Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors

Abstract

Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk.

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

“…Third, the species-specific sensitivity for in vitro testing is critical to the interpretation of toxicity across species. It has been reported that BPA concentration required to impair testosterone production in human is about 100-fold lower than that in rodent fetal testis explants (Habert et al, 2014). Thus, more cell lines or primary cells from different species, especially humans, would be helpful to extrapolate current in vitro findings to human health risk assessment.…”

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

“…Entsprechende Experimente liegen für DEHP oder MEHP nicht vor. In Ex-situ-Organkultursystem-Experimenten hatte 0,1 mM MEHP keinen Effekt auf die Testosteronproduktion in fetalen Hoden des Menschen (Lambrot et al 2009) und induzierte nur bei Mäuse-und Rattenhodenkulturen vielkernige Keimzellen, nicht jedoch in denen des Menschen (Habert et al 2014). Aus diesen Experimenten wird geschlossen, dass humane Leydigzellen gegen-über dem antiandrogenen Effekt der Phthalate resistent sind.…”

“…Die Maus hat sich als weniger empfindlich gegen die DEHP-induzierten Effekte auf die fetalen männlichen Reproduktionsorgane herausgestellt als die Ratte (Johnson et al 2012;Kay et al 2014). Aufgrund der genannten Speziesunterschiede werden Bedenken über die Extrapolation der Daten aus Versuchen an Nagern auf den Menschen geäußert (Habert et al 2014;Kay et al 2014). Die Ratte hat sich als die empfindlichste Tierspezies für die DEHP-induzierten Effekte auf die männlichen Reproduktionsorgane erwiesen.…”

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

“…It was concluded from these studies that human Leydig cells are resistant to the anti-androgenic effect of phthalates. The molecular pathways that control steroidogenesis in human foetal testes have yet to be clarified (Johnson et al 2012).Mice were found to be less sensitive to DEHP-induced effects on the reproductive organs of male foetuses than rats (Johnson et al 2012;Kay et al 2014).These species differences raised concerns about the extrapolation of data from rodents to humans (Habert et al 2014;Kay et al 2014).Rats proved to be the most sensitive animal species for DEHP-induced effects on male reproductive organs. In conclusion, species differences in the toxicokinetics and toxicodynamics of DEHP-induced effects are very complex.…”