A review of Leydig cell hyperplasia in fish models: Implications for endocrine toxicity studies

Leydig cell hyperplasia (LCH) refers to an increased abundance of androgen-producing cells within the vertebrate testicular interstitium. LCH is considered a key histopathologic diagnosis in ecotoxicological bioassays such as the Fish Short Term Reproduction Assay (FSTRA), Fish Sexual Development Test (FSDT) and the Medaka Extended One-Generation Reproduction Test (MEOGRT), which were developed by the United States Environmental Protection Agency and/or the Organisation for Economic Co-operation and Development to test chemicals for potential reproductive endocrine activity and disruption, respectively. Although much has been written about the diagnosis and toxicologic implications of chemically-induced LCH in mammals, published information concerning LCH in fish is relatively sparse. The current review attempts to lessen this knowledge gap, by comparing and contrasting causes and consequences of Leydig cell proliferation in mammals and fish, investigating reports of LCH occurrence in fish toxicologic studies, exploring adverse and population-relevant effects that may (or may not) be associated with LCH, and providing suggestions for confirming the validity of LCH diagnoses. It is hoped that the material presented herein will help to facilitate the improved interpretation of LCH in the context of endocrine disruption research in fish.