(12.4)--2018 Journal of Molecular Endocr环境与健康环境与健康.pdf

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1、https:/doi.org/10.1530/JME-18-0081https:/ 2019 Society for EndocrinologyPrinted in Great BritainPublished by Bioscientifica Ltd.Disruptors of thyroid functionK J Oliveira etal.Journal of Molecular EndocrinologyR1R1962 1:REVIEWThyroid function disruptors:from nature to chemicalsKarenJesusOliveira1,Ma

2、riaIsabelChiamolera2,Gisele Giannocco2,3,CarmenCabanelas Pazos-Moura4 and TaniaMaria Ortiga-Carvalho51Departamento de Fisiologia e Farmacologia,Laboratrio de Fisiologia Endcrina e Metabologia,Universidade Federal Fluminense,Rio de Janeiro,Brazil2Disciplina de Endocrinologia e Metabologia,Laboratrio

3、de Endocrinologia Molecular e Translacional,Escola Paulista de Medicina,Universidade Federal de So Paulo,So Paulo,Brazil3Departamento de Cincias Biolgicas,Universidade Federal de So Paulo,Diadema,Brazil4Laboratorio de Endocrinologia Molecular,Instituto de Biofisica Carlos Chagas Filho,Universidade F

4、ederal do Rio de Janeiro,Rio de Janeiro,Rio de Janeiro,Brazil5Laboratrio de Endocrinologia Translacional,Instituto de Biofisica Carlos Chagas Filho,Universidade Federal do Rio de Janeiro,Rio de Janeiro,Rio de Janeiro,BrazilCorrespondence should be addressed to T M Ortiga-Carvalho:taniaortbiof.ufrj.b

5、rAbstractThe modern concept of thyroid disruptors includes synthetic chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamuspituitarythyroid axis,thyroid hormone biosynthesis and secretion,blood and transmembrane transport,metabolism and local actions of thyroi

6、d hormones.This review highlights relevant disruptors that affect populations through their diet:directly from food itself(fish oil and polyunsaturated fatty acids,pepper,coffee,cinnamon and resveratrol/grapes),through vegetable cultivation(pesticides)and from containers for food storage and cooking

7、(bisphenol A,phthalates and polybrominated diphenyl ethers).Due to the vital role of thyroid hormones during every stage of life,we review effects from the gestational period to adulthood,including evidence from in vitro studies,rodent models,human trials and epidemiological studies.Introduction:tem

8、poral description,definitions,basic conceptsAlthough the terms endocrine disruption and endocrine disruptors were coined at the Wingspread Conference in 1991,the concept of endocrine alterations caused by synthetic chemicals has followed the larger context of the environmental movement that has had

9、various influences on science since the 1960s and 1970s(Schugetal.2016).Several factors have guided this journey,such as Rachel Carsons 1962 book Silent Spring;several wildlife studies showing reproductive alterations in birds,alligators and fish(Gilbertson&Reynolds 1972,Aulerichetal.1973,Aulerich&R

10、inger 1977,Semenzaetal.1997,Joblingetal.2002);and the disastrous use of an estrogen analog,diethylstilbestrol,which was used by millions of women during pregnancy to reduce the risk of miscarriage:later this use was linked to the occurrence of unusual cancers and reproductive system malformations fo

11、r those exposed in utero(McLachlan et al.1980,Newbold et al.1985).Dietary phytoestrogens,which are phytochemicals that are structurally similar to estrogens,are able to bind and activate estrogen receptors(ERs),mimicking or interfering with endogenous estrogen pathways.Therefore,these plant-derived

12、compounds can induce many health Journal of Molecular Endocrinology (2019)62,R1R19Key Words f bioactive food compounds f chemical disruptors f TSH f thyroid hormones-18-0081162Downloaded from B at 04/10/2020 11:38:07PMvia free accesshttps:/doi.org/10.1530/JME-18-0081https:/ 2019 Society for Endocrin

13、ologyPrinted in Great BritainPublished by Bioscientifica Ltd.R2K J Oliveira etal.Disruptors of thyroid function62 1:Journal of Molecular Endocrinologybenefits but can also cause harmful effects,such as an elevated breast cancer risk and premature puberty(Sauve&Desrosiers 2014).In 2012,the Endocrine

14、Society published(Zoelleretal.2012,Schug et al.2016)a statement of principles and used the following definition to describe endocrine-disrupting chemicals(EDCs):chemicals,or mixtures of chemicals,which interfere with any aspect of hormone action(Patisaul&Jefferson 2010,Bode&Dong 2015).There are a gr

15、eat variety of agents that have been reported to have endocrine-related effects,including more than 1000 chemicals from several chemical classes(Diamanti-Kandarakisetal.2009).These chemicals are not identified by their chemical structure or by a specific type of usage but rather by their mechanisms

16、of action and ability to alter endocrine system function.In this context,there are a large number of chemicals with different structures present in food,and many of them have biological properties,including endocrine-disrupting-related effects(Goreetal.2015),which extends the concept of endocrine di

17、srupters beyond man-made chemicals.Several reviews have explored the effects of chemicals and bioactive compounds in food on the reproductive system.In addition to effects on the reproductive system,endocrine disruptors also affect different endocrine glands,including the thyroid,a fundamental gland

18、 for neural development.Thyroid hormones(THs)are released under the regulation of the hypothalamuspituitarythyroid(HPT,Fig.1)axis and other factors that control the mechanism of action of THs(Fig.2),which have been extensively reviewed elsewhere(Ortiga-Carvalhoetal.2014,2016,Bernaletal.2015).Importa

19、ntly,endocrine disruptors may act at any level of this regulation.In this review,we explore the effects of natural and artificial compounds on thyroid function and regulation.Bioactive food compounds as thyroid-disrupting factorsSome vegetables,such as cabbage,broccoli and cassava,are a source of an

20、tithyroid compounds,such as thiocyanate and thioamides,which are well-characterized goitrogens(Gaitan 1990,Felker et al.2016,Willemin&Lumen 2017).However,the consumption of other foods and food-related compounds,such as soy protein and soybean isoflavones,as well as other flavonoids,may interfere wi

21、th thyroid function.These effects of those compounds have been reviewed recently by several authors(Doerge&Chang 2002,Messina&Redmond 2006,Xiao 2008,de Souza Dos Santosetal.2011).Here,we focus on reviewing the thyroid-disrupting properties of other less well-known bioactive food compounds.Fish oil a

22、nd polyunsaturated fatty acidsEssential fatty acids play important roles in plasma membrane integrity and function,energy production and as precursors of bioactive lipids at all stages of life.The long chain n 3 polyunsaturated fatty acid(n 3 PUFA)docosahexaenoic acid(22:6n-3;DHA)is especially impor

23、tant to brain development during gestation and infancy(Chiltonetal.2017).Male rat pups supplemented with DHA during the first 6weeks of life exhibited higher serum thyroid-stimulating hormone(TSH)levels without changes in other pituitary hormones(Clandinin et al.1998),which suggests that DHA interfe

24、res in the HPT axis(Fig.1).However,other authors(Souzaetal.2010)studying rats supplemented with fish oil,which is enriched in n 3 PUFAs,from lactation until 11 weeks of age found no alterations in serum TSH or TH concentrations.The authors detected higher levels of the TH receptor (THR)protein in th

25、e liver,accompanied by increased mitochondrial glycerophosphate dehydrogenase(mGPD)activity;mGPD is a THR-mediated triiodothyronine(T3)target,suggesting that fish oil increases TH sensitivity in this tissue.However,deiodinase type 1(D1,DIO1)activity,another recognized marker of TH action in the live

26、r(Fig.2),was not changed,suggesting that the n 3 PUFAs present in fish oil might interfere with T3 action in a target-specific manner(Souzaetal.2011).Another study showed that hepatocytes treated with T3 and eicosapentaenoic acid(20:5n-3;EPA)showed a reduction of 70%in the effect of T3 on thyroid ho

27、rmone responsive spot 14(Thsrp)gene transcription(Jump et al.1993).However,the authors showed that the Thsrp TH-response element(TRE)was not directly sensitive to EPA inhibition.The PUFA-responsive element was found to be located in a region that potentiates T3-mediated activation of Thsrp gene tran

28、scription.In hypothyroid patients,higher levels of free fatty acids were associated with lower symptom severity,along with lower serum TSH and higher thyroxine(T4)and T3 levels,than in patients with low levels of plasma free fatty acids(Makinoetal.2001).These authors also showed,in methimazole-induc

29、ed hypothyroid rats,that chronic EPA supplementation for 28days reduced the methimazole-induced drop in TH levels and the consequent increase in serum TSH levels(Makino etal.2001).This study suggests that EPA exerts a direct stimulatory effect on the thyroid.Downloaded from B at 04/10/2020 11:38:07P

30、Mvia free accesshttps:/doi.org/10.1530/JME-18-0081https:/ 2019 Society for EndocrinologyPrinted in Great BritainPublished by Bioscientifica Ltd.R362 1:K J Oliveira etal.Disruptors of thyroid functionJournal of Molecular EndocrinologyPepper and piperinePiperine is the main alkaloid found in the fruit

31、 Piper nigrum,which is also known as black pepper.Studies have shown that piperine enhances the bioavailability of several drugs and nutraceuticals and possesses important pharmacological effects,including anticancer,anti-inflammatory and antimicrobial activities(Chavarriaetal.2016).Although there i

32、s no evidence for the effects of piperine in humans,studies conducted in rodents point to a thyroid-disrupting effect of pepper and isolated piperine.Two different preparations of the Piper fruit were tested in mice.A water extract induced a reduction in serum T3 and T4 levels after 15days of treatm

33、ent.An ethanolic extract had the opposite effect and induced an elevation in TH levels(Panda&Kar 2003b).The study did not evaluate the chemical composition of the extracts to identify the bioactive component responsible for the different effects observed.Another study investigated the effect of isol

34、ated piperine administered orally for 15days to mice.This study found suppressed hepatic D1 activity in the groups receiving high or low doses of piperine,with ChemicalsBioactive food compoundsHypothalamusThyroidPituitary123Blood vesselsTSH serum levels related effects Polyunsaturated fatty acid(DHA

35、)Polyunsaturated fatty acid(EPA)CaffeineResveratrol TH serum levels related effects Polyunsaturated fatty acid(EPA)Pepper PiperineCaffeineResveratrolCinnamonPituitary related effectsCaffeineThyroid related effects ResveratrolPituitary related effectsBPAPhthalatePerchlorateTH serum levels related eff

36、ects BPAPhthalatesPhenolsPerchloratePesticidesPBDETSH serum levels related effects BPAPhthalatePerchloratePesticidesPBDEThyroid related effects BPAPesticidesHypothalamus related effectsPhthalate PerchlorateTSHBlood vesselsT3T4TRHFigure1Simple scheme of the hypothalamuspituitarythyroid axis.The hypot

37、halamus produces thyrotropin-releasing hormone(TRH),which stimulates the pituitary to release thyrotropin(thyroid-stimulating hormone,TSH).TSH is released in circulation and stimulates the thyroid gland to produce thyroid hormones(THs)(Ortiga-Carvalho etal.2014).The thyroid produces the main THs,thy

38、roxine(T4)and triiodothyronine(T3).TSH stimulates all the steps of TH biosynthesis and release,as well as the expression and activity of several proteins:the solute carrier family 5A(also known as sodium-iodide symporter(NIS),pendrin(PDS),dual oxidase type 2(DUOX),thyroid peroxidase(TPO),thyroglobul

39、in(Agicetal.2007)and deiodinases type 1(D1,DIO1),2(D2,DIO2)and 3(D3,DIO3).In physiologic balance,T4 and T3(3)regulate their own concentrations in the blood by negative feedback acting at the hypothalamic(1)and pituitary(2)levels(Ortiga-Carvalho etal.2016).BPA,bisphenol A;DHA,docosahexaenoic acid;EPA

40、,eicosapentaenoic acid;PBDE,polybrominated diphenyl ether.Downloaded from B at 04/10/2020 11:38:07PMvia free accesshttps:/doi.org/10.1530/JME-18-0081https:/ 2019 Society for EndocrinologyPrinted in Great BritainPublished by Bioscientifica Ltd.R4K J Oliveira etal.Disruptors of thyroid function62 1:Jo

41、urnal of Molecular Endocrinologythe former showing reduced serum T3 and T4 levels and the latter only showing reduced serum T3 levels(Panda&Kar 2003a).These authors suggested that piperine has a direct suppressive effect on the thyroid at higher doses,but at lower doses,it directly inhibits the peri

42、pheral metabolism of THs mediated by the D1 in the liver.Coffee and caffeineCoffee contains over a thousand components,including many with biological activity,such as caffeine,diterpene alcohols and chlorogenic acid,which are potential nutraceuticals.Although the biological effects of coffee are not

43、 restricted to caffeine,this is the most studied component of coffee(OKeefe et al.2013).The effects of caffeine on thyroid function in animal models are inconclusive due to variations in the species,ages and doses studied.Caffeine has been used for more than 40years as a prescribed drug in neonatal

44、medicine,mostly for apnea treatment,but the overall effect of caffeine exposure at this age is poorly understood(Kreutzer&Bassler 2014).In newborn rats,a single administration of caffeine induced a biphasic response,with plasma T4 levels elevated after 4 h and then reduced 24 h after administration(

45、Clozeletal.1983).These authors suggested that the decrease in T4 concentration was a direct effect of caffeine on the thyroid gland since no significant change in thyrotropin-releasing hormone(TRH)-stimulated TSH levels were observed at the same point.However,after 10 days of caffeine administration

46、,basal serum TSH and T4 concentrations were increased,but after TRH stimulation,TSH levels were attenuated by caffeine,suggesting that chronic exposure to caffeine may lead to exhaustion of the pituitary reserve(Clozel etal.1983).A study performed in preterm infants showed that caffeine was negative

47、ly associated with TSH levels at the 7th postnatal day(PND)but was positively associated with TSH levels at the 14th day,and caffeine showed no correlation at the 28th day.The reverse T3(rT3)level was negatively correlated with caffeine exposure at the 7th PND.Therefore,these authors suggested a mil

48、d and transitory effect of caffeine on thyroid function in newborn humans(Williamsetal.2005).In adult rats,an acute injection of caffeine induced a decrease in TSH levels after 16 h,followed by a reduction in T3 and T4 levels after 4 h.An injection of anti-somatostatin antiserum blocked the inhibito

49、ry effect of caffeine on TSH secretion,and the incubation of an isolated pituitary gland with caffeine did not elicit changes in TSH release,suggesting that the effect of caffeine on TSH release appears to be mediated by hypothalamus-derived somatostatin(Spindel et al.1984).The chronic exposure to c

50、affeine associated with regular intake induces tolerance related to hemodynamic and humoral effects(OKeefe etal.2013),and this seems to extend to the effects on thyroid function as well.Figure2Schematic local action of thyroid hormones(THs).(1)Thyroxine(T4)and triiodothyronine(T3)reach the cytoplasm