Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate1

Akingbemi, Benson T.; Youker, Robert T.; Sottas, Chantal M.; Ge, Ren‐Shan; Katz, Emily; Klinefelter, Gary R.; Zirkin, Barry R.; Hardy, Matthew P.

doi:10.1095/biolreprod65.4.1252

Cited by 271 publications

(208 citation statements)

References 31 publications

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“…Testicular steroids were extracted from the testes of control and DEHP-exposed pups (n ϭ 10 control; n ϭ 12 DEHP), as described. T concentrations were measured by a tritium-based RIA validated for use with rat antiserum, as described (8,9).…”

Section: Methodsmentioning

confidence: 99%

“…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). This was in contrast to doses Ͼ750 mg/kg, which significantly reduced serum and testicular T (10).…”

mentioning

confidence: 96%

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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.

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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: Methodsmentioning

confidence: 99%

mentioning

confidence: 96%

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.

Self Cite

145

108

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“…Humans and wildlife populations are continuously exposed to EDCs, which are constantly discharged into the atmosphere and natural aquatic bodies (Kavlock et al, 2002). The PEs' mode of action, is not well understood, and may likely be dependent on developmental timing and dosing regimes (Akingbemi et al, 2001). Studies on rodents have identified Leydig cells as one of the main targets of phthalate-ester induced toxicity (Akingbemi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The effects on steroidogenesis and histopathology of adult male Japanese quails (Coturnix coturnix japonica) testis following pre-pubertal exposure to di(n-butyl) phthalate (DBP)

Bello

Madekurozwa

Groenewald

et al. 2014

Comparative Biochemistry and Physiology Part C: Toxicology &

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Keywords:Di-(n-butyl) phthalate Leydig cell Steroidogenesis Male Japanese quails Endocrine disruptionIn the present study, we have investigated the effects of 30-day dietary (pre-pubertal) exposure to different doses (0 (control), 1, 10, 50, 200 and 400 mg/kg bodyweight/day) of di(n-butyl) phthalate (DBP) on Leydig cells of adult male Japanese quails by quantifying the transcript levels for P450 side-chain cleavage (p450scc), P450c17 (CYP17), and 3β-and 17β-hydroxysteroid dehydrogenase (hsd) using quantitative (real-time) poly-merase chain reaction (qRT-PCR). In addition, the plasma testosterone levels were analysed using radioimmuno-assay (RIA) and testis was examined for evidence of gross pathology and histopathology. Our data showed that pre-pubertal exposure to DBP produced alterations in testicular architecture as evident by poorly developed or misshaped testis, and altered spermatogenesis due to tubular degeneration and atrophy of seminiferous tubules especially in the high DBP dose (200 and 400 mg/ kg) treated groups. In addition, DBP altered several key en-zymes involved in testicular steroidogenesis pathways in an apparent dose-dependent manner. For example, bi-phasic effects of DBP were observed for P450scc and 3β-hsd mRNA, that were generally increasing at low dose 10 mg/kg, and thereafter, an apparent dose-dependent decrease between 50 and 400 mg/kg. The steroidogenic acute regulatory (StAR) protein was at the lowest detectable limits and therefore not quantifiable. These effects did not parallel the non-significant changes observed for plasma testosterone levels. The present data is consis-tent with previous reports showing that DBP modulates Leydig cell steroidogenesis in several species, with a po-tential negative effect on reproduction in those avian species that are vulnerable to endocrine disrupting chemicals.

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“…Hingegen trat bei präpubertären Ratten eine erhöhte testikuläre Testosteronproduktion ab 10 mg/kg KG und Tag nach 14-tägiger Exposition vom 35 bis 48. Postnataltag über das Futter (Akingbemi et al 2001) und ab 5 mg/m 3 nach vier-und achtwöchiger inhalativer Exposition ab dem 28. Postnataltag (Kurahashi et al 2005) auf.…”

Section: Antiandrogene Wirkungunclassified

“…Postnataltag (Kurahashi et al 2005) auf. Die Steroidgenese in den Leydigzellen wird beeinflusst durch die Entwicklungsstufe während der Exposition und dürfte durch die Modulation der Aktivität von an der Steroidgenese beteiligten Enzyme und der Serum-LH (Luteinisierendes Hormon)-Konzentrationen erfolgen (Akingbemi et al 2001). Im Folgenden werden nur Untersuchungen an den Hoden männlicher Feten von während der Gestation behandelten Muttertieren sowie In-vitro-Experimente zur Klärung des Wirkungsmechanismus berücksichtigt.…”

Section: Antiandrogene Wirkungunclassified

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

Hartwig

Arand²

2016

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the developmental toxicity of di(2‐ethylhexyl) phthalate (DEHP). In 2014, the maximum concentration at the workplace (MAK value) of DEHP was set to 2 mg/m 3 for the inhalable fraction. In some studies, a correlation between prenatal DEHP exposure and effects on anogenital distance of male newborns, birth weight and pregnancy duration in humans is found; however, the results are not consistent. Teratogenicity is observed in rats only at maternally toxic doses of 1000 mg/kg bw and day and above, in mice at 91 mg/kg bw and day. NOAELs for teratogenicity are 200 mg/kg bw and day for rats and 44 mg/kg bw and day for mice, the latter corresponding to 29 mg/m 3 after scaling to a concentration at the workplace. In contrast to mouse and marmoset, the rat is very sensitive to the effects of DEHP on the male reproductive organs. From a three‐generation study, the Commission deduces a NOAEL for pre‐ and postnatal developmental toxicity to the male reproductive organs and for foetotoxicity of 46 mg/kg bw and day for rats, corresponding to 54 mg/m 3 after scaling to a concentration at the workplace. The Commission does not consider the reported effects – small testes, reduced absolute weights of testis and epididymis – to be adverse because they do not show correlating consequences for the next generation, there is no dose‐response relationship to changes in relative organ weights and histopathological correlates are not observed. Germ cell organization, mRNA expression and protein level of StAR („steroidogenic acute regulatory protein“) in testes are affected after in utero exposure to 100 mg/kg bw and day and above. These effects resulted in a NOAEL for prenatal developmental effects of the male reproductive organs of 30 mg/kg bw and day for rats, corresponding to 35 mg/m 3 . For mice a NOAEL for foetotoxicity as well as prenatal developmental toxicity of 48 mg/kg bw and day is derived in prenatal developmental studies, corresponding to 32 mg/m 3 . Thus, damage to the embryo or foetus is unlikely when the MAK value is observed and DEHP is classified in Pregnancy Risk Group C.

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Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate1

Cited by 271 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

The effects on steroidogenesis and histopathology of adult male Japanese quails (Coturnix coturnix japonica) testis following pre-pubertal exposure to di(n-butyl) phthalate (DBP)

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

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