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Human `testicular dysgenesis syndrome': a possible model using in-utero exposure of the rat to dibutyl phthalate
"... BACKGROUND: The disorders comprising human `testicular dysgenesis syndrome ' (TDS) may be increasing in incidence. TDS originates in fetal life but the mechanisms are not known, and discerning them requires an animal model. METHODS AND RESULTS: The study investigated whether male rats exposed i ..."
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BACKGROUND: The disorders comprising human `testicular dysgenesis syndrome ' (TDS) may be increasing in incidence. TDS originates in fetal life but the mechanisms are not known, and discerning them requires an animal model. METHODS AND RESULTS: The study investigated whether male rats exposed in utero to dibutyl phthalate [DBP; 500 mg/kg on gestational days (GD) 13±21] would provide a suitable model for human TDS. DBP induced a high rate (>60%) of cryptorchidism (mainly unilateral), hypospadias, infertility and testis abnormalities, similar to those in human TDS. Cell-speci®c immunohistochemistry and confocal microscopy were used to track development of Sertoli [anti-MuÈllerian hormone (AMH), Wilm's tumour (WT-1) protein, p27 kip], Leydig [3b-hydroxysteroid dehydrogenase (3b-HSD)], germ (DAZL protein) and peritubular myoid (smooth muscle actin) cells from fetal life to adulthood. In scrotal and cryptorchid testes of DBP-exposed males, areas of focal dysgenesis were found that contained Sertoli and Leydig cells, and gonocytes and partially formed testicular cords; these dysgenetic areas were associated with Leydig cell hyperplasia at all ages. Suppression (~90%) of testicular testosterone levels on GD 19 in DBP-exposed males, coincident with delayed peritubular myoid cell differentiation, may have contributed to the dysgenesis. Double immunohistochemistry using WT-1 (expressed in all Sertoli cells) and p27 kip (expressed only in mature Sertoli cells) revealed immature Sertoli cells in dysgenetic areas. DBP-exposed animals also exhibited Sertoli cell-only (SCO) tubules, sporadically in scrotal and predominantly in cryptorchid, testes, or foci of SCO within
Androgen-mediated development in male rat offspring exposed to flutamide in utero: Permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues
- Toxicol. Sci
, 2001
"... Male offspring exposed in utero to antiandrogens often display alterations in androgen-dependent developmental markers (e.g., anogenital distance [AGD], nipple retention) together with clearly adverse responses such as genital malformations and reproductive tract lesions. The objectives of this stud ..."
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Cited by 23 (6 self)
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Male offspring exposed in utero to antiandrogens often display alterations in androgen-dependent developmental markers (e.g., anogenital distance [AGD], nipple retention) together with clearly adverse responses such as genital malformations and reproductive tract lesions. The objectives of this study were to determine whether in utero exposure to flutamide results in permanent changes in male AGD and nipple retention, characterize the doseresponse relationship between flutamide-mediated alterations in these landmarks and clearly adverse antiandrogenic effects, and establish the predictive value and relationship between AGD and nipple retention, and other adverse manifestations. Male offspring were exposed in utero to 0, 6.25, 12.5, 25, or 50 mg/kg/day (po) of flutamide from gestation days 12 to 21. Offspring were uniquely identified at birth, and various androgen-mediated end points (AGD, areola/nipple retention, cryptorchidism, reproductive tract
Male Rats Exposed to Linuron in Utero Exhibit Permanent Changes in Anogenital Distance, Nipple Retention, and Epididymal Malformations That Result in Subsequent Testicular Atrophy
"... Prenatal exposure to the herbicide linuron, a weak androgen receptor antagonist, has been shown to perturb androgen-dependent male rat reproductive development as evidenced by slight decreases in anogenital distance (AGD), increased retention of areolae/nipples, and induction of epididymal malformat ..."
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Prenatal exposure to the herbicide linuron, a weak androgen receptor antagonist, has been shown to perturb androgen-dependent male rat reproductive development as evidenced by slight decreases in anogenital distance (AGD), increased retention of areolae/nipples, and induction of epididymal malformations in combination with testicular atrophy in the adult rat over dose levels ranging from 12.5 to 100 mg/kg/day. Studies were undertaken to determine whether linuron-mediated changes in AGD and nipple retention are permanent, whether linuron is a direct testicular toxicant, and if there was an association between areola/ nipple retention and malformations. Pregnant rats were administered corn oil vehicle or linuron by gavage at 0 or 50 mg/kg/day (n � 8 controls, 20 treated) from gestation days 12 to 21. Male offspring were necropsied on postnatal days (PND) 35 and 56. Linuron-exposed male rats exhibited a significant (8%) decrease in
Hypothesis: Does ochratoxin A cause testicular cancer
- Cancer Causes and Control
, 2002
"... Little is known about the etiology of testicular cancer, which is the most common cancer among young men. Epidemiologic data point to a carcinogenic exposure in early life or in utero, but the nature of the exposure is unknown. We hypothesize that the mycotoxin, ochratoxin A, is a cause of testicula ..."
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Little is known about the etiology of testicular cancer, which is the most common cancer among young men. Epidemiologic data point to a carcinogenic exposure in early life or in utero, but the nature of the exposure is unknown. We hypothesize that the mycotoxin, ochratoxin A, is a cause of testicular cancer. Ochratoxin A is a naturally occurring contaminant of cereals, pigmeat, and other foods and is a known genotoxic carcinogen in animals. The major features of the descriptive epidemiology of testicular cancer (a high incidence in northern Europe, increasing incidence over time, and associations with high socioeconomic status, and with poor semen quality) are all associated with exposure to ochratoxin A. Exposure of animals to ochratoxin A via the diet or via in utero transfer induces adducts in testicular DNA. We hypothesize that consumption of foods contaminated with ochratoxin A during pregnancy and/or childhood induces lesions in testicular DNA and that puberty promotes these lesions to testicular cancer. We tested the ochratoxin A hypothesis using ecologic data on the per-capita consumption of cereals, coffee, and pigmeat, the principal dietary sources of ochratoxin A. Incidence rates for testicular cancer in 20 countries were significantly correlated with the per-capita consumption of coffee and pigmeat (r = 0.49 and 0.54, p = 0.03 and 0.01). The ochratoxin A hypothesis offers a coherent explanation for much of the descriptive epidemiology of testicular cancer and suggests new avenues for analytic research.
Review Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis
"... BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the t ..."
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Cited by 8 (2 self)
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BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.
Monograph Use of the Three-Spined Stickleback (Gasterosteus aculeatus) As a Sensitive in Vivo Test for Detection of Environmental Antiandrogens
"... We have previously shown that exposure to exogenous androgens causes female sticklebacks (Gasterosteus aculeatus) to produce the glue protein, spiggin, in their kidneys. This protein can be quantified by an enzyme-linked immunosorbent assay developed and validated at the Centre for Environment, Fish ..."
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Cited by 8 (3 self)
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We have previously shown that exposure to exogenous androgens causes female sticklebacks (Gasterosteus aculeatus) to produce the glue protein, spiggin, in their kidneys. This protein can be quantified by an enzyme-linked immunosorbent assay developed and validated at the Centre for Environment, Fisheries and Aquaculture Science. Here we report the development of an in vivo test for the detection of environmental antiandrogens. The system involves the simultaneous exposure of female sticklebacks to 17α-methyltestosterone (a model androgen) at 500 ng/L and suspected environmental antiandrogens over a period of 21 days. The spiggin content of the kidneys is then measured, and any antiandrogenic activity is evaluated by comparing the spiggin levels of female fish exposed to antiandrogens to those of female fish exposed solely to the model androgen. The assay detects the antiandrogenic activity of flutamide, vinclozolin (both used at 250 µg/L), linuron (at 150 µg/L), and fenitrothion (at 15 and 150 µg/L). These results provide the first evidence of in vivo antiandrogenic activity of both linuron and fenitrothion in teleosts. Although there are other suggested fish species that could be used for this purpose, the stickleback is the only widely available species in which it is now possible to study both estrogenic and antiandrogenic end points in the same individual. Furthermore, the species is endemic and ubiquitous in Europe, and it possesses many ecological traits that make it better suited than other potential species for field research into endocrine disruption. Key words: antiandrogens, endocrine disruption, fenitrothion, flutamide, linuron, spiggin, stickleback, vinclozolin. Environ Health Perspect 114(suppl 1):115–121 (2006). doi:10.1289/ehp.8063 available via
Disposition and biotransformation of the estrogenic isoflavone daidzein in rats
- Toxicol Sci
, 2001
"... Daidzein is an estrogenic isoflavone present in many plants and therefore consumed in relatively high doses by humans. Daidzein has a low affinity for the estrogen receptor (3 orders of magnitude lower than estradiol) and has been demonstrated to have estro-genic effects in rodents after administrat ..."
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Cited by 7 (0 self)
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Daidzein is an estrogenic isoflavone present in many plants and therefore consumed in relatively high doses by humans. Daidzein has a low affinity for the estrogen receptor (3 orders of magnitude lower than estradiol) and has been demonstrated to have estro-genic effects in rodents after administration of high doses. We have studied the disposition and biotransformation of daidzein in rats fed a diet low in isoflavone content. Four male and four female Fischer 344 rats were orally administered 100 mg/kg daidzein; excreted urine and feces were collected for 96 h and unchanged daidzein as well as formed metabolites were quantified by HPLC. In urine of male rats, daidzein, daidzein-glucuronide, and daid-zein-sulfate were excreted; in females, only unchanged daidzein and daidzein-glucuronide were present. Total urinary excretion of daidzein accounted for < 10 % of dose in both males and females. The major pathway of daidzein elimination was excretion of un-
Bisphenol A induces both transient and permanent histofunctional alterations of the hypothalamic–pituitary–gonadal axis in prenatally exposed male rats. Endocrinology 144
, 2003
"... Exposure to bisphenol A (BPA) in utero has been shown to induce alterations in the prostate of 30-d-old Wistar rats. Herein, we examine both the time course of BPA action on the rat prostate and the effects of BPA on themale hypothalamic-pituitary-gonadal axis. This was achieved by exposing rats to ..."
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Exposure to bisphenol A (BPA) in utero has been shown to induce alterations in the prostate of 30-d-old Wistar rats. Herein, we examine both the time course of BPA action on the rat prostate and the effects of BPA on themale hypothalamic-pituitary-gonadal axis. This was achieved by exposing rats to BPA in utero, followed by immunohistochemistry and mor-phometric analysis of prostatic tissue, evaluation of estrogen receptor- (ER) and ER mRNA expression in both the pre-optic area (POA) and medial basal hypothalamus, and deter-mination of PRL, LH, and testosterone serum levels. On d 30 (peripubertal period), the prostatic periductal stroma of BPA-exposed rats demonstrated a significantly larger layer of fi-broblasts than that of controls, whereas on d 120 (adulthood) no significant differences were observed. Moreover, BPA-exposed rats on d 15 exhibited an increase in stromal cellular
Research Impact of PCB and p,p´-DDE Contaminants on Human Sperm Y:X Chromosome Ratio: Studies in Three European Populations and the Inuit Population in Greenland
"... OBJECTIVE: Recent studies indicate that persistent organohalogen pollutants (POPs) may contribute to sex ratio changes in offspring of exposed populations. Our aim in the present study was to investigate whether exposure to 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB-153) and dichlorodiphenyldichloroethe ..."
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OBJECTIVE: Recent studies indicate that persistent organohalogen pollutants (POPs) may contribute to sex ratio changes in offspring of exposed populations. Our aim in the present study was to investigate whether exposure to 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB-153) and dichlorodiphenyldichloroethene (p,p´-DDE) affects sperm Y:X chromosome distribution. SUBJECTS AND METHODS: We obtained semen and blood for analysis of PCB-153 and p,p´-DDE
Research Exposure to a Complex Cocktail of Environmental Endocrine-Disrupting Compounds Disturbs the Kisspeptin/GPR54 System in Ovine Hypothalamus and Pituitary Gland
"... Bac k g r o u n d: Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to “reallife, ..."
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Bac k g r o u n d: Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to “reallife,” environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal. Objectives: We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein–coupled receptor 54) system. Met h o d s: KiSS-1, GPR54, and ERα (estrogen receptor α) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semiquantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LHβ (luteinizing hormone β) and ERα in C and T fetal pituitary glands quantified using duallabeling immunohistochemistry. Re s u l t s: Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin
