Circulating microRNAs as promising testicular translatable safety biomarkers: current state and future perspectives

• Published in: Archives of toxicology Vol. 97; no. 4; pp. 947 - 961
• Main Authors: Zhang, Jiangwei, Campion, Sarah, Catlin, Natasha, Reagan, William J., Palyada, Kiran, Ramaiah, Shashi K., Ramanathan, Ragu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2023; Springer Nature B.V
• Subjects: Biomarkers; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Body fluids; Cell injury; Circulating MicroRNA - metabolism; Damage detection; Drug development; Environmental Health; Gene expression; Hormones; Humans; Injuries; Leydig cells; Leydig Cells - metabolism; Male; MicroRNAs; MicroRNAs - genetics; miRNA; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Post-transcription; Review Article; Safety; Semen; Testes; Testis - metabolism; Toxicants; Tubules; TransBioLine; DITI; miRNAs; Drug-induced testicular injury; PSTC
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-023-03460-0

Drug-induced testicular injury (DITI) is one of the often-observed and challenging safety issues seen during drug development. Semen analysis and circulating hormones currently utilized have significant gaps in their ability to detect testicular damage accurately. In addition, no biomarkers enable a mechanistic understanding of the damage to the different regions of the testis, such as seminiferous tubules, Sertoli, and Leydig cells. MicroRNAs (miRNAs) are a class of non-coding RNAs that modulate gene expression post-transcriptionally and have been indicated to regulate a wide range of biological pathways. Circulating miRNAs can be measured in the body fluids due to tissue-specific cell injury/damage or toxicant exposure. Therefore, these circulating miRNAs have become attractive and promising non-invasive biomarkers for assessing drug-induced testicular injury, with several reports on their use as safety biomarkers for monitoring testicular damage in preclinical species. Leveraging emerging tools such as ‘organs-on-chips’ that can emulate the human organ’s physiological environment and function is starting to enable biomarker discovery, validation, and clinical translation for regulatory qualification and implementation in drug development.