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Exposure to the bromodomain inhibitor N-methyl pyrrolidone blocks spermatogenesis in a hormonal and non-hormonal fashion

Khera, Nupur; Ghayor, Chafik; Pavlova, Ekaterina; Atanassova, Nina; Weber, Franz E (2021). Exposure to the bromodomain inhibitor N-methyl pyrrolidone blocks spermatogenesis in a hormonal and non-hormonal fashion. Toxicology and applied pharmacology, 423:115568.

Abstract

N-methyl pyrrolidone (NMP) is an FDA approved molecule used as an excipient in pharmaceutical industry. Besides having a central role in formulation of drugs, the most important function of any excipient is to guarantee the safety of the medicine during and after its administration. Several studies have shown that exposure to NMP and especially in rats produce a gonadotoxic effect leading to infertility. However, the mechanisms underlying the effect of NMP on male reproduction are unknown. The aim of this study was to assess the reproductive toxicity of NMP in male rats and to elucidate the underlying mechanism. Male Sprague Dawley rats were injected intraperitoneally, twice/ week, at a dose of 108 mg/ 100 g of body weight with NMP. Analysis of reproductive parameters revealed testicular atrophy in NMP treated animals compared to control animals. Germ cell composition within the seminiferous tubules was disturbed and manifested in an increase in number of cells with fragmented DNA. A subsequent decrease in number of spermatocytes and spermatids was observed. Alpha screen assay shows that NMP acts at the concentrations we applied in vivo as a low affinity inhibitor for BRDT (testis specific bromodomain protein). BRDT inhibition is mirrored by a significant decrease in the expression of early stage spermatocyte markers (lmna, aurkc and ccna1), during which BRDT expression predominates. A significant decrease in testosterone levels was also observed. Since NMP interferes with spermatogenesis on various levels, its use in humans must be carefully monitored.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Dental Medicine > Clinic of Cranio-Maxillofacial Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Toxicology
Life Sciences > Pharmacology
Language:English
Date:15 July 2021
Deposited On:10 Nov 2021 16:38
Last Modified:26 Oct 2024 01:38
Publisher:Elsevier
ISSN:0041-008X
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.taap.2021.115568
PubMed ID:33965371
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