Glucocorticoid Metabolism Research Articles

The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure

Context Patients with hypopituitarism have increased morbidity and mortality. There is ongoing debate about the optimum glucocorticoid (GC) replacement therapy. Objective To assess the effect of GC replacement in hypopituitarism on corticosteroid metabolism and its impact on body composition. Design and patients We assessed the urinary corticosteroid metabolite profile (using gas chromatography/mass spectrometry) and body composition (clinical parameters and full body DXA) of 53 patients (19 female, median age 46 years) with hypopituitarism (33 ACTH-deficient/20 ACTH-replete) (study A). The corticosteroid metabolite profile of ten patients with ACTH deficiency was then assessed prospectively in a cross over study using three hydrocortisone (HC) dosing regimens (20/10 mg, 10/10 mg and 10/5 mg) (study B) each for 6 weeks. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was assessed by urinary THF+5α-THF/THE. Setting Endocrine Centres within University Teaching Hospitals in the UK and Ireland. Main outcome measures Urinary corticosteroid metabolite profile and body composition assessment. Results In study A, when patients were divided into three groups - patients not receiving HC and patients receiving HC≤20 mg/day or HC>20 mg/day - patients in the group receiving the highest daily dose of HC had significantly higher waist-to-hip ratio (WHR) than the ACTH replete group. They also had significantly elevated THF+5α-THF/THE (P=0.0002) and total cortisol metabolites (P=0.015). In study B, patients on the highest HC dose had significantly elevated total cortisol metabolites and all patients on HC had elevated THF+5α-THF/THE ratios when compared to controls. Conclusions In ACTH-deficient patients daily HC doses of >20 mg/day have increased WHR, THF+5α-THF/THE ratios and total cortisol metabolites. GC metabolism and induction of 11β-HSD1 may play a pivitol role in the development of the metabolically adverse hypopituitary phenotype.

Social stress promotes changes in local metabolism of glucocorticoids

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The Application of Metabolomic Profiling to the Effects of Physical Activity

Physical activity and exercise are potent lifestyle interventions for the reduction of several psychosomatic risks, including cardiovascular disease, diabetes and mild-to-moderate depression. The current review describes the studies which have utilised a metabolomics/ metabolite profiling approach in combination with exercise in the period between 1999-2014 in predominantly healthy subjects (N:64) and in a smaller subset of patient cohorts (N:10) between 2011-2014. A broad range of intervention types were used in both healthy and patient cohorts with varying exercise regimes with or without supplement use. Effects on purine metabolism, which have been known for over 40 years, were by far the most well-cited and persistent finding. Other reported effects included observations of: glucocorticoid and androgen metabolism, glycolysis and Krebs cycle, gluconeogenesis, fatty acid metabolism, fatty acid oxidation and pantothenic acid, amino acid oxidation, tryptophan metabolism and effects on microbiome metabolites. The discussion section draws observations from the very disparate studies together and links them to the general aspects of human metabolism.

A simple LC–MS/MS method for the determination of cortisol, cortisone and tetrahydro-metabolites in human urine: Assay development, validation and application in depression patients

Chronic stress as well as major depressive disorders is associated with cortisol metabolism. Two enzymes modulate cortisol (F) and cortisone (E) interconversion: 11β-hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 11β-HSD2). Furthermore, F and E were inactivated by 5α and 5β reductases to their tetrahydro-metabolites: tetrahydrocortisol (THF), allo-tetrahydrocortisol (5α-THF) and tetrahydrocortisone (THE). To better understand depression a LC-MS/MS method for simultaneous determination of F, E THF, 5α-THF and THE in human urine has been developed and validated. The quantification range was 0.1–160ngmL−1 for F and E, and 0.2–160ngmL−1 for the tetrahydro-metabolites, with >86.1% recovery for all analytes. The nocturnal urine concentrations of F, E and tetrahydro-metabolites in 12 apparently healthy male adult volunteers and 12 drug-free male patients (age range, 20–50 years) with a diagnosis of depression were analyzed. A series of significant changes in glucocorticoid metabolism can be detected: F/E ratios and (THF+5α-THF)/THE ratios as well as F and THF concentrations were significantly higher in depression patients than in healthy subjects (p<0.05); 5α-THF/F ratios, 5α-THF/THF ratios as well as 5α-THF concentrations were significantly lower in depression patients (p<0.05). The results pointed to the decreased 11β-HSD2 activity and a dysfunction in the 5α-reductase pathway in depressed patients. This method allows the assessment of 11β-HSD1/2 and 5α/β-reductase activities in a single analytical run providing an innovative tool to explain the potential etiology of depression.

Adipose tissue hormones and their role for female fertility and metabolic disorders

Adipose tissue plays a crucial role in the regulation of energy homeostasis, insulin sensitivity, and lipid/carbohydrate metabolism. These actions are mediated by both actions of a number of non-secreted proteins and hormones produced in adipocytes. Adipose tissue is a complex, essential and highly active metabolic and endocrine organ. It does not only respond to afferent signals from hormone systems and the central nervous system but also produces and secrets factors with important endocrine functions. These factors include leptin, adiponectin, resistin, cytokines, complement components, plasminogen activator inhibitor‑1, proteins of the renin-angiotensin system. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. Hormones produced by adipose tissue play a critical role in the regulation of energy homeostasis, lipid and carbohydrate metabolism, reproduction, cardiovascular function and immunity. The hormones (leptin, adiponectin, resistin) and cytokines (tumor necrosis factor-α, interleukin‑6) produced by the adipose tissue are the link between obesity and obesity-related complications. A review discusses the role of these hormones in the regulation of energy homeostasis and insulin action. This article presents an overview of the endocrine functions of adipose tissue and discusses the structure, function and clinical significance of adipokines. The purpose of the present review is to summarize the most important aspects of the biology, actions, and regulation of these hormones and to give an updated concept based on recent publications.

Glycyrrhizic Acid as the Modulator of 11β -hydroxysteroid dehydrogenase (Type 1 and 2) in Rats under Different Physiological Conditions in Relation to the Metabolic Syndrome

Worldwide increase in the prevalence of metabolic syndrome has raised great attention to this disorder. Despite the effectiveness of the currently available therapeutic agents, most of the drugs elicit harmful side effects. Glycyrrhizic acid (GA) found in the licorice shrub, Glycyrrhiza glabra has been shown to exert anti-hyperglycaemic and antidyslipidaemic effects on rats under different physiological conditions via various mechanisms. The main route being the non-selective inhibition of 11β-hydroxysteroid dehydrogenase, an enzyme catalyzing the inter-conversion of active and inactive glucocorticoids. Altered intracellular glucocorticoid metabolism shows a stronger correlation to the development of metabolic syndrome compared to circulating glucocorticoid. Hence, this review focus on the role of GA in modulating glucocorticoid production in different tissues via regulation of 11β- hydroxysteroid dehydrogenase (both type 1 and 2) activities under different physiological conditions.

DS-01 * GLUCOCORTICOIDS POTENTLY INDUCE APOPTOSIS IN THE CEREBELLAR EXTERNAL GRANULE LAYER: IMPLICATIONS FOR MEDULLOBLASTOMA TREATMENT

Premature infants suffering from respiratory dysfunction are often administered glucocorticoids (GCs) to mature the lungs. Unfortunately, neonates exposed to GCs can exhibit neuromotor deficits and selective cerebellar stunting. In order to test the safety of GCs, we administered the synthetic GC dexamethasone to neonatal mouse pups and found it potently increased apoptosis in the external granule layer (EGL) of the cerebellum. The EGL is responsible for producing over 90% of the neurons in the cerebellum, which represents over half the neurons in the entire brain. We subsequently discovered that endogenous GC release, receptors, and enzymatic metabolism is carefully orchestrated to selectively increase stimulation in the EGL as it is naturally eliminated. This suggests the GC system may signal the permanent disappearance of the EGL during development. Unfortunately, EGL neural progenitor cells (NPCs) can transform into medulloblastomas (MBs), the most common malignant brain tumor in children. As a result, the GC system may play a critical role in MB development. Up to 30% of human medulloblastomas are thought to be driven by excessive Hedgehog signaling (a potent EGL mitogen). Consistent with this idea, mice with mutations causing constitutive Hedgehog signaling are also vulnerable to MB formation. Interestingly, excessive Hedgehog signaling is also thought to decrease GC stimulation in the EGL due to selective GC metabolism. Therefore, we used MB prone (Patched) mice to examine if this vulnerability still exists during preneoplastic tumor transformation. We found GC stimulation potently increased apoptotic cell death in preneoplasms. This suggests GCs may both play a role in MB development and have potential as a therapeutic treatment.

Detection of 11 beta-hydroxysteroid dehydrogenase type 1, the glucocorticoid and mineralocorticoid receptor in various adipose tissue depots of dairy cows supplemented with conjugated linoleic acids.

Early lactating cows mobilize adipose tissue (AT) to provide energy for milk yield and maintenance and are susceptible to metabolic disorders and impaired immune response. Conjugated linoleic acids (CLA), mainly the trans-10, cis-12 isomer, reduce milk fat synthesis and may attenuate negative energy balance. Circulating glucocorticoids (GC) are increased during parturition in dairy cows and mediate differentiating and anti-inflammatory effects via glucocorticoid (GR) and mineralocorticoid receptors (MR) in the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). Activated GC are the main ligands for both receptors in AT; therefore, we hypothesized that tissue-specific GC metabolism is effected by varying amounts of GR, MR and 11βHSD1 and/or their localization within AT depots. Furthermore, the lipolytic and antilipogenic effects of CLA might influence the GC/GR/MR system in AT. Therefore, we aimed to localize GR and MR as well as the expression pattern and activity of 11βHSD1 in different AT depots during early lactation in dairy cows and to identify potential effects of CLA. Primiparous German Holstein cows were divided into a control (CON) and a CLA group. From day 1 post-partum (p.p.) until sample collection, the CLA group was fed with 100 g/d CLA (contains 10 g each of the cis-9, trans-11 and the trans-10, cis-12-CLA isomers). CON cows (n = 5 each) were slaughtered on day 1, 42 and 105 p.p., while CLA cows (n = 5 each) were slaughtered on day 42 and 105 p.p. Subcutaneous fat from tailhead, withers and sternum, and visceral fat from omental, mesenteric and retroperitoneal depots were sampled. The localization of GR and 11βHSD1 in mature adipocytes - being already differentiated - indicates that GC promote other effects via GR than differentiation. Moreover, MR were observed in the stromal vascular cell fraction and positively related to the pre-adipocyte marker Pref-1. However, only marginal CLA effects were observed in this study.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue were studied. Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis.

5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.

Glucocorticoid metabolism in bovine cumulus-oocyte complex during in vitro maturation

Glucocorticoid metabolism in bovine cumulus-oocyte complex during in vitro maturation

Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue

Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, visceral obesity and insulin resistance. We hypothesized that changes in glucocorticoid metabolism and signaling in the visceral adipose tissue may contribute to disturbances of lipid metabolism in the rat model of PCOS obtained by 5α-dihydrotestosterone (DHT) treatment of prepubertal female Wistar rats. The results confirmed that DHT treatment caused anovulation, obesity and dyslipidemia. Enhanced glucocorticoid prereceptor metabolism, assessed by elevated intracellular corticosterone and increased 11 beta-hydroxysteroid dehydrogenase type 1 mRNA and protein levels, was accompanied by glucocorticoid receptor (GR) nuclear accumulation. In concert with the increased expression of GR-regulated prolipogenic genes (lipin-1, sterol regulatory element binding protein 1, fatty acid synthase, phosphoenolpyruvate carboxykinase), histological analyses revealed hypertrophic adipocytes. The results suggest that glucocorticoids influence lipid metabolism in the visceral adipose tissue in the way that may contribute to pathogenesis of metabolic disturbances associated with PCOS.

Mice deficient in intestinal epithelium cytochrome P450 reductase are prone to acute toxin-induced mucosal damage.

Cytochrome P450 (P450) enzymes are a superfamily of heme-containing enzymes involved in the metabolism of various endogenous compounds, including retinoids, glucocorticoids, and eicosanoids, that are postulated to participate in the maintenance and/or development of inflammatory and immune reactions in the intestinal mucosa. To investigate the role of P450 enzymes in intestinal inflammation and immunity, we took advantage of IE-Cpr-null mice, which are deficient in intestinal epithelium of NADPH-cytochrome P450 reductase (CPR), the obligate redox partner of all microsomal P450 enzymes. We report that IE-Cpr-null mice, following an acute toxin challenge, had higher levels of pro-inflammatory chemokines and increased tissue damage compared to wild-type mice. IE-Cpr-null mice had normal Peyer's patch numbers and elicited normal secretory IgA (SIgA) responses. However, SIgA baseline levels in IE-Cpr-null mice were consistently elevated over WT littermates. While neither retinoic acid nor glucocorticoid levels in serum and intestinal homogenates were altered in IE-Cpr-null mice, basal levels of arachidonic acid metabolites (11,12-DiHETE and 14,15-DiHETE) with known anti-inflammatory property were significantly lower compared to WT controls. Overall, these findings reveal immunological and metabolic changes resulting from a genetic deficiency in CPR expression in the intestine, and support a role for microsomal P450 enzymes in mucosal homeostasis and immunity.

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype.

Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. This was a prospective longitudinal observation study conducted over 5 years. A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity. Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.

Interdependence of the peripheral metabolism of glucocorticoids and thyroid hormones under calorie deficit in rats at different ages

Interdependence of the peripheral metabolism of glucocorticoids and thyroid hormones under calorie deficit in rats at different ages

Elevation of 11β-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure.

Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring. Holocaust offspring (n=85) and comparison subjects (n=27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-h urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11β-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol. Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p=.046), as had been shown for Holocaust survivors. However, 11β-HSD-2 activity was elevated for offspring compared to controls (p=.008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p=.032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample. The inverse association of offspring 11β-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a long standing reduction in 11β-HSD-2 activity among survivors is readily interpreted in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration.

The balance of cortisol–cortisone interconversion is shifted towards cortisol in neonates with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

BackgroundPatients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) have an impaired cortisol synthesis, but it is unknown whether the metabolism of glucocorticoids differs between neonates and infants with and without 21OHD. ObjectiveThe objective of this study was to compare the glucocorticoid metabolism between neonates and infants with and without 21OHD. MethodsWe analyzed 14 urinary glucocorticoid metabolites, 7 metabolites each of cortisol and cortisone, by gas chromatography–mass spectrometry of 89 untreated 21OHD neonates and infants and 161 neonates and infants without 21OHD. ResultsNeonates with 21OHD exhibit elevated relative amounts of cortisol metabolites in total glucocorticoid metabolism and an increased ratio of cortisol to cortisone metabolites (p<0.0001). This reflects a shift toward cortisol in the relative balance of the interconversion between cortisol and cortisone. The ratio of cortisol to cortisone metabolites correlated significantly with low urinary glucocorticoid concentrations (p<0.03), with low 21-hydroxylase activity (p<0.001) and high urinary sodium and chloride concentrations (p<0.05) in neonates with 21OHD. ConclusionsOur results demonstrate substantial changes in the relative cortisone to cortisol interconversion in neonates with 21OHD. The shift of glucocorticoid metabolism toward active cortisol in neonates with 21OHD seems to be related to the severity of 21OHD and adrenal dysfunction. Our data provide new insights into the regulation of glucocorticoid homeostasis in 21OHD.

Expression of 11β-hydroxysteroid dehydrogenase 1 and 2 in patients with chronic rhinosinusitis and their possible contribution to local glucocorticoid activation in sinus mucosa

It has been suggested that glucocorticoids might act in target tissues to increase their own intracellular availability in response to inflammatory stimuli. These mechanisms depend on the local metabolism of glucocorticoids catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). This study is to investigate the effect of chronic rhinosinusitis (CRS) on expression of 11β-HSD1, 11β-HSD2, steroidogenic enzymes (cytochrome P450, family 11, subfamily B, polypeptide 1 [CYP11B1] and cytochrome P450, family 11, subfamily A, polypeptide 1 [CYP11A1]), and endogenous cortisol levels in human sinus mucosa. Expression levels were compared with those of healthy control subjects. The expression levels of 11β-HSD1, 11β-HSD2, CYP11B1, CYP11A1, and cortisol were measured in healthy control subjects, patients with CRS with nasal polyps, and patients with CRS without nasal polyps by using real-time PCR, Western blotting, immunohistochemistry, and ELISA. Expression levels of 11β-HSD1, 11β-HSD2, CYP11B1, CYP11A1, and cortisol were determined in cultured epithelial cells treated with CRS-relevant cytokines. The conversion ratio of cortisone to cortisol was evaluated by using the small interfering RNA technique, 11β-HSD1 inhibitor, and measurement of 11β-HSD1 activity. 11β-HSD1, CYP11B1, and cortisol levels increased in patients with CRS with nasal polyps and those with CRS without nasal polyps, but 11β-HSD2 expression decreased. In cultured epithelial cells treated with IL-4, IL-5, IL-13, IL-1β, TNF-α, and TGF-β1, 11β-HSD1 expression and activity increased in parallel with expression levels of CYP11B1 and cortisol, but the production of 11β-HSD2 decreased. The small interfering RNA technique or the measurement of 11β-HSD1 activity showed that the sinus epithelium activates cortisone to cortisol in an 11β-HSD-dependent manner. These results indicate that CRS-relevant cytokines can modulate the expression of 11β-HSD1, 11β-HSD2, and CYP11B1 in the sinus mucosa, resulting in increasing intracellular concentrations of bioactive glucocorticoids.

Dioxin-induced fetal growth retardation: the role of a preceding attenuation in the circulating level of glucocorticoid.

Exposure of pregnant rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a low dose causes developmental disorders such as growth retardation and sexual immaturity in their pups. Our previous studies have demonstrated that TCDD attenuates the expression of pituitary luteinizing hormone in fetuses, resulting in the impairment of sexual behavior after they reach maturity. In this study, we focused on growth disturbance and investigated whether TCDD affects the expression of growth hormone (GH), another pituitary hormone which is essential for normal development in perinatal pups. The result showed that maternal exposure to TCDD (1 µg/kg) at gestational day (GD) 15 reduced the fetal expression of GH from the onset at GD18. In accordance with this, TCDD attenuated the pup weight during the perinatal period. We then examined the effect of TCDD on the serum concentration of corticosterone, which plays a key role in the proliferation of GH-producing cells, and found that TCDD reduces the circulating level of corticosterone in the mothers at GD18 and the male fetuses at GD19. The reduction in fetuses seems to be due to increased inactivation rather than reduced synthesis, because TCDD induces the fetal expression of hepatic enzymes participating in the metabolism of glucocorticoids without changing the expression of steroidogenic proteins in the pituitary-adrenal axis. Supplying corticosterone to TCDD-exposed mothers restored or tended to restore a TCDD-induced reduction in pup weight as well as the levels of pituitary GH mRNA and serum GH. These results suggest that TCDD lowers GH expression and growth retardation owing, at least partially, to a reduction in the circulating level of glucocorticoid in pregnant mothers and their fetuses.

Global Metabolite Profiling Reveals Transformation Pathways and Novel Metabolomic Responses inSolea senegalensisafter Exposure to a Non-ionic Surfactant

Alcohol polyethoxylate (AEO) surfactants are widely used in household and industrial products, but the health effects arising from short-term exposure to sublethal concentrations are unknown. A metabolomic approach was used to investigate the biotransformation and effects of exposure to sublethal concentrations of hexaethylene glycol monododecylether (C12EO6) in juvenile sole, Solea senegalensis. After 5 days, C12EO6 was rapidly metabolized in the sole by oxidation, glucuronidation, and ethoxylate chain shortening. C12EO6 exposure at either 146 or 553 μg L(-1) resulted in significant metabolite disruption in liver and blood samples, including an apparent fold increase of >10(6) in the circulating levels of C24 bile acids and C27 bile alcohols, disturbance of glucocorticoid and lipid metabolism, and a 470-fold decrease in levels of the fatty acid transport molecule palmitoyl carnitine. Depuration resulted in rapid elimination of the surfactant and normalization of metabolites toward pre-exposure levels. Our findings show for the first time the ability of metabolomic analyses to discern effects of this AEO on metabolite homeostasis at exposure levels below its no effect concentrations for survival and reproduction in juvenile fish. The pronounced alteration in levels of liver metabolites, phospholipids, and glucocorticoids in S. senegalensis in response to surfactant exposure may indicate that this contaminant could potentially impact a number of health end points in fish.