Abstract
Objective
The bioavailability of the non-hormonal male contraceptive adjudin is low in rats
due to the blood-testis barrier (BTB). This study was designed to examine if F5-peptide,
an endogenously produced reversible BTB modifier, could enhance the bioavailability
of adjudin to affect spermatogenesis and provide a contraceptive effect in rats while
reducing systemic toxicity.
Study Design
We overexpressed F5-peptide in adult male rats (n=10 rats; with 3 or 4 rats for each of the three different experiments noted in the
three regimens) by intratesticular injection of a mammalian expression vector pCI-neo
(pCI-neo/F5-peptide) vs. empty vector alone (pCI-neo/Ctrl) to be followed by treatment with adjudin by oral
gavage at a dose of 10 or 20 mg/kg. The status of spermatogenesis was assessed by
histological analysis and dual-labeled immunofluorescence analysis on Day 16. To assess
fertility, we allowed treated males (n=3–4 rats) to mate with mature female rats (n=3–4) individually, and assessed the number of pups on Days 23, 36 and 82 to assess
fertility and reversibility.
Results
All 4 treated rats overexpressed with F5-peptide and low-dose adjudin were infertile
by Day 36, and half of these rats were fertile by Day 82, illustrating reversibility.
However, overexpression of F5-peptide alone (or low-dose adjudin alone) had no effects
on fertility in n=3 rats. These findings were consistent with the histology data that illustrated the
BTB modifier F5-peptide promoted the action of adjudin to induce germ cell exfoliation,
mediated by changes in cytoskeletal organization of F-actin and microtubules across
the epithelium, thereby reducing the systemic toxicity of adjudin.
Conclusion
In this proof-of-concept study, it was shown that overexpression of the F5-peptide
prior to administration of adjudin to rats at a low (and ineffective dose by itself)
was found to induce reversible male infertility.
Implications
Overexpression of F5-peptide, an endogenously produced biomolecule in the testis known
to induce BTB remodeling, enhanced the contraceptive effect of adjudin in rats, supporting
proof of concept studies of BTB disrupters in men.
Keywords
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Article info
Publication history
Published online: February 11, 2019
Accepted:
January 19,
2019
Received in revised form:
January 7,
2019
Received:
July 5,
2018
Footnotes
☆This work was supported in part by grants from the National Institutes of Health (NICHD R01 HD056034 to C.Y.C.; U54 HD029990 Project 5 to C.Y.C.). HQ was supported in part by a fellowship from The F. Lau Memorial Fellowship and The S.Y. Law Memorial Fellowship.
☆☆DISCLOSURE SUMMARY: There are no financial and other conflicts of interest for all authors, and nothing to declare.
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