Neonatal lipopolysaccharide exposure exacerbates stress-induced suppression of luteinizing hormone pulse frequency in adulthood.
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 microg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17beta-estradiol capsules and i.v. cannulas. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 microg/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.
Li
X F
XF
Division of Reproduction and Endocrinology, 2.36D New Hunt's House, King's College London, Guy's Campus, London, United Kingdom.
Kinsey-Jones
J S
JS
Knox
A M I
AM
Wu
X Q
XQ
Tahsinsoy
D
D
Brain
S D
SD
Lightman
S L
SL
O'Byrne
K T
KT
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D011247:Pregnancy; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone