Expression of Insulin-Like Factor 3 Protein in the Rat Testis during Fetal and Postnatal Development and in Relation to Cryptorchidism Induced by in Utero Exposure to Di (n-Butyl) Phthalate

McKinnell, Chris; Sharpe, Richard M.; Mahood, Kim; Hallmark, Nina; Scott, Hayley M.; Ivell, Richard; Staub, Christophe; Jégou, Bernard; Haag, Friedrich; Koch-Nolte, Friedrich; Hartung, Stefan

doi:10.1210/en.2005-0676

Cited by 118 publications

(93 citation statements)

References 55 publications

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“…Our finding that PFLCs express Insl3, a factor of importance for the first phase of testicular descent (Ivell et al, 1997) is agreed well with previous studies demonstrating high levels of Insl 3 expression in FLCs (Balvers et al, 1998;McKinnell et al, 2005). We demonstrated that PFLCs lost their capacity to express Insl3 after long-term culturing and that (Bu) 2 cAMP prevented this down-regulation, indicating that Insl3 gene expression in PFLCs might be controlled by cAMP-dependent signaling pathway(s).…”

Section: Effect Of (Bu) 2 Camp and Paracrine Factors On Pflc Prolifersupporting

confidence: 93%

Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

Weisser¹,

Landreh²,

Söder³

et al. 2011

Molecular and Cellular Endocrinology

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Please cite this article as: Weisser, J., Landreh, L., Söder, O., Svechnikov, K., Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Our data indicate that cAMP-activated signaling pathway(s) play an important role in the regulation of PFLCs differentiation and function.

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Section: Effect Of (Bu) 2 Camp and Paracrine Factors On Pflc Prolifersupporting

confidence: 93%

Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

Weisser¹,

Landreh²,

Söder³

et al. 2011

Molecular and Cellular Endocrinology

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“…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. 26). In our study, a dose as low as 10 mg/kg per day for 20 days (GD2-GD20) elicited Leydig cell aggregation.…”

Section: Resultsmentioning

confidence: 99%

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.

144

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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“…Although in utero exposure of rats to DBP dramatically decreases the INSL3 gene expression in FLC, in utero exposure to flutamide has no effect (McKinnell et al 2005). This latter observation suggests that INSL3 expression in FLC is not androgen-regulated.…”

Section: Introductionmentioning

confidence: 89%

“…Homozygous INSL3-deficient mice exhibit bilateral cryptorchidism, reflecting a crucial role for INSL3 during the first, transabdominal phase of testicular descent (Nef andParada 1999, Zimmermann et al 1999). In utero exposure of rats to di(n-butyl) phthalate (DBP) suppresses INSL3 gene expression, leading to cryptorchidism (McKinnell et al 2005). However, the role for INSL3 peptide in the postnatal testis is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Expression of insulin-like peptide 3 in the postnatal rat Leydig cell lineage: timing and effects of triiodothyronine-treatment

Mendis‐Handagama¹,

Ariyaratne²,

Mrkonjich³

et al. 2007

Reproduction

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Fetal (FLC) and adult Leydig cells (ALC) secrete insulin-like peptide 3 (INSL3), which is linked to cryptorchidism in the newborn rat. Its gene regulation appears to be independent of that for most steroidogenic enzymes, and may thus be a marker for other aspects of ALC differentiation. Our study examined the following on INSL3 peptide expression in ALC lineage (i) timing, (ii) which cell stage, and (iii) effects of triiodothyronine (T3). Male Sprague-Dawley (SD) rats of postnatal days (pd) 1, 5, 7-21, 28, 40, 60, and 90 were used for the objectives (i) and (ii). For the objective (iii), control and T3-treated (daily T3 SC, 50 mg/kg bw) SD rats of pd7-16 and 21 were used. INSL3 was immunolocalized in Bouin's-fixed testes. FLC were positive and mesenchymal and Leydig progenitor cells were negative for INSL3 at tested ages. INSL3 in ALC lineage was first detected in newly formed ALC on pd16, although they were present from pd10. The intensity of INSL3 label was greater in ALC of pd40-90. ALC were present in T3-treated testes at pd9, but INSL3 first detected in them was on pd12. While INSL3 in FLC regulates testicular descent, INSL3 in ALC still has no well-defined function. However, its pattern of expression correlates temporally with the development of steroidogenic function and spermatogenesis. Thus, the delay between ALC differentiation and INSL3 expression in them implies that INSL3 in ALC is associated with maturation. The advancement of INSL3 expression in the ALC of T3-treated rats implies that this function is established earlier with T3-treatment.

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Expression of Insulin-Like Factor 3 Protein in the Rat Testis during Fetal and Postnatal Development and in Relation to Cryptorchidism Induced by in Utero Exposure to Di (n-Butyl) Phthalate

Cited by 118 publications

References 55 publications

Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells

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

Expression of insulin-like peptide 3 in the postnatal rat Leydig cell lineage: timing and effects of triiodothyronine-treatment

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