Perinatal Glucocorticoid Treatment Produces Molecular, Functional, and Morphological Changes in the Anterior Pituitary Gland of the Adult Male Rat

Abstract

Stress or glucocorticoid (GC) treatment in perinatal life can induce long-term changes in the sensitivity of the hypothalamo-pituitary-adrenocortical axis to the feedback actions of GCs and, hence, in GC secretion. These changes have been ascribed largely to changes in the sensitivity of the limbic system, and possibly the hypothalamus, to GCs. Surprisingly, the possibility that early life stress/GC treatment may also exert irreversible effects at the pituitary level has scarcely been addressed. Accordingly, we have examined the effects of pre- and neonatal dexamethasone treatment on the adult male pituitary gland, focusing on the following: 1) the integrity of the acute annexin 1 (ANXA1)-dependent inhibitory actions of GCs on ACTH secretion, a process requiring ANXA1 release from folliculostellate (FS) cells; and 2) the morphology of FS cells and corticotrophs. Dexamethasone was given to pregnant (d 16-19) or lactating (d 1-7 postpartum) rats via the drinking water (1 microg/ml); controls received normal drinking water. Pituitary tissue from the offspring was examined ex vivo at d 90. Both treatment regimens reduced ANXA1 expression, as assessed by Western blotting and quantitative immunogold labeling. In particular, the amount of ANXA1 located on the outer surface of the FS cells was reduced. By contrast, IL-6 expression was increased, particularly by the prenatal treatment. Pituitary tissue from untreated control rats responded to dexamethasone with an increase in cell surface ANXA1 and a reduction in forskolin-induced ACTH release. In contrast, pituitary tissue from rats treated prenatally or neonatally with dexamethasone was unresponsive to the steroid, although, like control tissue, it responded readily to ANXA1, which readily inhibited forskolin-driven ACTH release. Prenatal dexamethasone treatment reduced the size but not the number of FS cells. It also caused a marked reduction in corticotroph number and impaired granule margination without affecting other aspects of corticotroph morphology. Similar but less marked effects on pituitary cell morphology and number were evident in tissue from neonatally treated rats. Our study shows that, when administered by a noninvasive process, perinatal GC treatment exerts profound effects on the adult pituitary gland, impairing the ANXA1-dependent GC regulation of ACTH release and altering the cell profile and morphology.

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…On the basis that the mothers' daily intake of water was approximately 50 ml (McArthur et al, 2005), we calculate also that the dexamethasone dosage (approximately 75 and 150 mg/kg/ day for prenatal and neonatal treatments, respectively) is within the range of that used clinically to mature the fetal lung in cases of threatened premature birth. As previously reported (McArthur et al, 2005;Theogaraj et al, 2005;McArthur et al, 2006a), these dexamethasone treatments had no significant effects on the outcome of the pregnancies, no discernable influence on maternal behavior and no effect on adult body weight. However, in order to minimize any potential effects of litter of origin and individual differences in maternal care, animals for each of the dexamethasone treatment groups and the control group (normal drinking water) (n ¼ 8 per group) were drawn from three different litters for the analyses described below.…”

“…In order to avoid potential confounding effects of injection stress and also handling of the newborn pups, which may itself produce long-lasting effects on behaviour and mesencephalic DA systems in particular (Meaney et al, 2002), dexamethasone was administered non-invasively using the method established by McArthur et al (2005) and Theogaraj et al (2005) where dexamethasone sodium phosphate (Faulding Pharmaceuticals Plc., Royal Leamington Spa, UK) is added to the drinking water of pregnant or nursing dams between embryonic days 16-19 (E16-E19, 0.5 mg/ml) or postnatal days 1-7 (P1-P7, 1 mg/ml). Using this oral route, dexamethasone is able to reach the developing fetuses or neonates via the placenta (Funkhouser et al, 1978) or milk (Tainturier et al, 1982), respectively.…”

“…In addition, we have observed marked changes in striatal DA levels in adult rats that received 'control' manipulations (handling and saline injections; Murray, McArthur, and Gillies, unpublished observations). For these reasons we adopted the non-invasive method of administering dexamethasone via the maternal drinking water (McArthur et al, 2005(McArthur et al, , 2006aTheogaraj et al, 2005Theogaraj et al, , 2006. From the volume of water ingested, this represents a total daily dose of approximately 0.075 mg/kg prenatally and 0.15 mg/kg postnatally.…”

“…Hence, we have extended our investigations throughout the rostro-caudal extent of the adult SNc and VTA in order to assess effects on the volume and shape of these regions as well as the size and distribution of the DA populations and the size of the individual perikarya after brief exposure prenatally or neonatally to dexamethasone. The need to study both periods of exposure is governed by the knowledge that different outcomes have been reported for pre-and neonatal GC programming of the neuroendocrine axes governing the stress response and prolactin secretion Owen et al, 2005;Theogaraj et al, 2005;McArthur et al, 2006a) as well as behaviors and indicies of neurotransmitter signaling in the cerebral cortex and hippocampus Kreider et al, 2005;Owen et Moreover, many of these changes are sex-specific, and we have shown that GC programming effects on the DA population size in the hypothalamic arcuate nucleus are restricted to females (McArthur et al, 2006a). Therefore, the present investigations have been carried out in both males and females in order to investigate whether males and females are differentially affected by GC programming effects within the midbrain DA populations.…”

Histoquímica e morfometria da placenta de ratas tratadas com dexametasona

“…Os glicocorticóides são substâncias lipofílicas que afetam o metabolismo dos carboidratos, reduzem a resposta inflamatória e são essenciais no desenvolvimento de inúmeros tecidos, apresentando uma maior influência em órgãos como o fígado, os pulmões e os rins, além de reverter processos inflamatórios estabelecidos na endometriose (Theogaraj et al 2005, Batista et al 2006. Sua síntese e liberação ocorrem naturalmente pelo organismo, de acordo com sua necessidade, sob influência do ACTH (hormônio adrenocorticotrófico) (Schimmer & Parker 2003).…”