Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis

Wilson, Vickie S.; Lambright, Christy; Furr, Johnathan; Ostby, Joseph; Wood, Carmen R.; Held, Gary A.; Gray, L. Earl

doi:10.1016/j.toxlet.2003.09.012

Cited by 256 publications

(194 citation statements)

References 27 publications

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“…INSL3 specifically binds LRG8s in the gubernaculum (18) and, together with androgen, induces scrotal descent of the testis (18,19). Thus, interference with the development of FLCs may be a precipitating cause of cryptorchidism (20). Indeed, the incidence of cryptorchidism is significantly increased during the neonatal period after exposures to high doses of phthalates (20).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, interference with the development of FLCs may be a precipitating cause of cryptorchidism (20). Indeed, the incidence of cryptorchidism is significantly increased during the neonatal period after exposures to high doses of phthalates (20). Exposure to doses of phthalates at 250 mg/kg per day or higher also have been reported to be associated with increased frequencies of underdeveloped epididymides, testicular atrophy, hypospadias, and ectopic or absent testes (21).…”

Section: Resultsmentioning

confidence: 99%

“…In our study, a dose as low as 10 mg/kg per day for 20 days (GD2-GD20) elicited Leydig cell aggregation. The physiological consequences of FLC aggregation per se are uncertain, although there is evidence that it is associated with reduced fertility (27) and increased incidence of cryptorchidism (20). It seems unlikely that the expanded clusters of FLCs observed with DEHP represent tumors.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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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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“…However, the combined effect of MAA and AR antagonists on gene expression and physiology in vivo may be more complex than suggested by these simplified model system studies because many anti-androgens interact with multiple signaling pathways and can affect reproduction and development by more than one mechanism. For example, linuron not only acts as an AR antagonist, it also reduces fetal testosterone production significantly in male rats (Wilson et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Interactions of methoxyacetic acid with androgen receptor

Bagchi

Hurst

Waxman

2009

Toxicology and Applied Pharmacology

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Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC 50 for androgen responsiveness, partially alleviating the antagonistic effect of the antiandrogens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by ∼90%. De-regulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.

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“…DEP can be leached from the above-mentioned products and find a way to various environmental waters [16,17]. Some phthalates (the so-called endocrine disruptor compounds, EDC) can cause endocrine system disorder, produce carcinogenic effects and afflict the development of reproductive system [18,19]. Therefore, the studies on the adsorbing DEP in water have important significance.…”

Section: E-mail Address: Caiyaqi@rceesaccn (Y Cai)mentioning

confidence: 99%

Adsorption of di-ethyl-phthalate from aqueous solutions with surfactant-coated nano/microsized alumina

Shi

Cai

et al. 2008

Chemical Engineering Journal

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Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis

Cited by 256 publications

References 27 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

Interactions of methoxyacetic acid with androgen receptor

Adsorption of di-ethyl-phthalate from aqueous solutions with surfactant-coated nano/microsized alumina

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