title: The apical ES-BTB-BM functional axis is an emerging target for toxicant-induced infertility.
abstract: Testes are sensitive to toxicants, such as cadmium and phthalates, which disrupt a local functional axis in the seminiferous epithelium known as the 'apical ectoplasmic specialization (apical ES)-blood-testis barrier (BTB)-basement membrane (BM)'. Following exposure, toxicants contact the basement membrane and activate the Sertoli cell, which perturbs its signaling function. Thus, toxicants can modulate signaling and/or cellular events at the apical ES-BTB-BM axis, perturbing spermatogenesis without entering the epithelium. Toxicants also enter the epithelium via drug transporters to potentiate their damaging effects, and downregulation of efflux transporters by toxicants impedes BTB function such that toxicants remain in the epithelium and efficiently disrupt spermatogenesis. These findings support a novel model of toxicant-induced disruption of spermatogenesis that could be interfered with using small molecules.
authors: Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, USA.
authors: Hin-Ting
authors: HT
authors: Wan
authors: Dolores D
authors: DD
authors: Mruk
authors: Chris K C
authors: CK
authors: Wong
authors: C Yan
authors: CY
authors: Cheng
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000187:drug effects* / Q000378:metabolism*; D001814:Blood-Testis Barrier / Q000187:drug effects* / Q000378:metabolism*; D015386:Hazardous Substances / Q000009:adverse effects / Q000633:toxicity*; D006801:Humans; D007248:Infertility, Male / Q000209:etiology*; D008297:Male
chemical_list: D015386:Hazardous Substances
references: Adv Exp Med Biol. 2008;636:212-33
references: 19856170
references: Spermatogenesis. 2011 Jul;1(3):270-280
references: 22319674
references: Int J Biochem Cell Biol. 2009 Dec;41(12):2578-87
references: 19720156
references: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19623-8
references: 22106313
references: Pharmacol Rev. 2008 Jun;60(2):146-80
references: 18483144
references: Mol Cell Endocrinol. 2012 May 22;355(2):221-30
references: 22138051
references: Endocrinology. 2004 Feb;145(2):592-603
references: 14605012
references: Biol Reprod. 2011 Dec;85(6):1091-3
references: 21900678
references: Biol Reprod. 1993 Oct;49(4):840-9
references: 8218650
references: Philos Trans R Soc Lond B Biol Sci. 2010 May 27;365(1546):1607-20
references: 20403873
references: Pharmacol Rev. 2008 Sep;60(3):261-310
references: 18922965
references: Arch Histol Cytol. 2000 Mar;63(1):1-15
references: 10770585
references: FASEB J. 2009 Aug;23(8):2555-67
references: 19293393
references: Biol Reprod. 2004 Apr;70(4):945-64
references: 14645107
references: Biochim Biophys Acta. 1999 Aug 12;1451(1):93-100
references: 10446391
references: Nature. 1956 Jun 2;177(4518):1036
references: 13322022
references: Int J Androl. 2012 Feb;35(1):86-101
references: 21696392
references: Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10213-8
references: 19509333
references: Spermatogenesis. 2011 Jan;1(1):2-13
references: 21866273
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11411-6
references: 20534520
references: Endocrinology. 2009 Oct;150(10):4724-33
references: 19574397
references: Trends Pharmacol Sci. 2011 May;32(5):290-9
references: 21324536
references: Endocrinology. 2005 Apr;146(4):1893-908
references: 15618353
references: Tissue Cell. 1977;9(3):475-98
references: 929577
references: Prog Histochem Cytochem. 2011 Aug;46(2):49-127
references: 21705043
references: Nat Rev Endocrinol. 2010 Jul;6(7):380-95
references: 20571538
references: Am J Physiol Endocrinol Metab. 2013 Jan 15;304(2):E145-59
references: 23169788
references: Endocr Rev. 2009 Feb;30(1):75-95
references: 19074586
references: Endocrinology. 2003 May;144(5):2141-63
references: 12697723
references: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17998-8003
references: 20921394
references: Toxicol Appl Pharmacol. 2009 Aug 1;238(3):240-9
references: 19236889
references: J Androl. 2005 May-Jun;26(3):354-9
references: 15867003
references: Spermatogenesis. 2012 Oct 1;2(4):285-293
references: 23248770
references: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9657-62
references: 18621709
references: J Cell Sci. 2004 Feb 15;117(Pt 5):783-98
references: 14734653
references: Int Rev Cell Mol Biol. 2009;278:309-53
references: 19815182
references: J Toxicol Environ Health. 1989;27(1):95-105
references: 2724371
references: Toxicol Sci. 2008 Apr;102(2):207-18
references: 17947343
references: Mol Cell Endocrinol. 2011 Mar 15;335(1):60-8
references: 20363290
references: J Androl. 2001 May-Jun;22(3):413-23
references: 11330641
references: Birth Defects Res C Embryo Today. 2009 Mar;87(1):35-42
references: 19306349
references: Contraception. 2005 Oct;72(4):251-61
references: 16181968
references: Toxicol Appl Pharmacol. 2003 Jun 15;189(3):180-95
references: 12791303
references: Spermatogenesis. 2011 Jan;1(1):14-35
references: 21866274
references: Adv Exp Med Biol. 2008;636:186-211
references: 19856169
references: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12562-7
references: 22797892
references: Nat Commun. 2012;3:1185
references: 23149730
references: Spermatogenesis. 2011 Apr;1(2):137-146
references: 22319662
references: Biol Reprod. 2009 Mar;80(3):581-9
references: 19038859
references: Nat Cell Biol. 2004 Dec;6(12):1180-8
references: 15558031
references: Biol Reprod. 2010 Mar;82(3):516-27
references: 19828778
references: Pharmacol Ther. 2007 Apr;114(1):74-93
references: 17316817
references: FASEB J. 2008 Jun;22(6):1945-59
references: 18192323
references: Endocrinology. 2012 Oct;153(10):5023-35
references: 22872576
references: Spermatogenesis. 2011 Oct;1(4):283-290
references: 22332111
references: Pharmacol Rev. 2012 Jan;64(1):16-64
references: 22039149
references: Toxicol Appl Pharmacol. 2000 May 1;164(3):231-49
references: 10799334
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8950-5
references: 18579774
references: J Reprod Fertil Suppl. 1998;53:247-59
references: 10645284
references: Endocrinology. 2009 Jul;150(7):3336-44
references: 19213829
references: Biol Reprod. 2011 Dec;85(6):1203-15
references: 21832167
references: Endocr Rev. 2012 Jun;33(3):378-455
references: 22419778
references: Philos Trans R Soc Lond B Biol Sci. 2010 May 27;365(1546):1517-35
references: 20403867
references: Spermatogenesis. 2011 Apr-Jun;1(2):123-136
references: 22319661
references: Immunol Rev. 2006 Oct;213:66-81
references: 16972897
references: Spermatogenesis. 2011 Oct;1(4):303-317
references: 22332114
references: J Biol Chem. 2006 Jun 23;281(25):17286-17303
references: 16608848
references: Exp Cell Res. 2010 Oct 15;316(17):2945-60
references: 20682309
references: Trends Pharmacol Sci. 2011 Feb;32(2):99-106
references: 21168226
references: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11399-404
references: 20534521
references: Spermatogenesis. 2011 Apr;1(2):99-104
references: 22319657
references: J Endocrinol. 1970 May;47(1):81-6
references: 5428920
references: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a000125
references: 20182611
references: Int J Biochem Cell Biol. 2010 Nov;42(11):1864-75
references: 20713173
references: Spermatogenesis. 2011 Jul-Sep;1(3):209-220
references: 22319669
references: J Androl. 2000 Sep-Oct;21(5):625-35
references: 10975408
references: Spermatogenesis. 2012 Jan 1;2(1):23-31
references: 22553487
references: Endocr Rev. 1994 Feb;15(1):102-15
references: 8156935
references: Nat Cell Biol. 2006 Dec;8(12):1337-47
references: 17115031
references: Endocrinology. 2003 Jan;144(1):371-87
references: 12488366
references: Biochim Biophys Acta. 2008 Mar;1778(3):692-708
references: 18068662
references: Int J Androl. 2008 Apr;31(2):112-7
references: 18067563
references: J Biol Chem. 1997 Mar 7;272(10):6499-509
references: 9045675
references: Int Rev Cytol. 1985;94:177-211
references: 3894273
references: Philos Trans R Soc Lond B Biol Sci. 2010 May 27;365(1546):1581-92
references: 20403871
references: J Endocrinol. 2011 Mar;208(3):207-23
references: 21134990
references: Anat Rec. 1979 Jun;194(2):233-46
references: 464324
references: Endocr Rev. 2001 Jun;22(3):289-318
references: 11399746
references: Toxicol Appl Pharmacol. 1999 Jun 15;157(3):166-73
references: 10373400
references: Physiol Rev. 2003 Apr;83(2):433-73
references: 12663865
references: Toxicol Appl Pharmacol. 2002 Aug 1;182(3):255-65
references: 12183105
references: Endokrinologie. 1979 Apr;74(1):6-12
references: 510226
references: J Biol Chem. 2010 Sep 3;285(36):27944-57
references: 20566646
references: Bioessays. 2004 Sep;26(9):978-92
references: 15351968
references: J Endocrinol. 2006 Sep;190(3):759-70
references: 17003277
references: Adv Exp Med Biol. 2013;754:215-32
references: 22956504
references: Adv Exp Med Biol. 2012;763:237-59
references: 23397628
references: Spermatogenesis. 2011 Jul;1(3):231-239
references: 22319671
references: Adv Exp Med Biol. 2012;763:318-33
references: 23397632
references: Spermatogenesis. 2011 Oct;1(4):291-297
references: 22332112
references: Biol Reprod. 2012 Jan 10;86(1):1-14
references: 21900683
references: Bioessays. 2007 Jan;29(1):36-48
references: 17187371
references: Biochem J. 2010 Aug 1;429(3):419-33
references: 20626351
references: Chem Biol Interact. 2010 Jan 5;183(1):181-6
references: 19799886