Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants

Abstract

Background:Numerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life.Objectives:Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals.Methods:We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10–12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures.Results:We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose–response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight.Conclusions:Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life. https://doi.org/10.1289/EHP1014

Ibuprofen Is Deleterious for the Development of First-Trimester Human Fetal Ovary Ex Vivo

“…In our ex vivo model, the overall impact of ibuprofen was most pronounced when used at 10 μM and notably more variable at 100 μM. Non-monotonic dose-response curves have been described in the testis where several endocrine disruptor compounds exhibited these curves (Gaudriault et al, 2017). In the ovary, only two studies have investigated several concentrations (of either Bisphenol A or dexamethasone) and found linear doseresponse curves (Brieno-Enriquez et al, 2011;Poulain et al, 2012).…”

Impacts of food contact chemicals on human health: a consensus statement

“…However, more recent scientific information demonstrates that this assumption is not generally valid, with the available evidence showing that exposure to low levels of endocrine disrupting chemicals can contribute to adverse health effects [14][15][16][17][18][19][20]. In addition, chemical mixtures can play a role in the development of adverse effects [21][22][23][24], and human exposure to chemical mixtures is the norm but currently not considered when assessing health impacts of FCCs [1]. The timing of exposures during fetal and child development is another critical aspect for understanding development of chronic disease [25].…”

Mechanisms of Testicular Disruption from Exposure to Bisphenol A and Phtalates

“…Maternal exposure during fetal life offers the greatest risk to the developing organism: exposure in this phase is associated with disruption of testosterone production and reproductive tract development, as demonstrated by the in vivo and in vitro detection of multiple antiandrogenic EDCs in fetal life [17,31,32]. This is the phase in which sex is determined, with differentiation of the reproductive tissues, a fundamental step for the future development and maintenance of reproductive function.…”