Sexual dimorphism in the hypothalamo-pituitary-adrenal (HPA) axis and TNFα responses to phospholipase A2-related neurotoxin (from crotalus durissus terrificus) challenge

Neuroendocrine-immune interactions are vital for the individual’s survival in certain physiopathological conditions such as sepsis and tissular injury. It is known that several snake venoms (SV) are potent neurotoxic compounds and that their main component is a specific phospholipase type 2 (PLA2). It has been recently described that the venom from crotalus durissus terrificus (SV) possesses a cytotoxic effect in different in vitro and in vivo animal models. In the present study we investigated whether SV is able to stimulate both TNFα and neuroendocrine functions in a sexual dimorphic fashion. For this purpose the modulatory role of endogenous sex steroids during neurotoxemia was evaluated. Our results indicate that SV (25 μg/animal) stimulates the hypothalamo-pituitary-adrenal axis and TNFα secretion when administered (ip) to adult male mice, such responses were characterized by a time-related enhance in plasma glucose, ACTH, corticosterone and TNFα levels. SV-stimulated glycemia, corti-costeronemia and adrenal glucocorticoid were sexually dimorphic. Twenty-day gonadectomized mice showed a similar sexual dimorphism to that found in intact animals, however, they additionally showed a sexual dimorphic pattern in cytokine release in plasma 30 min post-SV. Estradiol (E2) treatment, in gonadectomized mice, abolished some characteristics of the sexual dimorphism, such as hyperglycemia, hypercorticosteronemia and hypercytokinemia. Finally, in vitro experiments indicate that: a) gonadectomy increased spontaneous and SV-stimulated cytokine output by incubated peripheral mononuclear cells (PMNC), regardless of the sex; and b) despite E2 treatment, in gonadectomized, did not modify the pattern of basal and SV-elicited TNFα secretion induced by orchidectomy, fully reversed the enhance in basal and SV-stimulated cytokine release found after ovariectomy alone. Our results further indicate that neurotoxemia, due to SV challenge, induces several symptoms common to those of inflammatory stress; they also strongly support that both gender and endogenous sex steroids are responsible for neuroendocrine-immunological sexual dimorphism.Instituto Multidisciplinario de Biología Celula