Abstract
Targeted and reversible disruption of the blood-testis barrier by an FSH mutant-occludin peptide conjugate
Wong,Ching-hang; Mruk,Dolores D.; Lee,Will M.; Cheng,Chuen-yan
FASEB Journal 21(2): 438-448
Publication date: 2007
The blood-testis barrier (BTB) is one of the tightest blood-tissuebarriers in mammals. As such, it poses a challenge to deliverany drugs to the seminiferous epithelium of the testis, suchas a nonhormonal male contraceptive. To circumvent this problem,a genetically engineered follicle-stimulating hormone (FSH)mutant protein was produced in Spodoptera furgiperda (Sf)-9insect cells to serve as a testis-specific carrier. Subsequently,a 22-amino acid peptide corresponding to the second extracellularloop of occludin, which was known to disrupt BTB integrity invivo, was inserted to the FSH mutant by polymerase chain reaction(PCR), as well as chemical cross-linking. This molecule wasfound to have negligible hormonal activity but was still capableof binding to FSH receptors, which are restricted to Sertolicells in mammals. When this FSH mutant-occludin peptide conjugatewas administered to adult rats at 40 µg/adult rat (300gm b.w.) via intraperitoneally (i.p.) injection, it inducedtransient and reversible disruption of the BTB, while at 150µg/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 theTJ-barrier integrity or cell adhesion in epithelia of otherorgans, such as kidney, liver, and small intestine. In summary,the use of an FSH mutant-occludin peptide conjugate is a feasiblenanodevice to transiently compromise the BTB.
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