Testicular and epididymal toxicity: Pathogenesis and potential mechanisms of toxicity.

Abstract

The toxicologic literature abounds with examples of drugs and environmental chemicals that cause changes in spermatogenesis and/or epididymal sperm in laboratory animals. Unless proven otherwise, the assumption must be made that similar changes are likely to occur in humans exposed to these chemicals. For those working in the pharmaceutical industry, this can mean the costly termination of a drug development program and the loss of a potentially valuable therapeutic molecule unless studies can be conducted to investigate potential mechanisms of toxicity and/or realistically predict human risk. For those working in regulatory environmental toxicity, mechanistic studies are rarely conducted but demonstration of a mode of action (MOA) can provide valuable information to allow a better understanding of the real threat of environmental toxicants versus the perceived threat. For both disciplines, it is essential to understand the basic science underlying spermatogenesis and sperm maturation in order to address any mechanistic approach to investigating a toxicologic lesion. The toxicologic pathologist is generally the person to first identify and sound the alarm regarding a male reproductive toxicant in a drug development or environmental chemical program. Organ weights and histopathology will be the main (often only) information that will be available from repeat dose studies. Given a good understanding of spermatogenesis and spermatogenic staging, the pathologist may be able to take a guess at the earliest cell type affected (Sertoli or germ cell), get a feel for the pathogenesis and recovery of the lesion over time, and they may even be able to assess whether endocrine disturbance is a major and primary event. Very soon after sounding the alarm, a lot of questions will be asked regarding the likely mechanism of toxicity, whether the spermatogenic disruption is “on or off target” for the therapeutic molecule, and is the toxicity, (which often affects one species and not the other) relevant to man? Such questions are extremely difficult to answer or even address when dealing with disturbances of spermatogenesis because of the complexity of the cellular interactions within the testis, the relative lack of knowledge of the physiology and molecular biology of spermatogenesis and the fact that we are often working with species (e.g. dog and monkey) for which there is remarkably little basic biologic information. In fact, many of these questions are never addressed by pharma companies with a reproductive issue, partly because of time and money constraints, but also because the main objective of repeat dose regulatory studies is risk assessment. So if any follow up mechanistic work is conducted, it is limited and only aimed at whether an effect is relevant to man or justifying why a higher dose can safely be used in clinical trials. This approach contrasts with basic research on cell physiology, endocrinology and molecular biology of spermatogenesis where individual processes are studied in great depth and where occasionally, chemicals may be used to disrupt a process. The objective of this special issue is to try and bring regulatory toxicology and academic, investigative toxicology together to provide relevant information that can benefit both academic and toxicologic-driven disciplines. Specifically, the authors of the main chapters here have been charged with explaining the biology underlying their topic. When we see a lesion, what is going on in the cells to produce that kind of lesion? The intent is to provide a quick path to understanding, and access to relevant literature. This Special Issue begins with a pictorial review of the broad types of changes that confront the pharmaceutical toxicologic pathologist on a daily basis. Morphologic manifestations of testicular and epididymal toxicity by Justin Vidal and Katherine Whitney provides an atlas and review of the typical features that lead the pathologist to draw conclusions regarding the main cell type injured, possible subcellular targets and the progression of a lesion from its subtle early features through to the non-specific endstages of tubular degeneration and tubular atrophy. This provides the backdrop for the subsequent detailed reviews from academic contributors explaining what might be expected (the Signature Lesion) when specific aspects of reproductive physiology are disturbed and the ways potential regulatory pathways could be disrupted to explain that lesion. This includes a detailed review of the cytoskeleton and the various critical functions that it regulates in Testicular histopathology associated with disruption of the Sertoli cell cytoskeleton by Kam Johnson, which details the roles of actin microfilaments, the intermediate filaments, and microtubules. The cytoskeleton is integral to the structural support of the seminiferous epithelium and the functioning of the multiplicity of cell junctions between Sertoli and germ cells and