Impact of Age on the Male Reproductive System from the Pathologist’s Perspective

Abstract

Age, and in particular young age, can significantly impact the response to toxicants in animals and can greatly influence the interpretation of tissue changes by the toxicologic pathologist. Although this applies to multiple organ systems, the current review focuses on the male reproductive system. When performing microscopic evaluation of male reproductive organs, the toxicologic pathologist must be aware of the dynamic changes in histomorphology, predominantly driven by timed hormonal alterations, at various life stages. Specific challenges pathologists face are understanding the appearance of male reproductive tissues throughout the neonatal, infantile, and juvenile developmental periods, recognizing when normal looks abnormal during tissue development, defining sexual maturity, and working with high interanimal variability in maturation rate and histologic appearance in developing large laboratory animals, such as nonhuman primates, dogs, and pigs. This review describes postnatal development of the male reproductive system in the rat, demonstrates how assessing toxicity during a defined window of postnatal development in the rat may improve definition of toxicant timing and targets, and discusses challenges associated with the interpretation of toxicity in immature large animal species. The emphasis is on key age-related characteristics that influence the interpretation of tissue changes by the toxicologic pathologist.

Comparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System

“…There is considerable variation in the published literature for the different developmental stages in any one species (Picut and Remick, ). There are multiple reasons for these disparities, not least of which is inconsistent practices among laboratories in how they define the first day of pregnancy or the day of birth, as well as, inconsistent use of terminology and definitions that describe various developmental milestones.…”

Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs

“…however, the putative degenerative, compound association with these changes is equivocal due to similar changes reported in peripubertal dogs as were used in this study. 24…”

Differentiating between Testicular Toxicity and Sexual Immaturity in Ortho-phthalaldehyde Inhalation Toxicity Studies in Rats and Mice

“…While male mice are considered sexually mature earlier, at >7 weeks of age (PND 49), male rats are considered sexually mature later, at >9 weeks of age (PND 63) (Lanning et al, 2002). In male rats, the peripubertal stage ranges from PND 33 to 55 (Picut and Remick, 2017, Picut et al, 2015). Puberty in male rats is a midpoint of this period, as defined microscopically by the appearance of mature step 19 spermatids at the lumen of stage VII seminiferous tubules around PND 46 (with preputial separation occurring at approximately PND 43) (Picut et al, 2015, Whitney, 2012, Marty et al, 2001).…”

“…However, there is continued and substantial growth in the sizes of the testis and epididymis, and increased numbers and density of elongating spermatids in the testis and sperm in the epididymis in the late pubertal period, PND 56 to 70, until establishment of the weight and morphological features that are typical of a sexually mature male rat around PND 70 (10 weeks) (Campion et al, 2013, Picut et al, 2015). For histologic changes during testis development in rats, the reader is referred to Picut and Remick (2017), Picut et al (2015), and Whitney (2012). Challenges in examination of the testes and epididymides in sexually immature animals include distinguishing test-article-related effects from normal age-appropriate physiological changes, as well as the lack of concurrent age-matched controls in the case of unscheduled deaths.…”