Male rats exposed in utero to di(n-butyl) phthalate: Age-related changes in Leydig cell smooth endoplasmic reticulum and testicular testosterone-biosynthesis enzymes/proteins

Motohashi, Masaya; Wempe, Michael F.; Mutou, Tomoko; Takahashi, Hiroyuki; Kansaku, Norio; Ikegami, Machiko; Inomata, Tomo; Asari, Masao; Wakui, Shin

doi:10.1016/j.reprotox.2015.12.001

Cited by 18 publications

(6 citation statements)

References 43 publications

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“…Experimental studies have shown that DBP is anti-androgenic and a reproductive toxicant, however, most studies have focused on in utero exposure 3,15,16 . There is limited evidence from epidemiologic studies on the association of background DBP exposure with serum reproductive hormones 17–21 .…”

Section: Introductionmentioning

confidence: 99%

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Nassan

Coull

Skakkebæk

et al. 2018

Environmental Research

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Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000× background) altered serum hormones. Methods Men (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3 yrs or H1≥3 yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. Results When B1HB2-arm (26 men, 134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6, −3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3 yrs (25 men, 107 samples) had no changes at crossover or crossback whereas in H1BH2-arm, H1<3 yrs (22 men, 100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2, 22.9), FSH decreased 9.9% (CI: −17.9, −1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. Conclusions High-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

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Section: Introductionmentioning

confidence: 99%

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

Nassan

Coull

Skakkebæk

et al. 2018

Environmental Research

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“…In experimental animal studies, several phthalates including dibutyl-phthalate ( DBP) were anti-androgens and male reproductive toxicants, adversely affecting testicular function 7-11 . The most studied window of exposure is in-utero exposure which led to male reproductive tract malformations in rats 12-14 . Less well-studied are puberty and adulthood exposure.…”

Section: Introductionmentioning

confidence: 99%

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease

Nassan

Coull

Skakkebæk

et al. 2016

Environment International

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Background Phthalates are widely used chemicals with ubiquitous exposure. Dibutyl-phthalate (DBP), a male reproductive toxicant in animals, is understudied in humans. Some mesalamine medications used to treat inflammatory bowel disease (IBD) have DBP in their coating, whereas other mesalamine formulations do not. Objectives Taking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters. Methods 73 men with IBD taking mesalamine participated in a crossover-crossback prospective study. Men taking non-DBP containing mesalamine at baseline i.e., background exposure, crossed-over for four months to high-DBP mesalamine and then crossed-back for four months to their non-DBP mesalamine (B1HB2-arm;Background1-High-Background2) and vice versa for men taking high-DBP mesalamine at baseline (H1BH2-arm;High1-Background-High2). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). Results We estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season and duration on high-DBP mesalamine at baseline. Semen parameters in B1HB2-arm (26 men, 133 samples) decreased after high-DBP mesalamine exposure (crossover versus baseline), especially motility parameters, and continued to decrease further even after crossback to non-DBP mesalamine (crossback versus crossover).The cumulative carryover effect of high-DBP (crossback versus baseline) was a decrease of % total sperm motility by 7.61(CI:-13.1, -2.15), % progressive sperm motility by 4.23(CI:-8.05, -0.4) and motile sperm count by 26.0% (CI:-46.2%, 1.7%). However, H1BH2-arm (47 men, 199 samples) had no significant change during crossover or crossback. Conclusions Men newly exposed to high-DBP mesalamine for four months had a cumulative reduction in several semen parameters, primarily sperm motility, that was more pronounced and statistically significant even after exposure ended for four months.

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“…The testicular T levels via the DBP treatment group were significantly lower ( p < .05) than the control group at all 4 time points (i.e., weeks 7, 9, 14, and 17; Figure 1I). We previously demonstrated that in utero DBP exposure decreased T levels by causing dysfunction of Leydig cells (Wakui, Muto, et al 2012; Wakui, Shirai, et al 2013; Shirai et al 2013; Motohashi, Wempe, Mutou, Okayama, et al 2016; Motohashi, Wempe, Mutou, Takahashi, et al 2016). Testicular T is a determinant of spermatogenesis, which binds with the androgen-binding protein of Sertoli cells to produce glycoprotein (β globulin).…”

Section: Discussionmentioning

confidence: 99%

“…Phthalates are widely distributed in the environment and designated as endocrine active substances (Fisher 2004; Wakui, Muto, et al 2012; Wakui, Shirai, et al 2013; Motohashi, Wempe, Mutou, Okayama, et al 2016; Motohashi, Wempe, Mutou, Takahashi, et al 2016), which means that they can interact or interfere with normal hormonal action. Previous epidemiological, animal, and molecular studies have shown that exposure of 3-week-old rats to DBP (500 mg/kg) disrupts spermatogenesis with testicular atrophy (Alam et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…on days 12 through 21 postconception. The phthalate dose was chosen based on several previous studies describing adverse effects on fetal rats at the level of 100 mg/kg/day (Mylchreest et al 1999; Barlow and Foster 2003; Motohashi, Wempe, Mutou, Okayama, et al 2016; Motohashi, Wempe, Mutou, Takahashi, et al 2016). The offspring were sexed at birth, and litters were reduced on day 1 so that each dam was left with 10 offspring (5 males and females per dam).…”

Section: Methodsmentioning

confidence: 99%

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In Utero Exposure to Di(n-butyl)phthalate Induces Morphological and Biochemical Changes in Rats Postpuberty

et al. 2017

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Pregnant Sprague-Dawley rats were orally administered di( n-butyl)phthalate (DBP; 100 mg/kg/day) on gestation days (GD) 12 to 21. We investigated the male offspring and probed morphological alterations in Sertoli cells at 7, 9, 14, and 17 weeks of age. Parameters assessed in this study included offspring number, sex ratios, body weights, testis weights, seminiferous tubule (ST) profile numbers and diameters, number of vimentin-labeled Sertoli cells, and both testosterone and follicle-stimulating hormone (FSH) levels. Testicular weight/body weight ratios and the numbers and diameters of ST in maximum transverse testicular sections were statistically similar at weeks 7 and 9; however, at weeks 14 and 17, they were statistically different and displayed higher BrdU-positive Sertoli cells/Sertoli cell ratios in the DBP treatment group. Noteworthily, the serum FSH levels were higher and testicular testosterone levels were lower in the DBP treatment group. To our knowledge, the present study is the first to report that in utero DBP exposure significantly increased Sertoli cell numbers and their cellular proliferation from postpuberty to adulthood, with a significant decrease in testicular testosterone and an increase in FSH.

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Male rats exposed in utero to di(n-butyl) phthalate: Age-related changes in Leydig cell smooth endoplasmic reticulum and testicular testosterone-biosynthesis enzymes/proteins

Cited by 18 publications

References 43 publications

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease

In Utero Exposure to Di(n-butyl)phthalate Induces Morphological and Biochemical Changes in Rats Postpuberty

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