neonatal ovary
While further studies are required to elucidate the immune mechanisms involved in the impaired ovarian development and functioning, our results importantly suggest that exposure to an immune challenge in early life, resulting in activation of TLR-related inflammatory pathways, may have significant consequences for programming of reproductive health in later life
Summary
Worldwide there is a trend for declining fertility This is apparent for the female population, whereby 10.9% of women suffer from impaired fertility and 6% are infertile (Martinez et al, 2012). Substantial epidemiological and experimental evidence indicates that adult physiological function and health status may have their origins in the early developmental period (Barker and Osmond, 1986; Barker et al, 1989; Barker, 1990). Plasticity during the perinatal period allows adequate adaptation of an organism to given environmental conditions and predicts later life functioning. While physiological plasticity holds a beneficial value for the developing organism, exposure to adverse environmental conditions during critical maturational periods, may result in alterations to the normal developmental trajectory, increasing susceptibility to physiological malfunction and pathology in later life. The process by which early life environment can have permanent effect on physiological systems has been described as perinatal programming (Welberg and Seckl, 2001; Davies and Norman, 2002)
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