Preliminary studies evidenced the presence of CRFr
Preliminary studies evidenced the presence of CRFr in gamma-aminobutyric acid-ergic (GABAergic) neurons of the hippocampus (Yan et al., 1998). In fact, in this Dryocrassin ABBA area, CRF inhibits glutamate release through CRF1r (Bagosi et al., 2015), leading to a decrease in the GABA concentration in the hypothalamic PVN (Bagosi et al., 2015) and the consequent stimulation of hypothalamic CRF synthesis (Konishi et al., 2003). In view of these considerations and the obtained results, PFOS seems to differently affect CRF1r transcription and translation in the hippocampus and to disrupt the regulation of hypothalamic CRF secretion by the hippocampal CRF1r. To date and according to the revised literature, there is only one study about the toxicity of PFOS in the Gr gene expression, in which rats treated with 18.75 mg of PFOS/kg/day for 4 weeks showed an activation of gene expression of the Gr in the kidney (Rogers et al., 2014). In this line, the obtained results in the present work report that high doses of PFOS (3.0 and 6.0 mg/kg/day) inhibit the protein expression of hypothalamic Gr in adult male rats, while the gene expression of this receptor is not modified. According to Laryea et al. (2013), a decrease in the Gr density in the hypothalamic PVN stimulates HPA axis activity. However, these high doses of PFOS induce a decrease in the secretion of CRF, ACTH and corticosterone (Pereiro et al., 2014) as well as the protein expression of Gr, indicating thus, that the inhibition exerted by this xenobiotic in the HPA axis activity is not mediated by the hypothalamic Gr. The individual variability of the HPA axis function seems to be due to the variability of the expression and function of the Gr in the pituitary gland (Briassoulis et al., 2011). At the same time, corticosterone, when bound to the pituitary Gr, activates the synthesis of this receptor and consequently, it inhibits ACTH and corticosterone release (Gupta et al., 2007). These facts support the study of PFOS effects on this receptor in this endocrine gland. According to these mechanisms of regulation, and the inhibition induced by PFOS in the protein expression of Gr in the pituitary gland as well as in the ACTH and corticosterone release, the inhibition of the HPA axis activity exerted by this contaminant is not mediated through Gr at pituitary level. PFOS-treated rats would try to maintain the physiological levels of corticosterone by reducing the protein expression of Gr in both hypothalamus and pituitary gland. There is a high density of Gr in the hippocampus in humans, indicating the importance of glucocorticoids in this limbic region (Wang et al., 2013). This receptor self-regulates its synthesis in cases of prolonged periods of exposure to elevated plasma glucocorticoid levels (Herman and Spencer, 1998). Unlike what occurs in other tissues, such as the prefrontal cortex, PFOS does not affect the hippocampal Gr in adult male rat, with the exception of the stimulation of its gene expression when PFOS is administered at the doses of 0.5 and 1.0 mg/kg/day. In prefrontal cortex, Gr are partially occupied at basal glucocorticoid levels, saturated at high circadian peaks and under stress conditions (Butts et al., 2011). Glucocorticoids act locally in this brain area modulating the dopaminergic variations that lead to acute stress (Butts et al., 2011). Therefore, the inhibition of PFOS in the gene and protein expression of this receptor in the prefrontal cortex could produce alterations of the dopaminergic system in situations of acute stress. However, under physiological conditions PFOS-treated rats show some variations in gene and protein expression of dopamine receptor D1r in this same region (Salgado et al., 2016). So that the cortical Gr could mediate these changes induced by PFOS administration. Besides, according to the administration guidelines followed in this work, PFOS inhibits the gene expression of Gr in the amygdala, remaining constant the protein expression of this receptor. Considering that the Gr located in the central nucleus of the amygdala is part of a neuroendocrine circuit activated in reactions to fear (Kolber et al., 2008), exposure to this toxic could modify this defense mechanism.