Male Reproductive Tract Malformations in Rats Following Gestational and Lactational Exposure to Di(n-butyl) Phthalate: An Antiandrogenic Mechanism?

Mylchreest, Eve; Cattley, Russell C.; Foster, Paul M.D.

doi:10.1006/toxs.1998.2436

Cited by 213 publications

(212 citation statements)

References 25 publications

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“…A significant effect observed in rats after exposure comparable to the higher dose was a reduction of testosterone secretion (Akingbemi et al, 2001; Foster, 2005; Foster, 2006; Lehmann et al, 2004; Mylchreest et al 1998). This was associated with a reduction in the expression of steroidogenic enzymes (Barlow et al, 2003; Chen et al, 2013; Lehmann et al, 2004; Wang et al, 2007).…”

Section: Discussionmentioning

confidence: 98%

“…For example, rats exposed to DBP and DEHP during the prenatal period show developmental abnormalities that are typical of the Testicular Dysgenesis Syndrome: cryptorchidism and alterations of the reproductive tract. These abnormalities have been associated with reductions in testosterone secretion and expression of steroidogenic enzymes (Barlow et al, 2003; Chen et al, 2013; Foster, 2005; Foster, 2006; Lehmann et al, 2004; Mylchreest et al, 1998). The postnatal period of development has been considered to be susceptible as well; prepubertal rats exposed to DEHP exhibit reduced testosterone secretion (Akingbemi et al, 2001), increased testicular apoptosis, and loss of the seminiferous epithelium (Park et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Rodriguez‐Sosa

Bondareva

Tang

et al. 2014

Molecular and Cellular Endocrinology

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Di-n-Butyl (DBP) and Di-(2-EthylHexyl) (DEHP) phthalates can leach from daily-use products resulting in environmental exposure. In male rodents, phthalate exposure results in reproductive effects. To evaluate effects on the immature primate testis, testis fragments from 6-month-old rhesus macaques were grafted subcutaneously to immune-deficient mice, which were exposed to 0, 10, or 500 mg/kg of DBP or DEHP for 14 weeks or 28 weeks (DBP only). DBP exposure reduced the expression of key steroidogenic genes, indicating that Leydig cell function was compromised. Exposure to 500 mg/kg impaired tubule formation and germ cell differentiation and reduced numbers of spermatogonia. Exposure to 10 mg/kg did not affect development, but reduced Sertoli cell number and resulted in increased expression of inhibin B. Exposure to DEHP for 14 week also affected steroidogenic genes expression. Therefore, long-term exposure to phthalate esters affected development and function of the primate testis in a time and dosage dependent manner.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Rodriguez‐Sosa

Bondareva

Tang

et al. 2014

Molecular and Cellular Endocrinology

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“…The effects of DBP on estrous cyclicity have been evaluated previously in large studies focused on evaluating outcomes from maternal exposures. For example, maternal exposure to DBP did not alter estrous cyclicity in the F 1 generation when CD rats were treated with DBP (0, 250, 500, and 750 mg/kg.bw/day) throughout pregnancy and lactation until their offspring were at postnatal day 20 [29]. Another study evaluated the reproductive toxicity of DBP in CD Sprague-Dawley rats treated (0, 80, 385, and 794 mg/kg/day) during a continuous-breeding and crossover mating study and found no effects on estrous cycle length in the dams and no effect on ante-mortem estrous cyclicity in the F 1 generation [30].…”

Section: Discussionmentioning

confidence: 99%

Short term exposure to di-n-butyl phthalate (DBP) disrupts ovarian function in young CD-1 mice

Sen

Liu

Craig

2015

Reproductive Toxicology

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Di-n-butyl phthalate (DBP) is present in many beauty and medical products. Human exposure estimates range from 0.007–0.01 mg/kg/day in the general population and up to 0.233 mg/kg/day in patients taking DBP-coated medications. Levels of phthalates tend to be higher in women, thus, evaluating ovarian effects of DBP exposure is of great importance. Mice were given corn oil (vehicle) or DBP at 0.01, 0.1, and 1000 mg/kg/day (high dose) for 10 days to test whether DBP causes ovarian toxicity. Estrous cyclicity, steroidogenesis, ovarian morphology, and apoptosis and steroidogenesis gene expression were evaluated. DBP exposure decreased serum E2 at all doses, while 0.1DBP increased FSH, decreased antral follicle numbers, and increased mRNA encoding pro-apoptotic genes (Bax, Bad, Bid). Interestingly, mRNAs encoding the steroidogenic enzymes Hsd17b1, Cyp17a1 and Cyp19a1 were increased in all DBP-treated groups. These novel findings show that DBP can disrupt ovarian function in mice at doses relevant to humans.

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“…Nevertheless, liver effects have been used to establish no observed adverse effect levels (NOAELs) for risk assessment. Evidence also exists that some phthalates and their metabolites affect reproduction and development, particularly in male rats (e.g., epididymal malformations or absence of the epididymis, testicular lesions, increased incidence of hypospadias, cryptorchidism, decreased anogenital distance, delayed preputial separation, and retention of thoracic nipples) (Barlow et al 2004; Barlow and Foster 2003; Carruthers and Foster 2005; Corton and Lapinskas 2005; Ema and Miyawaki 2001; Fisher 2004; Foster 2005; Gray et al 2000; Mylchreest et al 1998), apparently by a process involving inhibition of androgen biosynthesis (Parks et al 2000). …”

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confidence: 99%

Integrating Biomonitoring Exposure Data into the Risk Assessment Process: Phthalates [Diethyl Phthalate and Di(2-ethylhexyl) Phthalate] as a Case Study

Calafat

McKee

2006

Environ Health Perspect

176

114

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The probability of nonoccupational exposure to phthalates is high given their use in a vast range of consumables, including personal care products (e.g., perfumes, lotions, cosmetics), paints, industrial plastics, and certain medical devices and pharmaceuticals. Phthalates are of high interest because of their potential for human exposure and because animal toxicity studies suggest that some phthalates affect male reproductive development apparently via inhibition of androgen biosynthesis. In humans, phthalates are rapidly metabolized to their monoesters, which can be further transformed to oxidative products, conjugated, and eliminated. Phthalate metabolites have been used as biomarkers of exposure. Using urinary phthalate metabolite concentrations allows accurate assessments of human exposure because these concentrations represent an integrative measure of exposure to phthalates from multiple sources and routes. However, the health significance of this exposure is unknown. To link biomarker measurements to exposure, internal dose, or health outcome, additional information (e.g., toxicokinetics, inter- and intraindividual differences) is needed. We present a case study using diethyl phthalate and di(2-ethylhexyl) phthalate as examples to illustrate scientific approaches and their limitations, identify data gaps, and outline research needs for using biomonitoring data in the context of human health risk assessment, with an emphasis on exposure and dose. Although the vast and growing literature on phthalates research could not be covered comprehensively in this article, we made every attempt to include the most relevant publications as of the end of 2005.

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Male Reproductive Tract Malformations in Rats Following Gestational and Lactational Exposure to Di(n-butyl) Phthalate: An Antiandrogenic Mechanism?

Cited by 213 publications

References 25 publications

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

Short term exposure to di-n-butyl phthalate (DBP) disrupts ovarian function in young CD-1 mice

Integrating Biomonitoring Exposure Data into the Risk Assessment Process: Phthalates [Diethyl Phthalate and Di(2-ethylhexyl) Phthalate] as a Case Study

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