Abstract
Phthalates provide one of the most documented example evidencing how much we must be cautious when using the traditional paradigm based on extrapolation of experimental data from rodent studies for human health risk assessment of endocrine disruptors (EDs). Since foetal testis is known as one of the most sensitive targets of EDs, phthalate risk assessment is routinely based on the capacity of such compounds to decrease testosterone production by the testis or to impair masculinization in the rat during foetal life. In this paper, the well-established inhibiting effects of phthalates of the foetal Leydig cells function in the rat are briefly reviewed. Then, data obtained in humans and other species are carefully analysed. Already in January 2009, using the organotypic culture system named Fetal Testis Assay (FeTA) that we developed, we reported that phthalates might not affect testosterone production in human foetal testes. Several recent experimental studies using xenografts confirm the absence of detectable anti-androgenic effect of phthalates in the human foetal testes. Epidemiological studies led to contradictory results. Altogether, these findings suggest that phthalates effects on foetal Leydig cells are largely species-specific. Consequently, the phthalate threshold doses that disturb foetal steroidogenesis in rat testes and that are presently used to define the acceptable daily intake levels for human health protection must be questioned. This does not mean that phthalates are safe because these compounds have many deleterious effects upon germ cell development that may be common to the different studied species including human. More generally, the identification of common molecular, cellular or/and phenotypic targets in rat and human testes should precede the choice of the toxicological endpoint in rat to accurately assess the safety threshold of any ED in humans.
Highlights
The risk of chemicals for human health is routinely assessed by epidemiological and experimental studies
Using an organotypic culture system that we developed and named Foetal Testis Assay (FeTA) [16,47,103,104,105,106,107,108] (Figure 1), we affirmed for the first time in January 2009 that phthalates do not reduce testosterone production in human foetal testes [109] (Figure 2)
mono-(2-ethylhexyl) phthalate (MEHP) increased the size of lipid droplets and the expression of LXR alpha, of downstream genes, such as SREBP1, SREBP2, and of genes involved in cholesterol and lipid biosynthesis [111]. – Using the Fetal Testis Assay (FeTA) system we showed that human foetal Leydig cells can respond to other endocrine disruptors (EDs) as indicated by the finding that exposure to 10−8 M bisphenol A (BPA) reduces testosterone production and INSL3 expression [102]. – In the FeTA system, exposure to 10−4 and 10−5 M MEHP reduced the basal testosterone production of rat testes explanted at 14.5 dpc and cultured for three days [1]
Summary
The risk of chemicals for human health is routinely assessed by epidemiological and experimental studies. The bias resulting from confounding factors could explain the inverse association between AGD and exposure to MEP, a compound without antiandrogenic effects, reported by Swan’s group These epidemiological studies do not allow confirming or infirming the existence of an association between phthalate exposure and reduced androgenic activity of foetal testes in humans. Our in vitro approach displays intrinsic limits (absence of vascularization, cell survival limited to a few days) it allows the sensitive, direct, rapid, not labour-intensive and relatively cheap evaluation of the toxic effects of a given compound on foetal testis development and functions [1] Using this method, we never detected any anti-androgenic effect of phthalates in human foetal testes, whereas we always did in rat foetal testes.
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