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  • The HPA axis controls its own activity

    2020-07-27

    The HPA axis controls its own activity through a negative feedback mechanism exercised by glucocorticoids (Keller-Wood, 2015), which limits the hypothalamic corticotropin-releasing factor (CRF) secretion and the pituitary Desfuroylceftiofur release (Keller-Wood, 2015). CRF binds to its specific receptors (corticotropin-releasing factor 1 receptor or CRF1r) on pituitary gland to increase ACTH synthesis and secretion, which stimulates glucocorticoid synthesis by the adrenal gland (Fig. 1). Moreover, CRF regulates HPA axis activity through CRF1r directly in adrenal gland (Nussdorfer, 1996; Müller et al., 2001) and indirectly in hippocampus (Yan et al., 1998; Bagosi et al., 2015) where CRF also acts as a neurotransmitter and participates in behavioural and autonomic responses to the stress (Beery et al., 2014). Glucocorticoids regulate their secretion by a direct action in their specific receptors (glucocorticoid receptors or Gr), thereby inhibit the synthesis and release of CRF and ACTH (Keller-Wood, 2015), and affect cerebral structures such as the limbic system (Herman et al., 2005). Feedback regulation of the HPA axis activity is dependent on the glucocorticoids action through Gr in the hypothalamic paraventricular nucleus (PVN) and in the pituitary gland, as well as in several limbic structures, mainly in the hippocampus, prefrontal cortex and amygdala (De Kloet et al., 2005). The hippocampus and the prefrontal cortex exert a negative feedback on the HPA axis through projections to the PVN, while the amygdala has a stimulatory influence on the PVN and thus the HPA axis (Ulrich-Lai and Herman, 2009). PFOS presents toxicity on the HPA axis activity in rats (Austin et al., 2003; Zhao et al., 2011a; Pereiro et al., 2014; Li et al., 2016), mice (Zheng et al., 2009, Zheng et al., 2011; Ribes et al., 2010), fishes (Shi et al., 2009; Mortensen et al., 2011; Du et al., 2016) and in human beings (Zhao et al., 2011a, Zhao et al., 2011b; Goudarzi et al., 2017). Oral PFOS exposure (at the doses of 0.5; 1.0; 3.0 and 6.0 mg PFOS/kg/day for 28 consecutive days) inhibits the overall activity of the HPA axis by decreasing the hypothalamic CRF concentration and the serum ACTH and corticosterone levels (Pereiro et al., 2014). Moreover PFOS, at these same doses, modifies CRF and adrenocorticotropic hormone receptor (ACTHr) gene expression in the hypothalamus, gene expression of proopiomelanocortin (POMC) and ACTHr in the pituitary gland and in the adrenal gland, respectively (Pereiro et al., 2014). This chemical also modifies relative weight and morphology of the adrenal gland (Pereiro et al., 2014). However, studies by other authors suggest a stimulatory effect of PFOS on the HPA axis at high doses in rodents (Austin et al., 2003; Zheng et al., 2009). Specifically, mice orally exposed to PFOS for 7 days at doses of 20 and 40 mg/kg/day show an increase in serum corticosterone concentration (Zheng et al., 2009). This same stimulation is reported in mice treated with 5 and 20 mg of PFOS/kg/day (Zheng et al., 2011). Likewise, rats treated with 10 mg PFOS/kg/day for 2 weeks exhibit an increase in serum corticosterone concentration (Austin et al., 2003). Similarly, the administration of 5 and 20 mg of PFOS/kg/day in pregnant rats results in an increase in corticosterone levels in the foetal serum (Li et al., 2016). The same effect was observed in pregnant mice with the dose of 6 mg/kg/day of PFOS (Ribes et al., 2010). On the other hand, gene expression of CRF appears to be increased in zebrafish after exposure of PFOS (200 and 400 μg/L) (Shi et al., 2009). However, the expression of this gene is not significantly altered in mice after exposure to 75 μg PFOS/kg/h for 4 h (Asakawa et al., 2007). A recent study in human beings shows that prenatal exposure to PFOS is significantly associated with glucocorticoid levels in cord blood samples (Goudarzi et al., 2017). These observed differences in the effects of PFOS on the HPA axis could be due to the wide range of doses administered of this chemical as well as to the different animal species treated.