The Influence of Phthalate Esters on Leydig Cell Structure and Function in Vitro and in Vivo

Jones, Huw B.; Garside, Deborah A.; Liu, R.; Roberts, Jennifer

doi:10.1006/exmp.1993.1016

Cited by 113 publications

(67 citation statements)

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“…These mirror similar effects seen in rats and mice exposed perinatally to the strong estrogen agonist diethylstilbestrol (DES) (40,41) and are consistent with the possibility that the effects seen in the present study were mediated through an interaction with the estrogen receptor system. Interestingly, there are also reports showing that some phthalates have hormone-disrupting effects in male adult rats (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Reproductive Toxicity of Di-n-Butylphthalate in a Continuous Breeding Protocol in Sprague-Dawley Rats

Wine¹,

Li²,

Barnes³

et al. 1997

Environmental Health Perspectives

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The esters of o-phthalic acid are employed extensively in the manufacture of plastics where they are used to impart flexibility. Since they are not covalently linked to the plastic polymer, they can leach from the matrix, providing opportunity for widespread exposure [see Thomas and Thomas (1) for review]. The phthalate ester di-nbutylphthalate (DBP) is used in the manufacture of consumer products as diverse as nail polish, insect repellents, and denture base material (2-4). DBP has recently been found to have clinical applications as well, selectively eliminating tumor cells from bone marrow (5,6).DBP has been previously characterized as a developmental and reproductive toxicant in the rat (7)(8)(9)(10)(11)(12). Comparable oral doses of DBP given to juvenile and adult male rats produces a testicular lesion characterized by early sloughing of germ cells, vacuolization of the Sertoli cell cytoplasm, and testicular atrophy (7,10). It has also been shown that the testicular toxicity of phthalates is age dependent, with immature animals being more sensitive than mature animals (13,14). However, the reproductive toxicity following exposure during development has not been addressed. Although no data are available specifically on the transfer of DBP across the placenta, studies with other phthalate esters show that these compounds readily cross the placenta of rats (15)(16)(17) (195) under the RACB protocol. This is expected in the RACB design because the Fo rats are exposed only as adults, the F1 rats are born to mothers that are treated during gestation and lactation, and the F1 animals themselves are treated during maturation to sexual maturity and through mating. The results of this DBP RACB study are presented below; the results show that structural defects are seen in the second generation rats that were not found in the first. MethodsGeneral. This study was conducted using the National Toxicology Program's RACB protocol for which the detailed methods have been previously described (20,21). Briefly, the protocol is composed of four segments, or tasks. Task 1 is a 14-day range-finding study that is used to set three dose levels used in Task 2. Task 2 is the 14-week continuous breeding phase, generating up to five litters per pair. Task 3 consists of crossover matings between treated and control Fo animals to determine the affected sex, and Task 4 assesses the fertility of the last litter (F1) born during continuous breeding (Task 2).Chemical. DBP was obtained from Chem Central via Midwest Research Institute (Kansas City, MO, Lot/Batch # L-121 1-83/02). The purity of DBP used in preparation of the feed formulations was greater than 99% as determined by gas chromatography. Dosed feed formulations. DBP was blended into powdered NIH-07 (Zeigler Bros., Gardeners, PA) feed on a weight-to-

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Section: Discussionmentioning

confidence: 99%

Reproductive Toxicity of Di-n-Butylphthalate in a Continuous Breeding Protocol in Sprague-Dawley Rats

Wine¹,

Li²,

Barnes³

et al. 1997

Environmental Health Perspectives

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show abstract

“…Although Sertoli cells were thought to be the primary targets of phthalate exposure [17,18], exposures to DEHP and its metabolite, mono-(2-ethylhexyl) phthalate (MEHP), have been found to result in decreased testicular testosterone levels in mice [19,20], suggesting that Leydig cells also might be targets. Indeed, previous studies showed that MEHP inhibited LH-stimulated testosterone secretion by purified adult rat and MA-10 mouse tumor Leydig cells [21,22].…”

Section: Introductionmentioning

confidence: 99%

In Utero Exposure to Di-(2-ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat1

Culty

Thuillier

et al. 2008

Biology of Reproduction

140

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We examined the effects of fetal exposure to a wide range of di-(2-ethylhexyl) phthalate (DEHP) doses on fetal, neonatal, and adult testosterone production. Pregnant rats were administered DEHP from Gestational Day (GD) 14 to the day of parturition (Postnatal Day 0). Exposure to between 234 and 1250 mg/kg/day of DEHP resulted in increases in the absolute volumes of Leydig cells per adult testis. Despite this, adult serum testosterone levels were reduced significantly compared to those of controls at all DEHP doses. Organ cultures of testes from GD20 rats exposed in utero to DEHP showed dose-dependent reductions in basal testosterone production. Surprisingly, however, no significant effect of DEHP was found on hCG-induced testosterone production by GD20 testes, suggesting that the inhibition of basal steroidogenesis resulted from the alteration of molecular events upstream of the steroidogenic enzymes. Reduced fetal and adult testosterone production in response to in utero DEHP exposure appeared to be unrelated to changes in testosterone metabolism. In view of the DEHP-induced reductions in adult testosterone levels, a decrease in the expression of steroidogenesis-related genes was anticipated. Surprisingly, however, significant increases were seen in the expression of Cyp11a1, Cy17a1, Star, and Tspo transcripts, suggesting that decreased testosterone production after birth could not be explained by decreases in steroidogenic enzymes as seen at GD20. These changes may reflect an increased number of Leydig cells in adult testes exposed in utero to DEHP rather than increased gene expression in individual Leydig cells, but this remains uncertain. Taken together, these results demonstrate that in utero DEHP exposure exerts both short-term and long-lasting effects on testicular steroidogenesis that might involve distinct molecular targets in fetal and adult Leydig cells.

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“…Additionally, in vitro studies using primary Sertoli cell cultures or Sertoli/ gonocyte cocultures showed that acute phthalate monoester exposure could inhibit signaling downstream of the FSH receptor, reduce Sertoli cell proliferation, and induce detachment of gonocytes [29][30][31]. In contrast, direct adverse effects of phthalates on postnatal primary Leydig cell function generally are not reported or occur in vitro only at phthalate concentrations (!1 mM) that may be cytotoxic [32,33], although a recent report showed increased steroidogenesis following in vitro phthalate exposure of postnatal Leydig cells [33]. In the past several years, the possibility that fetal Leydig cells could be directly targeted by phthalates has emerged [14].…”

Section: Mapping Dbp-induced Testis Gene Expressionmentioning

confidence: 99%

Mapping Gene Expression Changes in the Fetal Rat Testis Following Acute Dibutyl Phthalate Exposure Defines a Complex Temporal Cascade of Responding Cell Types1

Johnson

Hensley

Kelso

et al. 2007

Biology of Reproduction

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Phthalates are chemical plasticizers used in a variety of consumer products; in rodents, they alter testicular development, leading to decreased testosterone synthesis and maldevelopment of the reproductive tract. Here, our goals were to discover a set of biomarker genes that respond early after relatively low-dose-level dibutyl phthalate (DBP) exposure and map the responding testicular cell types. To identify testicular phthalate biomarker genes, 34 candidate genes were examined by quantitative PCR at 1, 2, 3, or 6 h after exposure of Gestational Day 19 rats to DBP dose levels ranging from 0.1 to 500 mg/kg body weight. Twelve genes (Ctgf, Cxcl10, Dusp6, Edn1, Egr1, Fos, Ier3, Junb, Nr4a1, Stc1, Thbs1, and Tnfrsf12a) were identified with increased expression by 1-3 h at 100 or 500 mg/kg DBP, and 7 of these 12 genes had increased expression by 6 h at 10 mg/kg DBP. Using in situ hybridization of fetal testis cryosections from DBP-exposed rats, the temporal cellular expression of 10 biomarker genes was determined. Genes with a robust response at 1 h (Dusp6, Egr1, Fos, and Thbs1) were induced in peritubular myoid cells. For Egr1 and Fos, the interstitial compartment also showed increased expression at 1 h. Cxcl10 and Nr4a1 were induced by 1-3 h in both sparsely located interstitial cells and peritubular myoid cells. By 3 h, Stc1 was induced in Leydig cells, and Edn1, Ier3, and Tnfrsf12a were increased in Sertoli cells. These data reveal a complex early cascade of phthalate-induced cellular responses in the fetal testis, and for the first time suggest that peritubular myoid cells are an important proximal phthalate target cell.

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The Influence of Phthalate Esters on Leydig Cell Structure and Function in Vitro and in Vivo

Cited by 113 publications

References 0 publications

Reproductive Toxicity of Di-n-Butylphthalate in a Continuous Breeding Protocol in Sprague-Dawley Rats

Reproductive Toxicity of Di-n-Butylphthalate in a Continuous Breeding Protocol in Sprague-Dawley Rats

In Utero Exposure to Di-(2-ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat1

Mapping Gene Expression Changes in the Fetal Rat Testis Following Acute Dibutyl Phthalate Exposure Defines a Complex Temporal Cascade of Responding Cell Types1

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