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. 2021 Dec;49(8):1416-1424.
doi: 10.1177/01926233211045331. Epub 2021 Sep 23.

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

Cynthia J Willson  1
Affiliations

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

Cynthia J Willson. Toxicol Pathol. 2021 Dec.

Abstract

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.

Keywords: dysgenesis; maldevelopment; male; phthalate; reproductive; testicular dysgenesis syndrome; testis.

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Conflict of interest statement

Declaration of Conflicting Interests

The author declares no real, perceived, or potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
The Testicular Dysgenesis Syndrome (TDS) hypothesis states that events occurring during fetal development of the testis are related to increasing trends in certain human reproductive disorders/diseases. These include cryptorchidism and hypospadias in infants, decreased anogenital distance in both infants and adults, and decreased sperm counts and testicular cancer in adults. In addition to these clinical manifestations, there are microscopic lesions in the testis, including abnormal Leydig cell aggregation, persistent and/or multinucleated gonocytes, and focal seminiferous tubule dysgenesis. Based on Skakkebaek et al. 2001, Skakkebaek et al. 2016, and van den Driesche et al. 2017.,,
Figure 2.
Figure 2.
Examples of seminiferous tubule dysgenesis in juvenile rats (PND23 or 24) from a US National Toxicology Program 2-year study of diethylhexyl phthalate with perinatal exposure (beginning on gestation day 6). (A) Focal seminiferous tubule dysgenesis near the center of a section of the testis, associated with abnormal Leydig cell aggregation (arrowheads). (B) At higher magnification, the tubular dysgenesis lesion is comprised almost solely of Sertoli cells. Abnormal Leydig cell aggregation (*) is adjacent to the malformed tubules. (C) Seminiferous tubule dysgenesis that does not feature prominent, abnormal Leydig cell aggregation and contains some germ cells. (D) It is difficult to ascertain the tubular borders in this focus of dysgenesis, and it is possible that the adjacent abnormal Leydig cell aggregate (*) contains ectopic cells. (E, F) Multinucleated germ cells (arrows) in the center of tubule lumens, concomitant in testes that also contain tubular dysgenesis lesions. The persistence of gonocytes in the tubular lumen beyond PND10 is also abnormal. H&E.
Figure 3.
Figure 3.
Examples of seminiferous tubule dysgenesis in 2-year-old rats from US National Toxicology Program 2-year studies of diethylhexyl phthalate (A, B) or dibutyl phthalate (C, D) with perinatal exposure (beginning on gestation day 6). (A) A nodular lesion of malformed seminiferous tubules closely associated with a large aggregation of spindloid Leydig cells. The surrounding interstitium is edematous, with nearby Sertoli-cell-only tubules with thickened basement membranes. H&E. (B) Seminiferous tubule dysgenesis with malformed tubules that are surrounded by aggregated, spindloid Leydig cells. H&E. (C) When tubular dysgenesis lesions are stained with PAS/H, the irregular, thickened tubular borders are especially prominent, with invaginations that appear as “islands” of Leydig cells inside tubules. PAS/H. (D) At high magnification, the Sertoli cells within the malformed tubules appear immature, with disorderly distribution within the tubule and small, elongated, and occasionally cleaved nuclei. They lack the prominent tripartite nucleoli and large nuclei of mature Sertoli cells. The tubular borders are irregularly thickened and hyalinized. H&E.
Figure 4.
Figure 4.
Proposed timeline of appearance and disappearance or persistence of microscopic lesions of testicular maldevelopment (dysgenesis) in rats exposed to phthalates during the masculinization programming window (MPW) during gestation based on several studies.–,
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References

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