Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis

Borch, Julie; Metzdorff, Stine Broeng; Vinggaard, Anne Marie; Brokken, Leon J. S.; Dalgaard, Majken

doi:10.1016/j.tox.2006.03.015

Cited by 211 publications

(176 citation statements)

References 34 publications

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“…Although several mammalian studies have also reported elevated plasma androgen concentrations following phthalate exposure at lower doses [30,31], the majority of studies report significant decreases in plasma testosterone concentrations at doses of >500 mg/kg/d [32,33]. It is currently unclear why apparently contradictory effects occur.…”

Section: Plasma Hormone Concentrations Spiggin Concentrations and Rmentioning

confidence: 99%

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

Aoki

Harris

Katsiadaki

et al. 2011

Enviro Toxic and Chemistry

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Abstract-Phthalate ester plasticizers are anti-androgenic in mammals. High doses of certain phthalates consistently interfere with the normal development of male offspring exposed in utero, causing disrupted sperm production, abnormal development of the genitalia, and in some cases, infertility. In the environment, phthalates are considered ubiquitous, and are commonly measured in aquatic ecosystems at low ng to µg per litre concentrations. Given the similarity between mammalian and teleost endocrine systems, phthalate esters may be able to cause anti-androgenic endocrine disruption in fish in the wild. In the present study, adult male three-spined sticklebacks (Gasterosteus aculetaus) (n=8) were exposed to di-n-butyl phthalate (DBP) (0, 15, and 35 µg DBP/L) for 22 d and analyzed for changes in nesting behavior, plasma androgen concentrations, spiggin concentrations, and steroidogenic gene expression. Plasma testosterone concentrations were significantly higher in males from the 35 µg DBP/L group compared to the solvent 2 control, while plasma 11-ketotestosterone concentrations were not significantly affected.Expression of steroid acute regulatory protein and 3β-hydroxysteroid dehydrogenase remained unchanged. Spiggin concentrations were significantly lower in the males exposed to 35 µg DBP/L. Nest-building appeared to be slower in some males exposed to DBP, but this was not statistically significant. These results suggest that DBP has antiandrogenic effects in fish. However, further research is required to firmly establish the consequences of chronic DBP exposure in fish.

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Section: Plasma Hormone Concentrations Spiggin Concentrations and Rmentioning

confidence: 99%

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

Aoki

Harris

Katsiadaki

et al. 2011

Enviro Toxic and Chemistry

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“…Männliche Feten von während der Gestation mit DEHP per Schlundsonde behandelten Ratten wiesen ab etwa 300 mg/kg KG und Tag eine erniedrigte testikuläre Testosteronproduktion auf (Borch et al 2006;Hannas et al 2011). Hingegen trat bei präpubertären Ratten eine erhöhte testikuläre Testosteronproduktion ab 10 mg/kg KG und Tag nach 14-tägiger Exposition vom 35 bis 48.…”

Section: Antiandrogene Wirkungunclassified

“…B. Borch et al 2006;Hannas et al 2011;Johnson et al 2012). Reduzierte mRNA-Expressionen ergaben sich bei Sr-B1 ("scavenger-receptor B1" = HDL ("high density lipid")-Rezeptor), Star ("steroidogenic acute regulatory protein"), Pbr ("peripheral benzodiazepine receptor"), P450scc ("side-chain cleavage"= CYP11A1 = mitochondriale Cholesterinmonooxigenase) (Borch et al 2006;Hannas et al 2011).…”

Section: Antiandrogene Wirkungunclassified

“…Bei den männlichen Feten von Wistar-Ratten, deren Mütter vom 7. bis 21. Gestationstag mit 300 mg DEHP/kg KG und Tag behandelt wurden, trat eine erniedrigte Insl3-Expression auf (Borch et al 2006). Über makroskopische Befunde wird in dieser Arbeit nicht berichtet.…”

Section: öStrogene Wirkungunclassified

“…Stränge mit größerem Durchmesser, die eine große Anzahl von vielkernigen Keimzellen im Zentrum beinhalten, die Folge (Johnson et al 2012). Mit DEHP wurden diese Effekte ab 100 mg/kg KG und Tag bei Wistar-Ratten beobachtet (Borch et al 2006). Effekte auf die Hodenstränge wurden auch bei Mäusen festgestellt, die unempfindlich gegenüber der gestörten Steroidsynthese und Testosteronproduktion durch DEHP sind.…”

Section: Hodensträngeunclassified

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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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Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

Hartwig

Arand²

2017

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

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) [117‐81‐7]. In 2014, the maximum concentration at the work place (MAK value) of DEHP has been set to 2 mgm 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 are 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 body weight and day for mice, the latter corresponding to 29 mg/m 3 after scaling to a concentration at the work place. In contrast to mouse and marmoset the rat is very sensitive to DEHP effects 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 fetotoxicity of 46 mg/kg bw and day for rats, corresponding to 54 mg/m 3 after scaling to a concentration at the work place. The reported effects, small testes, reduced absolute weights of testis and epididymis, are considered by the Commission as not being adverse because they do not show correlating consequences for the next generation or dose‐response relationship and changes in relative organ weights and histopathological correlates are not observed. After in utero exposure, germ cell organization, mRNA expression and protein level of StAR („steroidogenic acute regulatory protein“) in testes are affected at 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 in prenatal developmental studies a NOAEL for fetotoxicity as well as prenatal developmental toxicity of 48 mg/kg bw and day is derived, corresponding to 32 mg/m 3 . 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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Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis

Cited by 211 publications

References 34 publications

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

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

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

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