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Submitted on September 9, 2004
Accepted on December 20, 2004
LINE, Dorothy Hodgkin Building, Whitson Street, University of Bristol, Bristol. BS1 3NY, UK
* To whom correspondence should be addressed. E-mail: Stafford.Lightman{at}bristol.ac.uk.
Organizational effects of testosterone during a critical period of neonatal life have major irreversible effects on adult sexual behavior. We have investigated whether perinatal androgen changes can also affect another major sexually differentiated system - the hypothalamo-pituitary-adrenal axis. This was assessed in male rats who had been exposed to perinatal flutamide or 1, 4, 6-androstatriene-3, 17 dione (ATD). Once the animals reached adulthood an automated sampling system was used to collect blood from freely moving animals at 10 min intervals over 24 h followed by a noise stress and then the administration of lipopolysaccharide (LPS). Perinatal flutamide and ATD treated rats not only had higher mean corticosterone levels and increased frequency and amplitude of corticosterone pulses over the 24 h in comparison with vehicle injected controls, but they also showed markedly increased corticosterone responses to both noise and LPS. All the parameters of increased HPA activity resembled the normal physiological state of the intact adult female rather than the intact adult male rat. Furthermore, three hours post LPS administration, both flutamide and ATD treated animals had markedly higher levels of corticotrophin-releasing factor (CRF) mRNA in the parvocellular PVN and pro-opiomelanocortin (POMC) mRNA in the adenohypophysis. Flutamide treated rats also had a greater level of PVN arginine vasopressin (AVP) mRNA. PVN glucocorticoid receptor (GR) mRNA levels were significantly lower in both the flutamide and the ATD treated male rats. These data highlight the importance of perinatal exposure to both testosterone and estrogen(s) on the development of a masculinised circadian corticosterone profile and stress-induced HPA axis activity in the adult male rat.
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