Evidence for enhanced pro-inflammatory cytokine response to endotoxemia in the adult, neonatally flutamide-primed, male rat.

ONGARO L; CASTROGIOVANNI D; GIOVAMBATTISTA A; GAILLARD RC; SPINEDI E

Luxemburg

Congreso; Inflammation 2010; 2010

Recherches Scientifiques Luxembourg

It is accepted that a sexual dimorphism exists in the mammals’ immune function. In fact, evidences suggest that while estrogens enhance the immune response, androgens inhibit it and gonadectomy alters this response. Exposure to androgens early in life development is essential for masculinization of the male phenotype. Male fetuses exposed to anti-androgens during peri-natal life are permanently demasculinized in their morphology and physiology. The discovery of androgen-active chemicals in the environment has placed increased emphasis on describing the effects of both natural and environmental androgens and antiandrogens on the physiology of the male individual. Thus, the aim of the present study was explore in the male rat the effect of neonatal flutamide (F) treatment, a selective androgen receptor blocker, on peripheral TNFa levels during the acute phase response of endotoxemia at adult age. Five day-old male Sprague-Dawley rats were s.c. treated with a single injection of a small volume of either sterile corn oil alone (control animals, C) or containing 1.75 mg F. After weaning, rats were individually housed and kept with free access to Purina chow diet and water until experimentation. On the experimental day (age 100 days), animals were submitted to ketamine anesthesia and the right jugular vein was exposed, in a room with sterile atmosphere. Thereafter, rats were bled before (sample time zero) and at several hours (1-4 h) after i.v. injection of 25 micrograms/Kg BW of bacterial lipopolysaccharide (LPS, Sigma-Aldrich; dissolved in a small volume of sterile physiological NaCl solution as vehicle). The volume of blood collected at every time was immediately replaced by the same volume of red blood cells resuspended in heparinized-sterile vehicle. Due to the small blood volume of samples, only plasma tumor necrosis factor alpha (TNFa) concentrations were measured (ELISA) in samples taken from C and F rats. Our data indicated that no group differences were found in circulating TNFa concentrations when evaluated in samples from the time zero (n=9 rats per group). On the other hand, significantly (p<0.05 vs. C values) higher TNFa plasma concentrations were found in the F group at 1 h post-LPS. Thereafter, circulating TNFa levels remained (samples taken at 2 and 3 h post-LPS) elevated (albeit not significantly) over C values in F rats. Finally, TNFa values on time 4 h post-LPS recovered sample time zero-values in both groups examined. The area under the curve of circulating TNFa concentrations during the study resulted significantly (p<0.05) higher in F than in C rats. Our study add new data sustaining a suppressive role of endogenous androgens on proinflammatory cytokine release in plasma during acute endotoxemia and, strongly supports a sex steroid basis for immunological sexual dimorphism in mammals.