Atypical Leydig Cell Hyperplasia in Adult Rats with Low T and High LH Induced by Prenatal Di(n-butyl) Phthalate Exposure

Wakui, Shin; Takahashi, Hiroyuki; Mutou, Tomoko; Shirai, Masaru; Jutabha, Promsuk; Anzai, Naohiko; Wempe, Michael F.; Kansaku, Norio; Hano, Hiroshi; Inomata, Tomo; Endou, Hitoshi

doi:10.1177/0192623312457272

Cited by 20 publications

(31 citation statements)

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“…These abnormalities are consistent with inhibiting fetal testosterone production (Scott et al, 2009). Moreover, decreases in testicular or serum testosterone levels in juvenile male rats (≤ postnatal days 35) (Shultz et al, 2001;Mylchreest et al, 2002;Fisher et al, 2003;Fisher, 2004) and in adult male rats Wakui et al, 2013Wakui et al, , 2014Giribabu et al, 2014) were described after in utero DBP exposure. Leydig cells (LC) are the cells that synthesize testosterone.…”

Section: Introductionsupporting

confidence: 59%

“…1C, D). Electron microscopic morphologies of rat LC with in utero DBP exposure have previously been described and therefore an in depth discussion is not presented herein Wakui et al, 2013). However, the LC's are centrally placed with a round to ovoid nucleus containing marginal heterochromatin; many Mts are round to oval shaped, some display lipid droplets with many smooth endoplasmic reticulum (sER), Golgi complex, and matrix granules present (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Dose solutions were prepared fresh every morning and administered at 9:00 am. The regimen was based upon previous studies that demonstrated adverse effects of DBP on fetal male rats at 100 mg/kg/day (Mylchreest et al, 2000;Barlow and Foster, 2003;Shirai et al, 2013;Wakui et al, 2013Wakui et al, , 2014. Offspring were weighed and sexed at birth.…”

Section: Chemicals Animals and Compound Dosingmentioning

confidence: 99%

“…The non-aqueous extract portion was decanted, dried overnight in a fume hood, and reconstituted in assay buffer. The assay limit of detection (LOD) was 40 pg/testis Wakui et al, 2013Wakui et al, , 2014.…”

Section: Testosterone Level Analysismentioning

confidence: 99%

“…Consequently, efforts in our laboratories have been focused on studying phthalate exposure in female rats and subsequent effects to their offspring. We have mainly studied di(n-butyl) phthalate (DBP), the phthalate prepared from butanol Wakui et al, 2013Wakui et al, , 2014. DBP is widely used as a plasticizer and the general population appears to be exposed to it in disproportionately higher amounts compared to other phthalates (Blount et al, 2000;Barlow et al, 2003Barlow et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

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Retraction: In utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats

Motohashi

Wempe

Mutou³

et al. 2016

J. Toxicol. Sci.

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-Female pregnant Sprague-Dawley rats were intragastrically (ig) administered di(n-butyl) phthalate (DBP) at four doses (0, 10, 50 and 100 mg/kg) during gestation days (GD) 12-21 (n = 5 per group). The age-related morphological changes of Leydig cell mitochondrion (LC-Mt) and testosterone biosynthesis enzymes/associated genes/proteins expression levels were investigated. As compared to the control (no DBP), the 10 mg, and 50 mg DBP dose groups, the 100 mg DBP dose group at weeks 5 and 7 showed a significant amount of small LC-Mt. Thereafter, from weeks 9 to 17, the LC-Mt size and quantity in the100 mg DBP dose group increased and became statistically similar to the other dose groups; hence, dose and time-dependent LC-Mt changes were observed. Throughout the study, the 100 mg DBP dose group had significantly lower testosterone levels. In addition, the 100 mg DBP dose group displayed lower StAR (StAR, steroidogenic acute regulatory protein) and P450scc (CYP11a1, cholesterol side-chain cleavage enzyme) levels at weeks 5 and 7, but they became statistically similar to all other dose groups at weeks 9 to 17; in contrast, the SR-B1 (Sarb1, scavenger receptor class B member 1) levels were similar for all DBP dose groups. The rats in utero 100 mg DBP /kg/day (GD 12-21) exposure results from this study indicate a dose-dependent, age-related morphological change in LC-Mt which are linked to reductions in testosterone biosynthesis genes / proteins expression, specifically StAR and P450scc.

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Section: Introductionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Chemicals Animals and Compound Dosingmentioning

confidence: 99%

Section: Testosterone Level Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Retraction: In utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats

Motohashi

Wempe

Mutou³

et al. 2016

J. Toxicol. Sci.

Self Cite

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Di‐n‐butylphthalat [MAK Value Documentation in German language, 2017]

Hartwig

2017

The MAK‐Collection for Occupational Health and Safety

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Di‐n‐butyl phthalate [dibutyl benzene‐1,2‐dicarboxylate] The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the developmental toxicity of di‐n‐butyl phthalate. Available publications are described in detail. In prenatal developmental toxicity studies in rats, the most sensitive endpoint was altered morphometry (size and organization) of the seminiferous cords, the precursor of the seminiferous tubules, at 50 mg/kg body weight and day and above; the NOAEL was 30 mg/kg body weight and day. In rats, teratogenic effects like hypospadia and underdeveloped or absent epididymides were observed at 250 mg/kg KG body weight and day and above; the NOAEL was 100 mg/kg body weight and day. In a two‐generation reproduction toxicity study in rats, a LOAEL of 52 mg/kg body weight and day, the lowest dose, could be derived for foetotoxicity and decreased birth weight in the male animals. In rats, the NOAEL for behavioural toxicity is 291 mg/kg body weight and day in male pups. From a one‐generation reproduction toxicity study in mice, a NOAEL of 1410 mg/kg body weight and day could be derived for foetotoxicity and decreased number of live pups. The NOAEL/LOAEL for developmental toxicity and foetotoxicity can be scaled to concentrations of 32/107 and 84/252 mg/m 3 , respectively, at the workplace. Thus, damage to the embryo or foetus is unlikely when the MAK value of 0.58 mg/m 3 is observed, and the classification in Pregnancy Risk Group C is confirmed.

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Di‐ n ‐butyl phthalate [MAK value documentation, 2017]

Hartwig¹,

Arand²

2019

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‐ n ‐butyl phthalate. Available publications are described in detail. In prenatal developmental toxicity studies in rats, the most sensitive endpoint was altered morphometry (size and organization) of the seminiferous cords, the precursor of the seminiferous tubules, at 50 mg/kg body weight and day and above; the NOAEL was 30 mg/kg body weight and day. In rats, teratogenic effects like hypospadia and underdeveloped or absent epididymides were observed at 250 mg/kg KG body weight and day and above; the NOAEL was 100 mg/kg body weight and day. In a two‐generation reproduction toxicity study in rats, a LOAEL of 80 mg/kg body weight and day, the lowest dose, could be derived for foetotoxicity and decreased live pup weight at birth. In rats, the NOAEL for behavioural toxicity is 291 mg/kg body weight and day in male pups. From a one‐generation reproduction toxicity study in mice, a NOAEL of 420 mg/kg body weight and day could be derived for foetotoxicity and decreased number of live pups. The NOAELs and the LOAEL for developmental toxicity and foetotoxicity can be scaled to concentrations of 32, 107, 84 (LOAEL) and 252 mg/m 3 , respectively, at the workplace. Thus, damage to the embryo or foetus is unlikely when the MAK value of 0.58 mg/m 3 is not exceeded, and the classification in Pregnancy Risk Group C is confirmed.

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Atypical Leydig Cell Hyperplasia in Adult Rats with Low T and High LH Induced by Prenatal Di(n-butyl) Phthalate Exposure

Cited by 20 publications

References 20 publications

Retraction: <i>In utero</i>-exposed di(<i>n</i>-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats

Retraction: <i>In utero</i>-exposed di(<i>n</i>-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats

Di‐n‐butylphthalat [MAK Value Documentation in German language, 2017]

Di‐ n ‐butyl phthalate [MAK value documentation, 2017]

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