Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

The American Journal of Human Genetics - Tập 107 - Trang 911-931 - 2020
Faycal Guedj1,2, Ashley E. Siegel1,2, Jeroen L.A. Pennings3, Fatimah Alsebaa2, Lauren J. Massingham2, Umadevi Tantravahi4, Diana W. Bianchi1,2
1Prenatal Genomics and Therapy Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
2Mother Infant Research Institute, Tufts Medical Center and Tufts Children's Hospital, Boston, MA 02111, USA
3Center for Health Protection, National Institute for Public Health and the Environment, Bilthoven, BA 3720, the Netherlands
4Department of Pathology, Women and Infants’ Hospital, Providence, RI 02912, USA

Tài liệu tham khảo

Taylor-Phillips, 2016, Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis, BMJ Open, 6, e010002, 10.1136/bmjopen-2015-010002 Ralston, 2001, Pregnancy outcomes after prenatal diagnosis of aneuploidy, Obstet. Gynecol., 97, 729 Guedj, 2013, Noninvasive prenatal testing creates an opportunity for antenatal treatment of Down syndrome, Prenat. Diagn., 33, 614, 10.1002/pd.4134 Bianchi, 2012, From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges, Nat. Med., 18, 1041, 10.1038/nm.2829 Schmidt-Sidor, 1990, Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months, Clin. Neuropathol., 9, 181 Guidi, 2008, Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of fetuses with Down syndrome, Brain Pathol., 18, 180, 10.1111/j.1750-3639.2007.00113.x Guidi, 2011, Widespread proliferation impairment and hypocellularity in the cerebellum of fetuses with down syndrome, Brain Pathol., 21, 361, 10.1111/j.1750-3639.2010.00459.x Wisniewski, 1989, Postnatal delay of myelin formation in brains from Down syndrome infants and children, Clin. Neuropathol., 8, 55 Ábrahám, 2012, Impaired myelination of the human hippocampal formation in Down syndrome, Int. J. Dev. Neurosci., 30, 147, 10.1016/j.ijdevneu.2011.11.005 Hepper, 1992, Habituation in normal and Down’s syndrome fetuses, Q. J. Exp. Psychol. B, 44, 305 Guedj, 2014, Prenatal treatment of Down syndrome: a reality?, Curr. Opin. Obstet. Gynecol., 26, 92, 10.1097/GCO.0000000000000056 Stagni, 2015, Timing of therapies for Down syndrome: the sooner, the better, Front. Behav. Neurosci., 9, 265, 10.3389/fnbeh.2015.00265 Gardiner, 2014, Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations, Drug Des. Devel. Ther., 9, 103, 10.2147/DDDT.S51476 Lee, 2020, Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome, Trends Mol. Med., 26, 150, 10.1016/j.molmed.2019.10.001 Rice, 2000, Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models, Environ. Health Perspect., 108, 511, 10.1289/ehp.00108s3511 Meredith, 2015, Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders, Neurosci. Biobehav. Rev., 50, 180, 10.1016/j.neubiorev.2014.12.001 Guidi, 2014, Prenatal pharmacotherapy rescues brain development in a Down’s syndrome mouse model, Brain, 137, 380, 10.1093/brain/awt340 Incerti, 2012, Prenatal treatment prevents learning deficit in Down syndrome model, PLoS ONE, 7, e50724, 10.1371/journal.pone.0050724 Ash, 2014, Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice, Neurobiol. Dis., 70, 32, 10.1016/j.nbd.2014.06.001 Slonim, 2009, Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses, Proc. Natl. Acad. Sci. USA, 106, 9425, 10.1073/pnas.0903909106 Guedj, 2016, An integrated human/murine transcriptome and pathway approach to identify prenatal treatments for Down syndrome, Sci. Rep., 6, 32353, 10.1038/srep32353 Lamb, 2006, The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease, Science, 313, 1929, 10.1126/science.1132939 Venigalla, 2015, Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer’s disease, Neural Regen. Res., 10, 1181, 10.4103/1673-5374.162686 Venigalla, 2016, Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer’s disease, Neurochem. Int., 95, 63, 10.1016/j.neuint.2015.10.011 Kalivarathan, 2017, Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet, Biomed. Pharmacother., 89, 323, 10.1016/j.biopha.2017.01.162 Rezai-Zadeh, 2008, Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression, J. Neuroinflammation, 5, 41, 10.1186/1742-2094-5-41 Aziz, 2018, Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome, Dis. Model Mech., 11, dmm031013, 10.1242/dmm.031013 Sullivan, 2016, Trisomy 21 consistently activates the interferon response, Elife, 5, e16220, 10.7554/eLife.16220 Zhao, 2013, Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model, Molecules, 18, 9949, 10.3390/molecules18089949 Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J. R. Stat. Soc. B., 57, 289 Krämer, 2014, Causal analysis approaches in Ingenuity Pathway Analysis, Bioinformatics, 30, 523, 10.1093/bioinformatics/btt703 Ricci, 2012, Dosing animal via diet: This can be a simple and efficient method for delivering compounds to lab animals when done correctly, ALN World., 5, 1 Ferrés, 2016, Perinatal Natural History of the Ts1Cje Mouse Model of Down Syndrome: Growth Restriction, Early Mortality, Heart Defects, and Delayed Development, PLoS ONE, 11, e0168009, 10.1371/journal.pone.0168009 Hill, 2008, Developmental Milestones in the Newborn Mouse, Neuromethods, 39, 131, 10.1007/978-1-60327-099-1_10 Guedj, 2015, The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome, Am. J. Med. Genet. A., 167A, 1993, 10.1002/ajmg.a.37156 Androutsopoulos, 2011, Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoids, Bioorg. Med. Chem., 19, 2842, 10.1016/j.bmc.2011.03.042 Juliusson, 2018, Lifetime alcohol intake and pattern of alcohol consumption in patients with alcohol-induced pancreatitis in comparison with patients with alcohol use disorder, Scand. J. Gastroenterol., 53, 748, 10.1080/00365521.2018.1455893 Gheghiani, 2017, PLK1 Activation in Late G2 Sets Up Commitment to Mitosis, Cell Rep., 19, 2060, 10.1016/j.celrep.2017.05.031 Lee, 2018, SERPINB2 is a novel indicator of stem cell toxicity, Cell Death Dis., 9, 724, 10.1038/s41419-018-0748-x Zhang, 2011, Apigenin accelerates lipopolysaccharide induced apoptosis in mesenchymal stem cells through suppressing vitamin D receptor expression, Chin. Med. J. (Engl.), 124, 3537 Boeckx, 2014, Overcoming cetuximab resistance in HNSCC: the role of AURKB and DUSP proteins, Cancer Lett., 354, 365, 10.1016/j.canlet.2014.08.039 Barone, 2018, Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism, Free Radic. Biol. Med., 114, 84, 10.1016/j.freeradbiomed.2017.07.009 Muchová, 2014, Oxidative stress and Down syndrome. Do antioxidants play a role in therapy?, Physiol. Res., 63, 535, 10.33549/physiolres.932722 Pagano, 2012, Oxidative stress and mitochondrial dysfunction in Down syndrome, Adv. Exp. Med. Biol., 724, 291, 10.1007/978-1-4614-0653-2_22 Lott, 2012, Antioxidants in Down syndrome, Biochim. Biophys. Acta, 1822, 657, 10.1016/j.bbadis.2011.12.010 Iannello, 1999, Oxidative stress and neural dysfunction in Down syndrome, J. Neural Transm. Suppl., 57, 257 Gimeno, 2014, Decreased cell proliferation and higher oxidative stress in fibroblasts from Down Syndrome fetuses. Preliminary study, Biochim. Biophys. Acta, 1842, 116, 10.1016/j.bbadis.2013.10.014 Perluigi, 2011, Oxidative stress occurs early in Down syndrome pregnancy: A redox proteomics analysis of amniotic fluid, Proteomics Clin. Appl., 5, 167, 10.1002/prca.201000121 de Haan, 2003, An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the “gene dosage effect” hypothesis, J. Neural Transm. Suppl., 67, 67, 10.1007/978-3-7091-6721-2_6 Sharma, 2014, Plant flavone apigenin binds to nucleic acid bases and reduces oxidative DNA damage in prostate epithelial cells, PLoS ONE, 9, e91588, 10.1371/journal.pone.0091588 Kang, 2004, Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblostoma cells, Bioorg. Med. Chem. Lett., 14, 2261, 10.1016/j.bmcl.2004.02.003 An, 2015, Attenuation of oxidative stress of erythrocytes by the plant-derived flavonoids vitexin and apigenin, Pharmazie, 70, 724 Nabavi, 2018, Apigenin as neuroprotective agent: Of mice and men, Pharmacol. Res., 128, 359, 10.1016/j.phrs.2017.10.008 Jeon, 2015, Apigenin inhibits indoxyl sulfate-induced endoplasmic reticulum stress and anti-proliferative pathways, CHOP and IL-6/p21, in human renal proximal tubular cells, Eur. Rev. Med. Pharmacol. Sci., 19, 2303 Wu, 2015, Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells, PLoS ONE, 10, e0130599, 10.1371/journal.pone.0130599 McKay, 2006, A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.), Phytother. Res., 20, 519, 10.1002/ptr.1900 Corsi, 2006, Plasma nerve growth factor (NGF) and inflammatory cytokines (IL-6 and MCP-1) in young and adult subjects with Down syndrome: an interesting pathway, Neuroendocrinol. Lett., 27, 773 Licastro, 2006, Altered vessel signalling molecules in subjects with Downs syndrome, Int. J. Immunopathol. Pharmacol., 19, 181, 10.1177/205873920601900118 Iulita, 2016, An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation, Alzheimers Dement., 12, 1132, 10.1016/j.jalz.2016.05.001 Zhang, 2014, Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages, PLoS ONE, 9, e107072, 10.1371/journal.pone.0107072 Hong, 2018, Apigenin and Luteolin Attenuate the Breaching of MDA-MB231 Breast Cancer Spheroids Through the Lymph Endothelial Barrier in Vitro, Front. Pharmacol., 9, 220, 10.3389/fphar.2018.00220 Bauer, 2017, Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells, PLoS ONE, 12, e0175558, 10.1371/journal.pone.0175558 Qi, 2018, WAC Promotes Polo-like Kinase 1 Activation for Timely Mitotic Entry, Cell Rep., 24, 546, 10.1016/j.celrep.2018.06.087 Saito, 2000, The developmental and aging changes of Down’s syndrome cell adhesion molecule expression in normal and Down’s syndrome brains, Acta Neuropathol., 100, 654, 10.1007/s004010000230 Barlow, 2001, Down syndrome cell adhesion molecule is conserved in mouse and highly expressed in the adult mouse brain, Cytogenet. Cell Genet., 94, 155, 10.1159/000048808 Cooper, 2012, Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice, Proc. Natl. Acad. Sci. USA, 109, 2642, 10.1073/pnas.1109099109 Jiang, 2015, Genetic dissection of the Down syndrome critical region, Hum. Mol. Genet., 24, 6540, 10.1093/hmg/ddv364 Raveau, 2017, Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction, Hum. Mol. Genet., 26, 923 Mouton-Liger, 2014, Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression: implications for Down syndrome, Neurobiol. Dis., 63, 92, 10.1016/j.nbd.2013.11.016 Taupin, 2009, Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483, Expert Opin. Ther. Pat., 19, 523, 10.1517/13543770902721279 Zhou, 2019, Luteolin induces hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome, Neural Regen. Res., 14, 613, 10.4103/1673-5374.248519 Anusha, 2017, Protective role of apigenin on rotenone induced rat model of Parkinson’s disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis, Chem. Biol. Interact., 269, 67, 10.1016/j.cbi.2017.03.016 Smolinski, 2003, Modulation of lipopolysaccharide-induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb(1) (ginseng) and parthenolide (feverfew), Food Chem. Toxicol., 41, 1381, 10.1016/S0278-6915(03)00146-7 Patil, 2014, Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice, Neuropharmacology, 86, 192, 10.1016/j.neuropharm.2014.07.012 Chen, 2017, Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats, Arch. Gerontol. Geriatr., 73, 29, 10.1016/j.archger.2017.07.004 Kirsammer, 2016, Signaling a link between interferon and the traits of Down syndrome, Elife, 5, e20196, 10.7554/eLife.20196 Tan, 1974, Human chromosome 21 dosage: effect on the expression of the interferon induced antiviral state, Science, 186, 61, 10.1126/science.186.4158.61 Zhang, 2017, Aberrations in circulating inflammatory cytokine levels in patients with Down syndrome: a meta-analysis, Oncotarget, 8, 84489, 10.18632/oncotarget.21060 Häusler, 2002, Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages, Eur. J. Neurosci., 16, 2113, 10.1046/j.1460-9568.2002.02287.x Abbas, 2002, Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice, J. Neuroimmunol., 126, 50, 10.1016/S0165-5728(02)00050-4 Tribouillard-Tanvier, 2009, Analysis of protein levels of 24 cytokines in scrapie agent-infected brain and glial cell cultures from mice differing in prion protein expression levels, J. Virol., 83, 11244, 10.1128/JVI.01413-09 D’Andrea, 1993, Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells, J. Exp. Med., 178, 1041, 10.1084/jem.178.3.1041 Karunarathne, 2020, Anthocyanins isolated from Hibiscus syriacus L. attenuate lipopolysaccharide-induced inflammation and endotoxic shock by inhibiting the TLR4/MD2-mediated NF-κB signaling pathway, Phytomedicine, 76, 153237, 10.1016/j.phymed.2020.153237 Jeong, 2009, Anti-inflammatory effects of apigenin on nicotine- and lipopolysaccharide-stimulated human periodontal ligament cells via heme oxygenase-1, Int. Immunopharmacol., 9, 1374, 10.1016/j.intimp.2009.08.015 Cetiner, 2010, Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome, Int. J. Immunogenet., 37, 233, 10.1111/j.1744-313X.2010.00914.x Nateghi Rostami, 2012, Altered serum pro-inflammatory cytokines in children with Down’s syndrome, Eur. Cytokine Netw., 23, 64, 10.1684/ecn.2012.0307 Huggard, 2020, Increased systemic inflammation in children with Down syndrome, Cytokine, 127, 154938, 10.1016/j.cyto.2019.154938 Cavalcante, 2012, Expression of the interleukin-10 signaling pathway genes in individuals with Down syndrome and periodontitis, J. Periodontol., 83, 926, 10.1902/jop.2011.110056 Rodrigues, 2014, Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: relation with inflammatory parameters, Clin. Chim. Acta, 433, 105, 10.1016/j.cca.2014.03.002 Zhang, 2016, Apigenin Attenuates Experimental Autoimmune Myocarditis by Modulating Th1/Th2 Cytokine Balance in Mice, Inflammation, 39, 678, 10.1007/s10753-015-0294-y Karamese, 2016, Anti-oxidant and anti-inflammatory effects of apigenin in a rat model of sepsis: an immunological, biochemical, and histopathological study, Immunopharmacol. Immunotoxicol., 38, 228, 10.3109/08923973.2016.1173058 Dourado, 2020, Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer’s Disease, Front. Aging Neurosci., 12, 119, 10.3389/fnagi.2020.00119 Greene, 2009, Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: pharmacological and cellular characterization, Neuropsychopharmacology, 34, 2459, 10.1038/npp.2009.68 Jais, 2016, Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity, Cell, 165, 882, 10.1016/j.cell.2016.03.033 Norman, 1986, The growth and development of microvasculature in human cerebral cortex, J. Neuropathol. Exp. Neurol., 45, 222, 10.1097/00005072-198605000-00003 Virgintino, 2003, VEGF expression is developmentally regulated during human brain angiogenesis, Histochem. Cell Biol., 119, 227, 10.1007/s00418-003-0510-y Breier, 1995, Coordinate expression of vascular endothelial growth factor receptor-1 (flt-1) and its ligand suggests a paracrine regulation of murine vascular development, Dev. Dyn., 204, 228, 10.1002/aja.1002040303 Ferrara, 1996, Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene, Nature, 380, 439, 10.1038/380439a0 Carmeliet, 1996, Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele, Nature, 380, 435, 10.1038/380435a0 Shalaby, 1995, Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice, Nature, 376, 62, 10.1038/376062a0 Licht, 2011, Reversible modulations of neuronal plasticity by VEGF, Proc. Natl. Acad. Sci. USA, 108, 5081, 10.1073/pnas.1007640108 Hohman, 2015, The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease, JAMA Neurol., 72, 520, 10.1001/jamaneurol.2014.4761 Paterson, 2014, Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals, Transl. Psychiatry, 4, e419, 10.1038/tp.2014.58 Salvolini, 2011, VEGF and nitric oxide synthase immunoexpression in Down’s syndrome amniotic fluid stem cells, Eur. J. Clin. Invest., 41, 23, 10.1111/j.1365-2362.2010.02370.x Tranquilli, 2003, Amniotic levels of vascular endothelial growth factor and nitric oxide at the second trimester in Down’s syndrome, J. Matern. Fetal Neonatal Med., 13, 28, 10.1080/jmf.13.1.28.31 Zhu, 2005, Reduction of neural and vascular damage by transplantation of VEGF-secreting neural stem cells after cerebral ischemia, Acta Neurochir. Suppl. (Wien), 95, 393, 10.1007/3-211-32318-X_80 Zhu, 2005, Transplantation of vascular endothelial growth factor-transfected neural stem cells into the rat brain provides neuroprotection after transient focal cerebral ischemia, Neurosurgery, 57, 325, 10.1227/01.NEU.0000166682.50272.BC Baburamani, 2013, VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain, Pediatr. Res., 73, 310, 10.1038/pr.2012.191 Swanson, 2016, Maternal Therapy with Ad.VEGF-A165 Increases Fetal Weight at Term in a Guinea-Pig Model of Fetal Growth Restriction, Hum. Gene Ther., 27, 997, 10.1089/hum.2016.046 Moors, 2010, Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells, Genes Immun., 11, 11, 10.1038/gene.2009.77 Araujo, 1993, Trophic effects of interleukin-4, -7 and -8 on hippocampal neuronal cultures: potential involvement of glial-derived factors, Brain Res., 600, 49, 10.1016/0006-8993(93)90400-H Michaelson, 1996, Interleukin-7 is trophic for embryonic neurons and is expressed in developing brain, Dev. Biol., 179, 251, 10.1006/dbio.1996.0255 Sharma, 2020, Apigenin reverses behavioral impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus, Nutr. Neurosci., 23, 118, 10.1080/1028415X.2018.1478653 Crupi, 2013, Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression, CNS Neurol. Disord. Drug Targets, 12, 989, 10.2174/18715273113129990084 Tsai, 2010, The ameliorating effects of luteolin on beta-amyloid-induced impairment of water maze performance and passive avoidance in rats, Am. J. Chin. Med., 38, 279, 10.1142/S0192415X10007841 Tu, 2017, Apigenin Ameliorates Post-Stroke Cognitive Deficits in Rats Through Histone Acetylation-Mediated Neurochemical Alterations, Med. Sci. Monit., 23, 4004, 10.12659/MSM.902770 Gradolatto, 2005, Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration, Drug Metab. Dispos., 33, 49, 10.1124/dmd.104.000893 Lóránd, 2010, Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens, Curr. Med. Chem., 17, 3542, 10.2174/092986710792927813