Leukemia Inhibitory Factor Expression and Regulation within the Testis

Piquet‐Pellorce, Claire; Dorval-Coiffec, Isabelle; Pham, Minh-Duc; Jégou, Bernard

doi:10.1210/endo.141.3.7399

Cited by 55 publications

(28 citation statements)

References 45 publications

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“…One possible explanation is that these cells are initially more diffusely distributed but then form aggregates under the influence of local growth factors. One such growth factor that may be active in this respect is LIF, which is primarily produced by peritubular myoid cells (28). We herein showed that LIF caused dose-dependent increases in the cluster size of FLCs in vitro.…”

Section: Resultsmentioning

confidence: 57%

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: 57%

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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“…LIF is required for long-term self renewal of neural stem cell cultures (21) and for maintenance of primordial germ cells in vitro (22). In the rat testis, LIF is detectable from 13.5 days of gestation onward and is predominantly expressed by peritubular myoid cells surrounding the seminiferous tubules (23). In the first week postnatally, the peritubular cells have a fibroblastic ultrastructure, appearing spindle-shaped by light microscopy (2), and form a two-to three-cell-layer-thick boundary tissue (lamina propria).…”

Section: Discussionmentioning

confidence: 99%

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

Dong

Sottas

et al. 2006

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

240

315

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Leydig cells (LCs) are thought to differentiate from spindle-shaped precursor cells that exhibit some aspects of differentiated function, including 3␤-hydroxysteroid dehydrogenase (3␤HSD) activity. The precursor cells ultimately derive from undifferentiated stem LCs (SLCs), which are postulated to be present in testes before the onset of precursor cell differentiation. We searched for cells in the neonatal rat testis with the abilities to: (i) proliferate and expand indefinitely in vitro (self renew); (ii) differentiate (i.e., 3␤HSD and ultimately synthesize testosterone); and (iii) when transplanted into host rat testes, colonize the interstitium and subsequently differentiate in vivo. At 1 week postpartum, spindle-shaped cells were seen in the testicular interstitium that differed from the precursor cells in that they were 3␤HSD-negative, luteinizing hormone (LH) receptor (LHR)-negative, and platelet-derived growth factor receptor ␣ (PDGFR␣)-positive. These cells were purified from the testes of 1-week-old rats. The cells contained proteins known to be involved in LC development, including GATA4, c-kit receptor, and leukemia inhibitory factor receptor. The putative SLCs expanded over the course of 6 months while remaining undifferentiated. When treated in media that contained thyroid hormone, insulin-like growth factor I, and LH, 40% of the putative SLCs came to express 3␤HSD and to synthesize testosterone. When transplanted into host rat testes from which LCs had been eliminated, the putative SLCs colonized the interstitium and subsequently expressed 3␤HSD, demonstrating their ability to differentiate in vivo. We conclude that these cells are likely to be the sought-after SLCs.c-kit ͉ leukemia inhibitory factor ͉ platelet-derived growth factor receptor ␣ ͉ puberty ͉ steroidogenesis L eydig cells (LCs) are the primary source of testosterone in the male, and their differentiation in the testes during puberty is a signature event in the development of the male body plan. It is hypothesized, but far from proven, that LCs first arise from undifferentiated stem cells [stem LCs (SLCs)] (1-3). It has been suggested that, in rats, the putative SLCs are present in the testis at birth, and that by 11 days postpartum, at least some of their progeny express LC-specific genes and thus become committed to the LC lineage (4, 5).The committed cells subsequently undergo phased transitions through progenitor and immature stages and ultimately to terminally differentiated adult LC stage (6). In particular, progenitor LCs (PLCs) form during days 12-28 postpartum (presumably from SLCs). The PLCs proliferate and also exhibit some aspects of differentiated function, including 3␤-hydroxysteroid dehydrogenase (3␤HSD) activity (7). Luteinizing hormone (LH) receptors (LHRs) first appear as the PLCs differentiate, suggesting that SLCs are likely to be independent of LH control (8). The development of the steroidogenic capacity of PLCs requires stimulation by LH (9). The mitotic activity of PLCs gradually is reduced, and the cells enlarge...

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“…Since the discovery of LIF, the factor has been shown to display a numerous pluripotent actions on various types of cells and tissues including macrophage cell line (Gearing et al, 1987), embryonic stem cells (Smith and Hooper, 1987;Williams et al, 1988;Duval et al, 2000), primordial germ cells (Hara et al, 1998), uterus (Yue et al, 2000), testis (Piquet-Pellorce et al, 2000), neuronal cell (Turnley and Bartlett, 2000), heart (Wang et al, 2001), skeletal muscle cell (White et al, 2001), mast cell (Hiragun et al, 2000;Tanaka et al, 2001), bone cell (Dazai et al, 2000), hypothalamus (Chesnokova and Melmed, 2000), anterior pituitary cell (Schwartz et al, 1999), adrenal gland (Bamberger et al, 2000), adipocyte (Aubert et al, 1999), and skin . Thus, LIF is a pleiotropic cytokine able to act in a variety of cells and tissues in both adult and embryo.…”

Section: Discussionmentioning

confidence: 99%

Role of leukemia inhibitory factor in the regulation of the proliferation and differentiation of neonatal mouse epidermal melanocytes in culture

Hirobe¹

2002

Journal Cellular Physiology

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Mouse epidermal melanoblasts/melanocytes preferentially proliferated from disaggregated epidermal cell suspensions derived from newborn mouse skin in a serum-free melanoblast/melanocyte-proliferation medium supplemented with dibutyryl adenosine 3':5'-cyclic monophosphate (DBcAMP) and/or basic fibroblast growth factor (bFGF). Leukemia inhibitory factor (LIF) supplemented to the medium from initiation of primary culture increased the proliferation of melanoblasts or melanocytes as well as the differentiation of melanocytes. Pure cultured primary melanoblasts or melanocytes were further cultured with the medium supplemented with LIF from 14 days (keratinocyte depletion). LIF stimulated the proliferation of melanoblasts or melanocytes as well as the differentiation of melanocytes in the absence of keratinocytes. Moreover, anti-LIF antibody supplemented to the medium from initiation of primary culture inhibited the proliferation of melanoblasts or melanocytes as well as the differentiation of melanocytes. These results suggest that LIF is one of the keratinocyte-derived factors involved in regulating the proliferation and differentiation of neonatal mouse epidermal melanocytes in culture in cooperation with cAMP elevator and bFGF.

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Leukemia Inhibitory Factor Expression and Regulation within the Testis

Cited by 55 publications

References 45 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

In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development

Role of leukemia inhibitory factor in the regulation of the proliferation and differentiation of neonatal mouse epidermal melanocytes in culture

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