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Targeted and reversible disruption of the blood‐testis barrier by an ΔFSH mutant‐occludin peptide conjugate
Author(s) -
Wong ChingHang,
Mruk Dolores D.,
Lee Will M.,
Yan Cheng C.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4144com
Subject(s) - occludin , blood–testis barrier , sertoli cell , mutant , biology , microbiology and biotechnology , tight junction , follicle stimulating hormone receptor , transcytosis , medicine , endocrinology , peptide , hormone , follicle stimulating hormone , receptor , chemistry , biochemistry , spermatogenesis , luteinizing hormone , gene , endocytosis
The blood‐testis barrier (BTB) is one of the tightest blood‐tissue barriers in mammals. As such, it poses a challenge to deliver any drugs to the seminiferous epithelium of the testis, such as a nonhormonal male contraceptive. To circumvent this problem, a genetically engineered follicle‐stimulating hormone (FSH) mutant protein was produced in Spodoptera furgiperda ( Sf )‐9 insect cells to serve as a testis‐specific carrier. Subsequently, a 22‐amino acid peptide corresponding to the second extracellular loop of occludin, which was known to disrupt BTB integrity in vivo , was inserted to the ΔFSH mutant by polymerase chain reaction (PCR), as well as chemical cross‐linking. This molecule was found to have negligible hormonal activity but was still capable of binding to ΔFSH receptors, which are restricted to Sertoli cells in mammals. When this ΔFSH mutant‐occludin peptide conjugate was administered to adult rats at 40 µg/adult rat (~300 gm b.w.) via intraperitoneally (i.p.) injection, it induced transient and reversible disruption of the BTB, while at 150 g/rat, it induced partial germ cell loss from the testis, particularly elongating/elongate spermatids. Most importantly, this effect was limited to the BTB without compromising the TJ‐barrier integrity or cell adhesion in epithelia of other organs, such as kidney, liver, and small intestine. In summary, the use of an ΔFSH mutant‐occludin peptide conjugate is a feasible nanodevice to transiently compromise the BTB.—Wong, C.‐H., Mruk, D. D., Lee, W. M., Cheng, C. Y. Targeted and reversible disruption of the blood‐testis barrier by an ΔFSH mutant‐occludin peptide conjugate. FASEB J. 21, 438–448 (2007)