<i>In Utero</i>
            Exposure to Di(
            <i>n</i>
            -butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity

Mahood, I Kim; Scott, Hayley M.; Brown, Richard W.; Hallmark, Nina; Walker, Marion; Sharpe, Richard M.

doi:10.1289/ehp.9366

Cited by 130 publications

(96 citation statements)

References 49 publications

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“…Interestingly, we observed that BPAF induced a dose-dependent increase of multinucleated cells. Induction of abnormal testicular germ cells, such as multinucleated germ cells (MNGs), has been reported following gestational exposure to di-(n-butyl) phthalate (DBP) (Fisher et al, 2003;Kleymenova et al, 2005;Mahood et al, 2007;Saffarini et al, 2012). Ferrara and colleagues speculated that germ cells presenting DBP-induced MNGs may develop into carcinoma in situ cells, the known precursors of testicular germ cell tumors in men (Ferrara et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

Liang

Yin

et al. 2016

Toxicol. Sci.

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Bisphenol A (BPA), an endocrine-disrupting compound, was found to be a testicular toxicant in animal models. Bisphenol S (BPS), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) were recently introduced to the market as alternatives to BPA. However, toxicological data of these compounds in the male reproductive system are still limited so far. This study developed and validated an automated multi-parametric high-content analysis (HCA) using the C18-4 spermatogonial cell line as a model. We applied these validated HCA, including nuclear morphology, DNA content, cell cycle progression, DNA synthesis, cytoskeleton integrity, and DNA damage responses, to characterize and compare the testicular toxicities of BPA and 3 selected commercial available BPA analogues, BPS, BPAF, and TBBPA. HCA revealed BPAF and TBBPA exhibited higher spermatogonial toxicities as compared with BPA and BPS, including dose-and time-dependent alterations in nuclear morphology, cell cycle, DNA damage responses, and perturbation of the cytoskeleton. Our results demonstrated that this specific culture model together with HCA can be utilized for quantitative screening and discriminating of chemical-specific testicular toxicity in spermatogonial cells. It also provides a fast and cost-effective approach for the identification of environmental chemicals that could have detrimental effects on reproduction.

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Section: Discussionmentioning

confidence: 99%

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

Liang

Yin

et al. 2016

Toxicol. Sci.

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“…The presence of dysgenetic tubules in testis in exposed groups is a finding that is commonly seen with exposure to certain phthalates including DEHP and DBP (Jarfelt et al 2005, Mahood et al 2007, and these effects are assumed to be related to the phthalate content of the mixture, but are not directly related to the sperm count reduction.…”

Section: Reproductive Aging In Malesmentioning

confidence: 99%

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters

et al. 2014

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This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.

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“…In mammals, including humans, phthalate exposure is associated with endocrine disruption [15][16][17] and metabolic disorders [18,19]. In rodents, in utero exposure to phthalates results in developmental and reproductive defects similar to those termed testicular dysgenesis syndrome in humans [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

Eveillard¹,

Mselli-Lakhal²,

Mogha³

et al. 2009

Biochemical Pharmacology

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To cite this version:Alexandre Eveillard, Laïla Mselli-Lakhal, Ariane Mogha, Frédéric Lasserre, Arnaud Polizzi, et al.. Di-(2-ethylhexyl)-phthalate (DEHP) activates the Constitutive Androstane Receptor (CAR): a novel signalling pathway sensitive to phthalates. Biochemical Pharmacology, Elsevier, 2009, 77 (11) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome.

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In Utero Exposure to Di( n -butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity

Cited by 130 publications

References 49 publications

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

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