Sertoli Cell-Mediated Mechanisms of Phthalate Toxicity in the Developing Seminiferous Cord

Abstract

Phthalates are a class of industrial chemicals that are present in numerous consumer products, and to which humans are universally exposed. Phthalates have posed significant concerns due to their potential to induce developmental and reproductive toxicity. The mechanisms through which phthalates compromise the structural and functional integrity of the fetal testis are unknown. This dissertation investigates the impact of effects of di-(2-ethylhexyl) phthalate (DEHP) and its metabolite mono-(2-ethylhexyl) phthalate (MEHP) on Sertoli cell function and seminiferous cord development in fetal mice and rats, with a focus on elucidating the mechanistic pathways through which phthalates induce morphological seminiferous cord effect. In Chapter 2, ex vivo culture experiments were utilized to examine the interaction between MEHP and all-trans retinoic acid (ATRA) signaling pathways in the context of seminiferous cord development. The combined exposure to MEHP and ATRA exacerbated the effects of ATRA alone on seminiferous cord number, FOXL2 expression, and testosterone levels, which suggests a significant modulation of retinoic acid signaling by a phthalate. In Chapter 3, Sox9-eGFP mice were utilized to investigate the effect of in utero DEHP exposure on fetal Sertoli cell function. In isolated Sertoli cells, gestational exposure to DEHP altered the expression of functional and structural genes such as Igsf11, Egr1, Esr2, Col14a1, Ppargc1a, and Tuba3b in Sertoli cells. Moreover, DEHP was found to dysregulate genes involved in amino acid transport in Sertoli cells. The effect of MEHP in combination with peroxisome proliferator-activated receptor gamma (PPARγ) signaling modulators, rosiglitazone (PPARγ agonist), and GW9662 (PPARγ antagonist) was studied using an ex vivo culture model. Findings suggested that MEHP can influence PPARγ signaling, but that this is not likely to be the primary mechanism of phthalate toxicity. Collectively, these results represent significant new insights into the mechanisms by which phthalates interfere with male reproductive development, emphasizing the critical role of Sertoli cell-mediated pathways in phthalate toxicity.