Endocrine Disruptors: Focus on the Adrenal Cortex

Benedikt Pötzl; Lydia Kürzinger; Helga Stopper; Martin Fassnacht; Max Kurlbaum; Ulrich Dischinger

doi:10.1055/a-2198-9307

Hormone and Metabolic Research, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Horm Metab Res 2024; 56(01): 78-90
DOI: 10.1055/a-2198-9307

Review

Endocrine Disruptors: Focus on the Adrenal Cortex

Benedikt Pötzl

¹Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany

,

Lydia Kürzinger

¹Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany

,

Helga Stopper

²Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany

,

Martin Fassnacht

¹Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany

,

Max Kurlbaum

¹Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany

³Central Laboratory, Core Unit Clinical Mass Spectrometry, University Hospital of Würzburg, Würzburg, Germany

,

Ulrich Dischinger

¹Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital of Würzburg, Würzburg, Germany

› Institutsangaben

Abstract

Endocrine-disrupting chemicals (EDCs) are exogenous substances known to interfere with endocrine homeostasis and promote adverse health outcomes. Their impact on the adrenal cortex, corticosteroids and their physiological role in the organism has not yet been sufficiently elucidated. In this review, we collect experimental and epidemiological evidence on adrenal disruption by relevant endocrine disruptors. In vitro data suggest significant alterations of gene expression, cell signalling, steroid production, steroid distribution, and action. Additionally, morphological studies revealed disturbances in tissue organization and development, local inflammation, and zone-specific hyperplasia. Finally, endocrine circuits, such as the hypothalamic-pituitary-adrenal axis, might be affected by EDCs. Many questions regarding the detection of steroidogenesis disruption and the effects of combined toxicity remain unanswered. Not only due to the diverse mode of action of adrenal steroids and their implication in many common diseases, there is no doubt that further research on endocrine disruption of the adrenocortical system is needed.

Key words

endocrine disrupting chemicals - adrenal gland - corticosteroids - HPA axis - bisphenol A

Volltext

Referenzen

References
1 Persson L M, Carney Almroth B, Collins CD. et al. Outside the safe operating space of the planetary boundary for novel entities. Environ Sci Technol 2022; 56: 1510-1521
2 United Nations Environment Programme. Global chemicals outlook II. From legacies to innovative solutions – Implementing the 2030 agenda for sustainable development. https://wedocs.unep.org/bitstream/handle/20.500.11822/28113/GCOII.pdf?sequence=1&isAllowed=y Accessed 23 May 2023
3 Landrigan PJ, Fuller R, Acosta NJR. et al. The Lancet commission on pollution and health. Lancet 2018; 391: 462-512
4 Bergman Å, Heindel JJ, Jobling S. et al. State of the science of endocrine disrupting chemicals – 2012. https://wedocs.unep.org/bitstream/handle/20.500.11822/12223/State%20of%20the%20Science%20of%20EDCs%20Summary%20Report%202012.pdf?sequence=1&isAllowed=y Accessed 23 May 2023
5 Martín-Pozo L, Del Gómez-Regalado MC, Moscoso-Ruiz I. et al. Analytical methods for the determination of endocrine disrupting chemicals in cosmetics and personal care products: a review. Talanta 2021; 234: 122642
6 Ionas AC, Dirtu AC, Anthonissen T. et al. Downsides of the recycling process: harmful organic chemicals in children’s toys. Environ Int 2014; 65: 54-62
7 Ullah S, Ahmad S, Guo X. et al. A review of the endocrine disrupting effects of micro and nano plastic and their associated chemicals in mammals. Front Endocrinol (Lausanne) 2022; 13: 1084236
8 Gore AC, Chappell VA, Fenton S. et al. EDC-2: The Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev 2015; 36: E1-E150
9 Napper IE, Davies BF, Clifford H. et al. Reaching new heights in plastic pollution—preliminary findings of microplastics on Mount Everest. One Earth 2020; 3: 621-630
10 Peng X, Chen M, Chen S. et al. Microplastics contaminate the deepest part of the world’s ocean. Geochem Perspect Lett 2018; 9: 1-5
11 Bernhardt A, Caravanos J, Fuller R. et al Pollution knows no borders. How the pollution crisis in low- and middle-income countries affects everyone’s health, and what we can do to address it. http://www.pureearth.org/wp-content/uploads/2021/03/PE_PollutionKnowsNoBordersOnline-1.pdf Accessed 23 May 2023
12 Liu C, Yang J, Guan L. et al. Filtered air intervention reduces inflammation and hypothalamus-pituitary-adrenal axis activation in adult male and female rats after PM 2.5 exposure. Environ Sci Pollut Res Int 2020; 27: 35341-35348
13 Llompart M, Sanchez-Prado L, Pablo Lamas J. et al. Hazardous organic chemicals in rubber recycled tire playgrounds and pavers. Chemosphere 2013; 90: 423-431
14 Danon-Schaffer MN, Mahecha-Botero A, Grace JR. et al. Mass balance evaluation of polybrominated diphenyl ethers in landfill leachate and potential for transfer from e-waste. Sci Total Environ 2013; 461–462: 290-301
15 Ng A, Weerakoon D, Lim E. et al. Fate of environmental pollutants. Water Environ Res 2019; 91: 1294-1325
16 Jiménez-Díaz I, Zafra-Gómez A, Ballesteros O. et al. Determination of bisphenol A and its chlorinated derivatives in placental tissue samples by liquid chromatography-tandem mass spectrometry. J Chromatogr B 2010; 878: 3363-3369
17 Buck Louis GM, Smarr MM, Sun L. et al. Endocrine disrupting chemicals in seminal plasma and couple fecundity. Environ Res 2018; 163: 64-70
18 Silva MJ, Reidy JA, Samandar E. et al. Detection of phthalate metabolites in human saliva. Arch Toxicol 2005; 79: 647-652
19 Edlow AG, Chen M, Smith NA. et al. Fetal bisphenol A exposure: concentration of conjugated and unconjugated bisphenol A in amniotic fluid in the second and third trimesters. Reprod Toxicol 2012; 34: 1-7
20 Ruiz D, Becerra M, Jagai JS. et al. Disparities in environmental exposures to endocrine-disrupting chemicals and diabetes risk in vulnerable populations. Diabetes Care 2018; 41: 193-205
21 Ougier E, Ganzleben C, Lecoq P. et al. Chemical prioritisation strategy in the European Human Biomonitoring Initiative (HBM4EU) – development and results. Int J Hyg Environ Health 2021; 236: 113778
22 Lambré C, Barat Baviera JM, Bolognesi C. et al. Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J 2023; 21: e06857
23 United Nations Environment Programme. Stockholm convention on persistent organic pollutants (POPs). http://chm.pops.int/Portals/0/download.aspx?d=UNEP-POPS-COP-CONVTEXT-2021.English.pdf Accessed 23 May 2023
24 Xin F, Susiarjo M, Bartolomei MS. Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation?. Semin Cell Dev Biol 2015; 43: 66-75
25 Eker F, Gungunes A, Durmaz S. et al. Nonfunctional adrenal incidentalomas may be related to bisphenol-A. Endocrine 2021; 71: 459-466
26 Fommei E, Turci R, Ripoli A. et al. Evidence for persistent organochlorine pollutants in the human adrenal cortex. J Appl Toxicol 2017; 37: 1091-1097
27 Harvey PW. Endocrine disruption of adrenocortical function. Endocr Disrupt Hum Health 2015; 219-235
28 Ribelin WE. The effects of drugs and chemicals upon the structure of the adrenal gland. Fundament Appl Toxicol 1984; 4: 105-119
29 Darnerud PO, Risberg S. Tissue localisation of tetra- and pentabromodiphenyl ether congeners (BDE-47, -85 and -99) in perinatal and adult C57BL mice. Chemosphere 2006; 62: 485-493
30 Hakk H, Larsen G, Klasson-Wehler E. Tissue disposition, excretion and metabolism of 2,2’,4,4’,5-pentabromodiphenyl ether (BDE-99) in the male Sprague-Dawley rat. Xenobiotica 2002; 32: 369-382
31 Lund B-O, Bergman Å, Brandt I. Metabolic activation and toxicity of a DDT-metabolite, 3-methylsulphonly-DDE, in the adrenal zona fasciculata in mice. Chem Biol Interact 1988; 65: 25-40
32 Hinson JP, Raven PW. Effects of endocrine-disrupting chemicals on adrenal function. Best Pract Res Clin Endocrinol Metab 2006; 20: 111-120
33 La Merrill MA, Vandenberg LN, Smith MT. et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 2020; 16: 45-57
34 Vitku J, Starka L, Bicikova M. et al. Endocrine disruptors and other inhibitors of 11β-hydroxysteroid dehydrogenase 1 and 2: tissue-specific consequences of enzyme inhibition. J Steroid Biochem Mol Biol 2016; 155: 207-216
35 Bottalico LN, Weljie AM. Cross-species physiological interactions of endocrine disrupting chemicals with the circadian clock. Gen Comp Endocrinol 2021; 301: 113650
36 Olukole SG, Lanipekun DO, Ola-Davies EO. et al. Melatonin attenuates bisphenol A-induced toxicity of the adrenal gland of Wistar rats. Environ Sci Pollut Res Int 2019; 26: 5971-5982
37 Virant-Klun I, Imamovic-Kumalic S, Pinter B. From oxidative stress to male infertility: review of the associations of endocrine-disrupting chemicals (bisphenols, phthalates, and parabens) with human semen quality. Antioxidants 2022; 11: 1617
38 Zhang J, Yang Y, Liu W. et al. Glucocorticoid and mineralocorticoid receptors and corticosteroid homeostasis are potential targets for endocrine-disrupting chemicals. Environ Int 2019; 133: 105133
39 Rehan M, Ahmad E, Sheikh IA. et al. Androgen and progesterone receptors are targets for bisphenol A (BPA), 4-methyl-2,4-bis-(p-hydroxyphenyl)pent-1-ene--a potent metabolite of BPA, and 4-tert-octylphenol: a computational insight. PLoS One 2015; 10: e0138438
40 Kojima H, Takeuchi S, Sanoh S. et al. Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors. Toxicology 2018; 413: 48-55
41 Liu X, Sakai H, Nishigori M. et al. Receptor-binding affinities of bisphenol A and its next-generation analogs for human nuclear receptors. Toxicol Appl Pharmacol 2019; 377: 114610
42 Grimaldi M, Boulahtouf A, Toporova L. et al. Functional profiling of bisphenols for nuclear receptors. Toxicology 2019; 420: 39-45
43 Sarath Josh MK, Pradeep S, Vijayalekshmy Amma KS. et al. Human ketosteroid receptors interact with hazardous phthalate plasticizers and their metabolites: an in silico study. J Appl Toxicol 2016; 36: 836-843
44 Martinez-Arguelles DB, Papadopoulos V. Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation. Andrology 2016; 4: 573-584
45 Fan W, Yanase T, Morinaga H. et al. Herbicide atrazine activates SF-1 by direct affinity and concomitant co-activators recruitments to induce aromatase expression via promoter II. Biochem Biophys Res Commun 2007; 355: 1012-1018
46 Schaffert A, Karkossa I, Ueberham E. et al. Di-(2-ethylhexyl) phthalate substitutes accelerate human adipogenesis through PPARγ activation and cause oxidative stress and impaired metabolic homeostasis in mature adipocytes. Environ Int 2022; 164: 107279
47 Zhang J, Liu R, Niu L. et al. Determination of endocrine-disrupting potencies of agricultural soils in China via a battery of steroid receptor bioassays. Environ Poll 2018; 234: 846-854
48 van den Dungen MW, Rijk JCW, Kampman E. et al. Steroid hormone related effects of marine persistent organic pollutants in human H295R adrenocortical carcinoma cells. Toxicol In Vitro 2015; 29: 769-778
49 Martinez-Arguelles DB, Campioli E, Lienhart C. et al. In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate induces long-term changes in gene expression in the adult male adrenal gland. Endocrinology 2014; 155: 1667-1678
50 Martinez-Arguelles DB, Guichard T, Culty M. et al. In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 2011; 85: 51-61
51 Chen X, Mo J, Zhang S. et al. 4-Bromodiphenyl ether causes adrenal gland dysfunction in rats during puberty. Chem Res Toxicol 2019; 32: 1772-1779
52 Lan H-C, Lin I-W, Yang Z-J. et al. Low-dose bisphenol A activates Cyp11a1 gene expression and corticosterone secretion in adrenal gland via the JNK signaling pathway. Toxicol Sci 2015; 148: 26-34
53 Medwid S, Guan H, Yang K. Bisphenol A stimulates adrenal cortical cell proliferation via ERβ-mediated activation of the sonic hedgehog signalling pathway. J Steroid Biochem Mol Biol 2018; 178: 254-262
54 Lee S, Martinez-Arguelles DB, Campioli E. et al. Fetal exposure to low levels of the plasticizer dehp predisposes the adult male adrenal gland to endocrine disruption. Endocrinology 2017; 158: 304-318
55 Buha A, Manic L, Maric D. et al. The effects of endocrine-disrupting chemicals (EDCs) on the epigenome – a short overview. Toxicol Res Appl 2022; 6: 1-9
56 Kirtana A, Seetharaman B. Comprehending the role of endocrine disruptors in inducing epigenetic toxicity. Endocrine Metab Immune Disord Drug Targets 2022; 22: 1059-1072
57 Pandey A, Rudraiah M. Analysis of endocrine disruption effect of Roundup^® in adrenal gland of male rats. Toxicol Rep 2015; 2: 1075-1085
58 Medwid S, Guan H, Yang K. Bisphenol A stimulates steroidogenic acute regulatory protein expression via an unknown mechanism in adrenal cortical cells. J Cell Biochem 2019; 129: 2429-2438
59 Dungar BM, Schupbach CD, Jacobson JR. et al. Adrenal corticosteroid perturbation by the endocrine disruptor BDE-47 in a human adrenocortical cell line and male rats. Endocrinology 2021; 162: bqab160
60 Källsten L, Pierozan P, Martin JW. et al. Di-n-butyl phthalate and its monoester metabolite impairs steroid hormone biosynthesis in human cells: mechanistic in vitro studies. Cells 2022; 11: 3029
61 Duan C, Fang Y, Sun J. et al. Effects of fast food packaging plasticizers and their metabolites on steroid hormone synthesis in H295R cells. Sci Total Environ 2020; 726: 138500
62 Sohn J, Kim S, Koschorreck J. et al. Alteration of sex hormone levels and steroidogenic pathway by several low molecular weight phthalates and their metabolites in male zebrafish (Danio rerio) and/or human adrenal cell (H295R) line. J Hazard Mater 2016; 320: 45-54
63 Knížatová N, Greifová H, Tokárová K. et al. Assessment of the effective impact of bisphenols on mitochondrial activity, viability and steroidogenesis in a dose-dependency in human adrenocortical carcinoma cells. Processes 2021; 9: 1471
64 Lin J, Deng L, Sun M. et al. An in vitro investigation of endocrine disrupting potentials of ten bisphenol analogues. Steroids 2021; 169: 108826
65 Ahmad S, Khan MF, Parvez S. et al. Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway. J Appl Toxicol 2017; 37: 265-277
66 Harris RM, Waring RH. Sulfotransferase inhibition: potential impact of diet and environmental chemicals on steroid metabolism and drug detoxification. Curr Drug Metab 2008; 9: 269-275
67 Inderbinen SG, Engeli RT, Rohrer SR. et al. Tributyltin and triphenyltin induce 11β-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor α. Toxicol Lett 2020; 322: 39-49
68 Ahmed KEM, Frøysa HG, Karlsen OA. et al. Effects of defined mixtures of POPs and endocrine disruptors on the steroid metabolome of the human H295R adrenocortical cell line. Chemosphere 2019; 218: 328-339
69 Solaiman AAE-M, Sawires SKS. Histological study of the effect of tributyltin on the adrenal cortical cells of adult male albino rats. Egypt J Histol 2019; 43: 104-121
70 Salgado-Freiría R, López-Doval S, Lafuente A. Perfluorooctane sulfonate (PFOS) can alter the hypothalamic-pituitary-adrenal (HPA) axis activity by modifying CRF1 and glucocorticoid receptors. Toxicol Lett 2018; 295: 1-9
71 Merlo E, Podratz PL, Sena GC. et al. The environmental pollutant tributyltin chloride disrupts the hypothalamic-pituitary-adrenal axis at different levels in female rats. Endocrinology 2016; 157: 2978-2995
72 Di Lorenzo M, Sciarrillo R, Rosati L. et al. Effects of alkylphenols mixture on the adrenal gland of the lizard Podarcis sicula. Chemosphere 2020; 258: 127239
73 Chen F, Zhou L, Bai Y. et al. Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A. J Biomed Res 2015; 29: 250-258
74 Chen F, Zhou L, Bai Y. et al. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A. Brain Res 2014; 1571: 12-24
75 Panagiotidou E, Zerva S, Mitsiou DJ. et al. Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats. J Endocrinol 2014; 220: 207-218
76 Repouskou A, Papadopoulou A-K, Panagiotidou E. et al. Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment. Sci Rep 2020; 10: 9367
77 Sheikh IA, Beg MA. Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin. J Appl Toxicol 2017; 37: 1471-1480
78 Sheikh IA, Turki RF, Abuzenadah AM. et al. Endocrine disruption: computational perspectives on human sex hormone-binding globulin and phthalate plasticizers. PLoS One 2016; 11: e0151444
79 Hong H, Branham WS, Ng HW. et al. Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein. Toxicol Sci 2015; 143: 333-348
80 Sun S, Wang J, Lu Y. et al. Corticosteroid-binding globulin, induced in testicular Leydig cells by perfluorooctanoic acid, promotes steroid hormone synthesis. Arch Toxicol 2018; 92: 2013-2025
81 Wu Z, Yi Z, Dong L. et al. Molecular simulation study of the specific combination between four kinds of phthalic acid esters and human serum albumin. Environ Toxicol Pharmacol 2016; 41: 259-265
82 Xie X, Wang X, Xu X. et al. Investigation of the interaction between endocrine disruptor bisphenol A and human serum albumin. Chemosphere 2010; 80: 1075-1080
83 Pan F, Xu T, Yang L. et al. Probing the binding of an endocrine disrupting compound-Bisphenol F to human serum albumin: insights into the interactions of harmful chemicals with functional biomacromolecules. Spectrochim Acta A Mol Biomol Spectrosc 2014; 132: 795-802
84 Ahmad S, Sharma S, Afjal MA. et al. mRNA expression and protein-protein interaction (PPI) network analysis of adrenal steroidogenesis in response to exposure to phthalates in rats. Environ Toxicol Pharmacol 2022; 89: 103780
85 Yaglova NV, Obernikhin SS, Yaglov VV. et al. Low-dose exposure to endocrine disruptor dichlorodiphenyltrichloroethane (DDT) affects transcriptional regulation of adrenal zona reticularis in male rats. Bull Exp Biol Med 2021; 170: 682-685
86 Tsomartova DA, Yaglova NV, Yaglov VV. Changes in canonical β-catenin/Wnt signaling activation in the adrenal cortex of rats exposed to endocrine disruptor dichlorodiphenyltrichloroethane (DDT) during prenatal and postnatal ontogeny. Bull Exp Biol Med 2018; 164: 493-496
87 Puglisi S, Calabrese A, Basile V. et al. New perspectives for mitotane treatment of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab 2020; 34: 101415
88 Li H, Cai J, Chen R. et al. Particulate matter exposure and stress hormone levels: a randomized, double-blind, crossover trial of air purification. Circulation 2017; 136: 618-627
89 Pryor JT, Cowley LO, Simonds SE. The physiological effects of air pollution: particulate matter, physiology and disease. Front Public Health 2022; 10: 882569
90 Di Criscio M, Lodahl JE, Stamatakis A. et al. A human-relevant mixture of endocrine disrupting chemicals induces changes in hippocampal DNA methylation correlating with hyperactive behavior in male mice. Chemosphere 2023; 313: 137633
91 Kitraki E, Nalvarte I, Alavian-Ghavanini A. et al. Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response. Mol Cell Endocrinol 2015; 417: 191-199
92 Wei Z, Song L, Wei J. et al. Maternal exposure to di-(2-ethylhexyl)phthalate alters kidney development through the renin-angiotensin system in offspring. Toxicol Lett 2012; 212: 212-221
93 Martinez-Arguelles DB, McIntosh M, Rohlicek CV. et al. Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring. Toxicol Appl Pharmacol 2013; 266: 95-100
94 Rainey WE, Bird IM, Mason J. The NCI-H295 cell line: a pluripotent model for human adrenocortical studies. Mol Cell Endocrinol 1994; 100: 45-50
95 Gracia T, Hilscherova K, Jones PD. et al. The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf 2006; 65: 293-305
96 Duranova H, Fialkova V, Valkova V. et al. Human adrenocortical carcinoma cell line (NCI-H295R): an in vitro screening model for the assessment of endocrine disruptors’ actions on steroidogenesis with an emphasis on cell ultrastructural features. Acta Histochemica 2022; 124: 151912
97 Organisation for Economic Co-operation and Development. Test No. 456: H295R steroidogenesis assay. OECD guidelines for the testing of chemicals. https://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en Accessed 23 May 2023
98 Soejima Y, Iwata N, Nakano Y. et al. Involvement of clock gene expression, bone morphogenetic protein and activin in adrenocortical steroidogenesis by human H295R cells. Endocr J 2021; 68: 243-250
99 Kinlein SA, Wilson CD, Karatsoreos IN. Dysregulated hypothalamic-pituitary-adrenal axis function contributes to altered endocrine and neurobehavioral responses to acute stress. Front Psychiatry 2015; 6: 31
100 Macedo S, Teixeira E, Gaspar TB. et al. Endocrine-disrupting chemicals and endocrine neoplasia: a forty-year systematic review. Environ Res 2023; 218: 114869
101 Palioura E, Diamanti-Kandarakis E. Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs). Rev Endocr Metab Disord 2015; 16: 365-371
102 Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol 2015; 145: 213-225