Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape
2014 Study Abstract
During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment.
Among the chemicals present in the environment (air, water, food, and many consumer products), several can act as endocrine disrupting compounds (EDCs), thus interfering with the endocrine system. Phthalates, bisphenol A (BPA), and diethylstilbestrol (DES) have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development.
As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review, we discuss the role of classical nuclear receptors (genomic pathway) in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA, and DES.
Among the nuclear receptors, we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR), androgen receptor (AR), estrogen receptors (ERα and β), liver X receptors (LXR), and small heterodimer partner (SHP).
First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models) of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s). We also point-out the involvement of other receptors and nuclear receptor-independent pathways.
DES and Nuclear Receptors
DES and ERs
Diethylstilbestrol exerts its anti-androgen effects mainly through classical ER signaling, particularly via ERα. In an organ culture system of mouse fetal testes, the reduction in testosterone production observed following DES exposure in wild type testes does not occur in ERα-deficient mice. Similarly, INSL3 gene expression and testis descent are not affected by in utero exposure to DES in ERαKO mice, whereas ERβ invalidation does not protect from DES effect.
DES and ARs and PPARs
To our knowledge, there is no data showing the direct involvement of AR or PPARs in DES testis effects. However, an indirect action of DES cannot be excluded in relation with the reduction of testosterone secretion observed in vitro in rodent testes incubated with DES.
DES and LXRs
Some studies have linked estrogens and LXRs in breast and in mouse adipose tissue. In the testis, LXRs could partially interfere with DES effects. Daily treatment with DES from day 1 to day 5 after birth induces an important increase in cell apoptosis in LXR-deficient mice at day 10 compared to wild type animals. Likewise, LXRs modify the neonatal effects of DES on the expression of Leydig and Sertoli cell markers. However, whether LXRs have a protective effect against or contribute to DES effects remains unclear.
DES and SHP
Treatment with DES promotes SHP mRNA accumulation in the testes of wild type SHP male mice (NR0B2+/+) at postnatal day 10 (P10). Moreover, neonatal DES exposure induces apoptosis, in P10 NR0B2+/+ mice, without any effect on cell proliferation. Conversely, DES does not have any effect on apoptosis in the testes of NR0B2L−/L− males, suggesting that SHP inactivation protects against DES effects. This seems to be germ cell-specific because DES treatment drastically decreases intratesticular testosterone in both NR0B2L−/L− and NR0B2L−/L− males. Interestingly, SHP, mediating the deleterious effects of DES in mice, is not detectable in human fetal testes, and incubation with DES does not modify testosterone production by human fetal testes in culture. SHP absence in human fetal testes could be an additional explanation for their lack of sensitivity to DES.
Sources and more information
- Full study (free access) : Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape, Frontiers in endocrinology, NCBI PubMed PMC4423451, 2014 Apr.
- Structural Organization of Nuclear Receptors featured image credit wikipedia.