Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-butyl) Phthalate during Late Gestation

Mylchreest, Eve; Wallace, Duncan G.; Cattley, Russell C.; Foster, Paul M.D.

doi:10.1093/toxsci/55.1.143

Cited by 418 publications

(314 citation statements)

References 31 publications

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“…FLCs were aggregated rather than dispersed when doses of DEHP were increased. Previous studies similarly reported that high-dose exposures to DEHP or DBP in utero resulted in focal disruptions in the structure of the seminiferous epithelium and in abnormal aggregations of FLCs (24,25). Stereological analyses have suggested that the increased FLC number per cluster in response to DEHP does not result from increased Leydig cell numbers (our results and ref.…”

Section: Resultssupporting

confidence: 84%

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Lin

Chen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

145

108

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Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function. Pregnant Long-Evans female rats received vehicle (corn oil) or DEHP at 10, 100, or 750 mg/kg by oral gavage from gestational day (GD)2-20. At GD21, T production, FLC numbers and distribution, and testicular gene expression were examined. The percentage of FLC clusters containing 6 -30 cells increased in all treatment groups, with 29 ؎ 2% in control vs. 37 ؎ 3, 35 ؎ 3, and 56 ؎ 4% in rats receiving 10, 100, and 750 mg/kg DEHP, respectively. In contrast, FLC numbers were 33% and 39% lower than control after exposures to 100 and 750 mg/kg DEHP, respectively. At these doses, mRNA levels of leukemia inhibitory factor (LIF) increased. LIF was found to induce cell aggregation in FLCs in vitro, consistent with the hypothesis that DEHP induced FLC aggregation. Testicular T levels were doubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNA levels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kg DEHP. These results, taken together, indicate that fetal exposures to DEHP have effects on FLC number, distribution, and most importantly, steroidogenic capacity and suggest that abnormal expressions of IGF1, KITL, and LIF genes may contribute to the reproductive toxicity of phthalates.di-(2-ethylhexyl) phthalate ͉ testosterone ͉ reproduction ͉ endocrine disruptor ͉ steroidogenesis P hthalates, widely used as plasticizers and solvents, are commonly found in a variety of consumer products including cosmetics, toys, medical tubing, and catheters and in the environment as an industrial waste product. Increasing public concern over lack of regulation on their use in the United States, in contrast to the European Union and 14 other countries (1), has arisen in response to reports that exposures to phthalates may be linked to abnormal reproductive development in the human male (2, 3). Epidemiological studies show statistical correlations between serum concentrations of phthalate monoesters, the primary metabolites of phthalates, and the incidence of anomalies such as cryptorchidism and shortened anogenital distance (AGD) (4, 5). Di-(2-ethylhexyl) phthalate (DEHP), the most abundant phthalate in the environment, has been shown to have adverse effects on androgen synthesis in the rodent (6).The Agency for Toxic Substances and Disease Registry reported that, although exposure to DEHP is generally low, the exposures of preterm infants can be as high as 10-20 mg per day (7). Controversy exists over whether DEHP, at the levels found in the environment, is harmful to humans, because most studies have been conducted in rodents administered high doses. In previous studies, we showed that the administration of low-dose (10 mg/kg body weight) DEHP for 28 days during pubertal development caused elevations in testosterone (T) (8, 9)....

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Section: Resultssupporting

confidence: 84%

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Lin

Chen³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

145

108

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“…gestation day (GD) 12-19, results in remarkable phenotypic alterations in normal development. 63,64 At adulthood the phenotypes included: cryptorchidism, epididymal agenesis, testicular atrophy with germ cell loss, hypospadias, and absent or smaller seminal vesicles and prostate. These phenotypes can be linked to androgen deprivation during the critical period of sexual differentiation.…”

Section: -62mentioning

confidence: 99%

Interpreting histopathology in the epididymis

Kempinas

Klinefelter

2014

Spermatogenesis

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“…and Rodgers and Rowland4 are listed in Table 2 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40…”

Section: Resultsmentioning

confidence: 99%

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

Pilari

Gaub

Block

et al. 2017

CPT Pharmacometrics Syst. Pharmacol.

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We extended a generic whole‐body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK‐Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework.

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Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-butyl) Phthalate during Late Gestation

Cited by 418 publications

References 31 publications

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Interpreting histopathology in the epididymis

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

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