1.
Karlsson, Sofia, et al.
(författare)
Ellagic acid inhibits lipopolysaccharide-induced expression of enzymes involved in the synthesis of prostaglandin E2 in human monocytes
2010
Ingår i: British Journal of Nutrition. - : Cambridge University Press. - 0007-1145 .- 1475-2662. ; 103:8, s. 1102-1109
Tidskriftsartikel (refereegranskat) abstract
Ellagic acid, a natural polyphenol found in certain fruits, nuts and vegetables, has in recent years been the subject of intense research within the fields of cancer and inflammation. Pain, fever and swelling, all typical symptoms of inflammation, are ascribed to elevated levels of PGE(2). In the present study, we have investigated the effects of ellagic acid on PGE(2) release and on prostaglandin-synthesising enzymes in human monocytes. Ellagic acid was found to inhibit Ca ionophore A23187-, phorbol myristate acetate- and opsonised zymosan-induced release of PGE(2) from monocytes pre-treated with the inflammatory agent lipopolysaccharide. Ellagic acid suppressed the lipopolysaccharide-induced increase in protein expression of cyclo-oxygenase-2 (COX-2), microsomal PGE synthase-1 (mPGEs-1) and cytosolic phospholipase A(2)alpha (cPLA(2)alpha), while it had no effect on the constitutively expressed COX-1 protein. Ellagic acid had no apparent inhibitory effect on these enzymes when the activities were determined in cell-free assays. We conclude that the inhibitory effect of ellagic acid on PGE(2) release from monocytes is due to a suppressed expression of COX-2, mPGEs-1 and cPLA(2)alpha, rather than a direct effect on the activities of these enzymes.
2.
Fagan, V., et al.
(författare)
COMPARE analysis of the toxicity of an iminoquinone derivative of the imidazo[5,4-f]benzimidazoles with NAD(P)H:quinone Oxidoreductase 1 (NQO1) activity and computational docking of quinones as NQO1 substrates
2012
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 20:10, s. 3223-3232
Tidskriftsartikel (refereegranskat) abstract
Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction. (C) 2012 Elsevier Ltd. All rights reserved.
3.
Repouskou, Anastasia, et al.
(författare)
Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment
2020
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10, s. 1-8
Tidskriftsartikel (refereegranskat) abstract
Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0x, 0.5x, 10x, 100x and 500x the geometric mean of SELMA mothers' concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.
4.
Alavian-Ghavanini, Ali, et al.
(författare)
Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans
2018
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
Tidskriftsartikel (refereegranskat) abstract
Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.
5.
6.
7.
Bornehag, Carl-Gustav, 1957-, et al.
(författare)
Prenatal exposure to bisphenols and cognitive function in children at 7 years of age in the Swedish SELMA study
2021
Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 150
Tidskriftsartikel (refereegranskat) abstract
Background: Experimental evidence demonstrates that exposure to bisphenol A (BPA), and the recently intro-duced alternatives bisphenol S (BPS) and bisphenol F (BPF) alter normal neurodevelopment. More research is needed to evaluate the associations between exposure to individual BPA alternatives and neurodevelopmental outcomes in humans. Objective: The present study aimed at examining the individual associations between prenatal BPA , BPS and BPF exposure and cognitive outcomes in children at age 7 years. Method: Women were enrolled in the Swedish Environmental Longitudinal Mother and Child, Asthma and Al-lergy (SELMA) study, at gestational median week 10.0, and their children were examined for cognitive function at 7 years of age (N = 803). Maternal urina r y BPA , BPS, and BPF concentrations were measured at enrollment and children?s cognitive function at the age of 7 years was measured using the Wechsler Intelligence Scale for Children IV (WISC-IV). Results: A l l three bisphenols were detected in over 90% of the women, where BPA had the highest geometric mean concentrations (1.55 ng/mL), followed by BPF (0.16 ng/mL) and BPS (0.07 ng/mL). Prenatal BPF exposure was associated with decreased f u l l scale IQ (13 =-1.96, 95%CI;-3.12;-0.80), as we l l as with a decrease in a l l four sub scales covering verbal comprehension, perceptual reasoning, working memor y and processing speed. This association corresponded to a 1.6-point lower IQ score for an inter-quartile-range (IQR) change in prenatal BPF exposure (IQR = 0.054 & ndash;0.350 ng/mL). In sex-stratified analyses, significant associations with f u l l scale IQ were found for boys (13 = - 2.86, 95%CI;-4.54;-1.18), while the associations for girls did not reach significance (13 =-1.38, 95%CI;-2.97; 0.22). No significant associations between BPA nor BPS and cognition were found. Discussion: Prenatal exposure to BPF was significantly associated with children?s cognitive function at 7 years. Since BPF is replacing BPA in numerous consumer products globally, this finding urgently ca l l for further studies.
8.
Cediel Ulloa, Andrea, et al.
(författare)
Impact of endocrine disrupting chemicals on neurodevelopment : the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity
2022
Ingår i: Expert Review of Endocrinology & Metabolism. - : Taylor & Francis. - 1744-6651 .- 1744-8417. ; 17:2, s. 131-141
Tidskriftsartikel (refereegranskat) abstract
Introduction: Brain development is highly dependent on hormonal regulation. Exposure to chemicals disrupting endocrine signaling has been associated with neurodevelopmental impairment. This raises concern about exposure to the suspected thousands of endocrine disruptors, and has resulted in efforts to improve regulation of these chemicals. Yet, the causal links between endocrine disruption and developmental neurotoxicity, which would be required for regulatory action, are still largely missing. Areas covered: In this review, we illustrate the importance of two endocrine systems, thyroid hormone and retinoic acid pathways, for neurodevelopment. We place special emphasis on TH and RA synthesis, metabolism, and how endocrine disrupting chemicals known or suspected to affect these systems are associated with developmental neurotoxicity. Expert opinion: While it is clear that neurodevelopment is dependent on proper hormonal functioning, and evidence is increasing for developmental neurotoxicity induced by endocrine disrupting chemicals, this is not grasped by current chemical testing. Thus, there is an urgent need to develop test methods detecting endocrine disruption in the context of neurodevelopment. Key to this development is further mechanistic insights on the involvement of endocrine signaling in neurodevelopment as well as increased support to develop and validate new test methods for the regulatory context.
9.
Connolly, Eamonn, et al.
(författare)
Norepinephrine-induced Na+ influx in brown adipocytes is cyclic AMP-mediated
1986
Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 261:31, s. 14377-14385
Tidskriftsartikel (refereegranskat) abstract
To examine the involvement of Na+ ions in adrenergic responses in brown adipose tissue, a method is described for measuring Na+ influx into isolated brown adipocytes, using short (30 s) incubations with 22Na+, followed by a two-step centrifugation recovery procedure. Using this method, a clear norepinephrine-stimulated accumulation of intracellular 22Na+ was observed, which was enhanced by the addition of ouabain, was insensitive to amiloride (a Na+/H+ exchange blocker), and could not be mimicked by the total removal of oxygen from the incubation medium. The norepinephrine-stimulated Na+ influx was dose-dependent for the hormone with an EC50 of 250 nM, was blocked by the beta-antagonist propranolol but not by the alpha 1-antagonist prazosin, and could be induced by adrenergic agonists with the order of potency: isoproterenol greater than norepinephrine greater than phenylephrine, indicating a beta-receptor-mediated process. The Na+ influx was found to be cAMP-dependent since it could be induced by both theophylline (a phosphodiesterase inhibitor) and forskolin (an adenylate cyclase activator), but it was independent of other known cellular cAMP-dependent responses since neither addition of fatty acid substrates (octanoate or palmitate), nor of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone could induce the phenomenon, despite having significant stimulatory effects on cellular respiration. Furthermore, total respiratory inhibition with rotenone, or total oxygen depletion of the medium with dithionite, did not prevent the normal norepinephrine-induced Na+ influx. The possibility that this beta-mediated norepinephrine-stimulated Na+ influx plays an important physiological role in brown adipose tissue activity is discussed, perhaps as one of the, as yet undefined, signals initiating tissue growth in the chronically beta-stimulated tissue of animals facing long-term increases in thermogenic demands.
10.
Di Criscio, Michela, et al.
(författare)
A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice
2023
Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 313
Tidskriftsartikel (refereegranskat) abstract
Humans are ubiquitously exposed to endocrine disrupting chemicals (EDCs), substances that interfere with endogenous hormonal signaling. Exposure during early development is of particular concern due to the programming role of hormones during this period. A previous epidemiological study has shown association between prenatal co-exposure to 8 EDCs (Mixture N1) and language delay in children, suggesting an effect of this mixture on neurodevelopment. Furthermore, in utero exposure to Mixture N1 altered gene expression and behavior in adult mice. In this study, we investigated whether epigenetic mechanisms could underlie the long term effects of Mixture N1 on gene expression and behavior. To this end, we analyzed DNA methylation at regulatory regions of genes whose expression was affected by Mixture N1 in the hippocampus of in utero exposed mice using bisulfite-pyrosequencing. We show that Mixture N1 decreases DNA methylation in males at three genes that are part of the hypothalamus-pituitary-adrenal (HPA) axis: Nr3c1, Nr3c2, and Crhr1, coding for the glucocorticoid receptor, the mineralocorticoid receptor, and the corticotropin releasing hormone receptor 1, respectively. Furthermore, we show that the decrease in Nr3c1 methylation correlates with increased gene expression, and that Nr3c1, Nr3c2, and Crhr1 methylation correlates with hyperactivity and reduction in social behavior. These findings indicate that an EDC mixture corresponding to a human exposure scenario induces epigenetic changes, and thus programming effects, on the HPA axis that are reflected in the behavioral phenotypes of the adult male offspring.
