**4. Conclusion**

It is known that both estrogens and androgens modulate the fish immune response, although the molecular mechanisms by which they act are not completely understood. *In vivo* and *in vitro* analyses have demonstrated that gilthead seabream leukocyte (macrophages, acidophilic granulocytes and lymphocytes) express intracellular AR and/or ER, whose expression pattern upon stimulation depend on the cell type and the stimuli in question. Estrogens and androgens compromise the immune response, affecting cell types other than leukocytes. Thus, endothelial cells are involved in the leukocyte trafficking that occurs during the inflammatory process and their activities are also modulated by sex steroids. A wide variety of chemicals discharged from industrial and municipal sources has been reported to disrupt the endocrine system of animals via the food chain and contaminated water. Some of these contaminants have a widespread presence in the aquatic environment. Although, current knowledge concerning the sensitivity of marine fish to estrogenic and androgenic chemical in the environment is limited, we have seen that the most widespread (estrogenic) disruptor compound drastically affects leukocyte trafficking and recruitment into tissues. The short time of exposure (3 hours) used in our *in vitro*  experiments suggests that, together with ER and AR activation, some transcriptionindependent non-genomic actions might be acting on sex steroid hormones-stimulated leukocytes. Taking all this into account, further effort will focus on the cloning and characterization of membrane AR and ER, their expression pattern in immune cells and the molecular characterization of the way of which estrogenic and androgenic compounds disrupt the molecular signalling pathways of intracellular and membrane androgen and estrogen receptors.

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## **5. Acknowledgments**

This work was supported by the Fundación Séneca, Coordination Center for Research, CARM (proyect 04538/GERM/06 to A.G.A and grant to I.C.), the Spanish Ministry of Science and Innovation (contract RYC-2009-05451 to E.C.P., project AGL2008-04575-C02-01 to A.G.A.). We thank the "Servicio de Apoyo a la Investigación" of the University of Murcia for their assistance with cell culture and gene expression analysis and the "Centro Oceanográfico de Murcia, Instituto Español de Oceanografía" for their assistance with fish care.

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**11** 

*Russian Federation* 

**Interactions Between Reproductive and** 

Liudmila A. Zakharova and Marina S. Izvolskaia *Institute of Developmental Biology/Russian Academy of Sciences* 

**Immune Systems During Ontogeny: Roles** 

**of GnRH, Sex Steroids, and Immunomediators** 

Reproduction is an essential function of every animal species, and its realization depends on a complex of interrelated neural, endocrine, immune, and behavioral reactions. It is now accepted that the neuroendocrine system (including its reproductive component) and the immune system have a reciprocal regulatory influence development and functioning during pre- and postnatal ontogeny (Watanobe & Hayakawa, 2003; Zakharova et al., 2005; Carreras et al., 2008; Li et al., 2007; Chapman et al., 2009; Wu et al., 2011). The functions of these systems change during ontogeny. In the perinatal period, they are involved not only in regulatory but also in morphogenetic processes, unlike in the postnatal period. The tight bilateral connection between these systems is of special significance during the early, critical period of ontogeny, when the functions necessary for postnatal life of newborns are being established. The key role in the interaction of the reproductive and immune systems is played by the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) and sex hormones. During the perinatal period, they regulate the growth and differentiation of various fetal tissues, including the lymphoid tissue. In postnatal life, the dynamics of endocrine processes related to reproduction are regulated by the level of GnRH secretion into the hypothalamo-pituitary portal circulation. GnRH regulates secretion of pituitary gonadotropins, which regulate secretion of sex hormones. GnRH is also involved in regulation of sexual behavior, transmission of olfactory signals, and control of humoral and cell-mediated immunity. Sex hormones, in turn, regulate GnRH production in the hypothalamus (and, therefore, secretion of pituitary gonadotropins) and also its production in the thymus and spleen (Azad et al, 1998; Hrabovszky et al., 2000). On the other hand, immune system mediators such as thymic peptides and proinflammatory cytokines have a

role in controlling the development and functioning of the reproductive system.

Interactions of the reproductive and immune systems during early ontogeny are prerequisite to their normal functioning in adult life. Changes in the normal levels of GnRH and sex steroids in the developing fetus or newborn and their exposure to adverse environmental factors cause disturbances in long-term programming of the regulatory mechanisms of both reproductive and immune systems (Jacobson et al., 2000; Razia et al., 2006; Cameron et al., 2008; Champagne & Curley, 2008). The brain is especially sensitive to perinatal programming by sex steroids, which not only contribute to the patterning of brain

**1. Introduction** 

