Phthalate Toxicity in Rats and Its Relation to Testicular Dysgenesis Syndrome in Humans

This work describes the relevance of toxicology studies of environmental chemicals, with a focus on phthalates, for a hypothesis that certain human male reproductive disorders and diseases have a common etiology of disturbance of normal development in utero. The “Testicular Dysgenesis Syndrome” hypothesis in humans has parallels in male reproductive tract abnormalities and microscopic lesions reported for phthalate toxicity in rats. Additionally, this work describes the histological findings of abnormal testicular development (testicular dysgenesis) in rats as compared to those in humans, as well as potential findings in rats at different ages, from the embryo to the adult.

Testicular dysgenesis syndrome and phthalate exposure: A review of literature

Endocrine disruptors are chemicals that interfere with the body's endocrine system and cause adverse effects in biological systems. Phthalates are a group of man-made chemicals which are mainly used as plasticizers and classified as endocrine disruptors. They are also used in cosmetic and personal care products as color or smell fixators. Moreover, phthalates are present in inks, adhesives, sealants, automobile parts, tools, toys, carpets, medical tubing and blood storage bags, and food packages. Pathological condition known as "testicular dysgenesis syndrome" (TDS) or "phthalate syndrome" is usually linked to phthalate exposure and is coined to describe the rise in alterations in reproductive health in men, such as reduced semen quality (decrease in sperm counts, sperm motility and increase in abnormal sperms), hypospadias, cryptorchidism, reduced anogenital distance and early-life testicular cancer. Phthalates are suggested to cause direct effect on gonadal and non-gonadal tissues, impair the differentiation and morphogenesis of seminiferous tubules and accessory sex organs and testicular cells (both Sertoli and Leydig cells), alter estradiol and/or testosterone levels, decrease insulin-like 3 (INSL3) peptide production, impair spermatogenesis and lead to epigenetic alterations, all of which may lead to TDS. This review will mainly focus on phthalates as causes of TDS and their mechanisms of action.

Reconstitution of rat fetal testis during the masculinisation programming window induces focal dysgenesis consistent with testicular dysgenesis syndrome

Focal dysgenesis is a consistent feature of testicular dysgenesis syndrome (TDS) in humans. Rodent studies show that perturbation of androgens (e.g. following phthalate exposure) during a fetal masculinisation programming window (MPW) predisposes to a TDS phenotype. This study aimed to determine whether dissociation and reconstitution of rat fetal testis tissue during the MPW can be used to model and manipulate seminiferous cord development, including induction of focal dysgenesis, as described in TDS. Dissociated fetal rat testes were xenotransplanted subcutaneously into recipient mice for 4 weeks. Transplanted mice were treated with vehicle or di-n-butyl-phthalate (DBP, a plasticising chemical known to induce testicular dysgenesis in vivo in rats). Testosterone production by the transplants was measured in recipient mice and immunofluorescence was performed on the retrieved transplants to identify features consistent with focal testicular dysgenesis. Re-aggregation of rat fetal testis tissue xenotransplants during the MPW results in reconstitution of seminiferous cords. Features of focal testicular dysgenesis were present in re-aggregated testis, including ectopic Sertoli cells and intratubular Leydig cells (ITLCs). DBP exposure of recipient mice reduced androgen-dependent seminal vesicle weight (8.3 vs 26.7 mg; p < 0.05), but did not enhance features of focal dysgenesis including number of ITLCs (0.07 vs 0.10 cells/mm2; p > 0.05). We conclude that seminiferous cord reformation during the MPW results in development of focal dysgenesis. The system may be used to separate specific effects (e.g. androgen suppression) of individual chemical exposures from other mechanisms that may be conserved in TDS.

Publisher Correction: Dibutyl phthalate induced testicular dysgenesis originates after seminiferous cord formation in rats

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