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Neonatal Lipopolysaccharide Exposure Exacerbates Stress-Induced Suppression of Luteinizing Hormone Pulse Frequency in Adulthood

Division of Reproduction and Endocrinology (X.F.L., J.S.K.-J., A.M.I.K., X.Q.W., D.T., K.T.O.), Cardiovascular Division (S.D.B.), King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom; and Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology (S.L.L.), University of Bristol, Bristol BS1 3NY, United Kingdom

Address all correspondence and requests for reprints to: Dr. Kevin O’Byrne, Division of Reproduction and Endocrinology, 2.36D New Hunt’s House, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom. E-mail: kevin.o'byrne{at}kcl.ac.uk.

Early life exposure to immunological challenge has programming effects on the adult hypothalamo-pituitary-adrenocortical axis stress responsivity, and stress is known to suppress GnRH pulse generator activity, especially LH pulses. We investigated the effects of neonatal exposure to endotoxin on stress-induced suppression of pulsatile LH secretion and the involvement of corticotropin-releasing factor (CRF) receptor mechanisms in adult rats. Pups at 3 and 5 d of age were administered lipopolysaccharide (LPS, 50 µg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17ß-estradiol capsules and iv cannulas. Blood samples (25 µl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 µg/kg, iv). CRF and CRF-R1 and CRF-R2 receptor mRNA was determined by RT-PCR in medial preoptic area (mPOA) micropunches collected at 3 h after LPS administration. There was no difference in basal LH pulse frequency between neonatal LPS- and neonatal saline-treated controls. However, neonatal endotoxin-treated rats exhibited a significantly greater LPS stress-induced suppression of LH pulse frequency. Basal mPOA CRF-R1 expression was unchanged in neonatal LPS- and neonatal saline-treated rats. However, CRF-R1 expression was significantly increased in response to LPS stress in neonatal LPS-treated animals but not in neonatal saline-treated controls. CRF and CRF-R2 expression was unchanged in all treatment groups. These data demonstrate that exposure to bacterial endotoxin in early neonatal life programs long-term sensitization of the GnRH pulse generator to the inhibitory influence of stress in adulthood, an effect that might involve up-regulation of CRF-R1 expression in the mPOA.