Dehydroepiandrosterone Inhibits Complex I of the Mitochondrial Respiratory Chain and is Neurotoxic In Vitro and In Vivo at High Concentrations

Safiulina, Dzhamilja; Peet, Nadezhda; Seppet, Enn; Zharkovsky, Alexander; Kaasik, Allen

doi:10.1093/toxsci/kfl064

Cited by 40 publications

(29 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DHEA is known to affect mitochondrial energy production through inhibition of enzymes associated with the respiratory chain [48] with variable findings in children with ASD [49], [50].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

et al. 2014

View full text Add to dashboard Cite

BackgroundThe diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age.ObjectivesTo discover metabolic features present in plasma samples that can discriminate children with ASD from typically developing (TD) children. The ultimate goal is to identify and develop blood-based ASD biomarkers that can be validated in larger clinical trials and deployed to guide individualized therapy and treatment.MethodsBlood plasma was obtained from children aged 4 to 6, 52 with ASD and 30 age-matched TD children. Samples were analyzed using 5 mass spectrometry-based methods designed to orthogonally measure a broad range of metabolites. Univariate, multivariate and machine learning methods were used to develop models to rank the importance of features that could distinguish ASD from TD.ResultsA set of 179 statistically significant features resulting from univariate analysis were used for multivariate modeling. Subsets of these features properly classified the ASD and TD samples in the 61-sample training set with average accuracies of 84% and 86%, and with a maximum accuracy of 81% in an independent 21-sample validation set.ConclusionsThis analysis of blood plasma metabolites resulted in the discovery of biomarkers that may be valuable in the diagnosis of young children with ASD. The results will form the basis for additional discovery and validation research for 1) determining biomarkers to develop diagnostic tests to detect ASD earlier and improve patient outcomes, 2) gaining new insight into the biochemical mechanisms of various subtypes of ASD 3) identifying biomolecular targets for new modes of therapy, and 4) providing the basis for individualized treatment recommendations.

show abstract

“…DHEA is known to affect mitochondrial energy production through inhibition of enzymes associated with the respiratory chain [48] with variable findings in children with ASD [49], [50].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

et al. 2014

View full text Add to dashboard Cite

show abstract

“…There are several animal studies that used a similar DHEA dose (6 g/kg of diet or 0.6%) to investigate the effects of feeding DHEA on several metabolic changes including weight loss using the Zucker rat model [8,21]. However, there is one study that used regular mice and not obese Zucker rats, and the study reported that mice fed with pellets containing 0.6% DHEA for 3 months showed a significant neuronal loss in the cerebral cortex and hippocampus, a slightly decreased dopamine/dihydroxyphenylacetic acid ratio, and motor impairment [28]. However, there are no reports of toxicity when using 6 g/kg of diet in the obese Zucker rat model.…”

Section: Methodsmentioning

confidence: 99%

Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model

Hakkak

Bell²,

Korourian

2017

Sci. Pharm.

View full text Add to dashboard Cite

Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p < 0.001) than control-fed rats and gained less weight (p < 0.001). DHEA feeding caused significant decreases (p < 0.001) in the serum levels of IGF-1 and IGFBP-3 and significantly increased (p < 0.001) serum levels of DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model.

show abstract

“…The administration of 500 nM DHEA (the highest concentration examined) was neurotoxic to rat hippocampal cultures [150]. High concentrations of DHEA (micromolar concentrations) have also been neurotoxic in vitro , with effects mediated through inhibition of complex I of the mitochondrial respiratory chain [269]. Neurotoxic effects have also been demonstrated in vivo .…”

Section: Neurobiological Actions Of Dhea(s)mentioning

confidence: 99%

Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)

Maninger

Wolkowitz

Reus

et al. 2009

Frontiers in Neuroendocrinology

634

603

View full text Add to dashboard Cite

DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.

show abstract

Dehydroepiandrosterone Inhibits Complex I of the Mitochondrial Respiratory Chain and is Neurotoxic In Vitro and In Vivo at High Concentrations

Cited by 40 publications

References 47 publications

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model

Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)

Contact Info

Product

Resources

About