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ABSTRACT: Triphenyltin (TPT) is an organotin compound (OTC) previously widely used as an antifouling agent in paints applied in the marine environment, a fungicide, and as an agricultural pesticide. In female aquatic invertebrates, certain OTCs induce the so-called imposex, an abnormal induction of male sex characteristics. OTC-induced environmental endocrine disruption also occurs in fish and mammals and a number of in vivo and in vitro studies have argued that OTCs may act through inhibition of the aromatase enzyme. In vivo studies supporting the aromatase inhibition hypothesis in mammals are lacking. Recently, the causal relationship between inhibition of aromatase and imposex was questioned, suggesting aromatase independent mechanisms of action for this phenomenon. We conducted a comprehensive investigation to identify the most sensitive window of exposure to TPTCl and to examine the effects of pre- and postnatal exposure on postnatal development in rats. The results on brain and gonadal aromatase activity obtained from offspring of dams exposed to 2 mg TPTCl/kg bw are reported here. Female and male offspring rats were exposed to 2 mg TPTCl/kg bw/d in utero from gestation day 6 through lactation until weaning on PND 21, or from gestation day 6 until termination at adulthood. Male offspring were sacrificed from PND 58 and female offspring at first estrus after PND 58. Pre- and postnatal TPT exposure clearly affected brain and gonadal aromatase activity in a sex-dependent fashion. While brain aromatase activity was significantly increased on PND 21 and at adulthood in female offspring, male offspring exhibited a significant decrease in brain aromatase activity only at adulthood. Ovarian aromatase activity was unaffected at both time points investigated. In contrast, testicular aromatase activity was significantly increased in males on PND 21 and significantly decreased at adulthood independent from the duration of treatment. The results of the present study confirm our previously reported observations regarding sex-dependent differences in sexual development after TPT exposure with the male rat being more susceptible to disturbances through this endocrine active compound than the female. We conclude that TPT administered during the particularly vulnerable period of development can affect aromatase activity in rats.
Toxicology 10/2010; 276(3):198-205. · 3.68 Impact Factor
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ABSTRACT: Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeostasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals indicate a wide variety of effects associated with exposure to these compounds, causing concern regarding potential risk to human health. For example, the spectrum of effects following perinatal exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels observed in human foetal blood have produced effects in animal experiments. Finally, thyroid hormones are essential for normal neurological development and reproductive function. Human body burdens of these chemicals are detected with high prevalence, and concentrations in young children, a group particularly sensitive to exogenous insults, are typically higher, indicating the need to decrease exposure to these compounds.
Philosophical Transactions of The Royal Society B Biological Sciences 08/2009; 364(1526):2079-96. · 6.40 Impact Factor
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ABSTRACT: Consumers are exposed to organotin compounds (OTCs) via contaminated fish and seafood due to the accumulation of these compounds in marine organisms. Certain OTCs are immunotoxic and may also have endocrine disrupting properties resulting in adverse effects on the reproductive tract in mollusks and mammals. Since effects of in utero exposure to endocrine disrupting chemicals on the reproductive system are dependent on the critical window of exposure during its development, we conducted a comprehensive study with the aim to identify the most sensitive window of exposure to TPTCl and to investigate the effects of pre- and postnatal treatment on sexual development in rats. Male and female offspring rats were exposed to 2 or 6 mg TPTCl/kg b.w. and day either in utero and during lactation (gestation day 6 until weaning on PND 21) or from gestation day 6 until termination. As previously reported, offspring in the 6 mg TPTCl dose group exhibited high perinatal mortality and therefore no further evaluation was carried out at this dose level (Grote, K., Hobler, C, Andrade, A.J.M., Wichert Grande, S., Gericke, C., Talsness, C.E., Appel, K.E., Chahoud, I., 2007. Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring. Toxicology 238, 177-185). In the present paper, results on postnatal development obtained from surviving offspring of dams exposed to 2mg TPTCl/kg b.w. are reported. Male offspring were sacrificed on PND 64 or 65 and female offspring at first estrus after PND 58. A clear sex difference in response to treatment was observed. Male postnatal development was severely affected with decreases in body weight gain, reproductive organ weights and testosterone concentration as well as a significant delay in the age at preputial separation. In contrast, females exhibited a precocious completion of vaginal opening while all other endpoints were unaffected. Most of these effects were already present in animals that were only exposed until weaning indicating that these effects may be irreversible and continued treatment until termination had contributed less than expected to the severity of the observed effects. The results of the present study suggest that the sensitive window for the evaluated endpoints seems to be the period of prenatal development and that male offspring rats were more susceptible to treatment.
Toxicology 07/2009; 260(1-3):53-9. · 3.68 Impact Factor
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John Peterson Myers,
Frederick S vom Saal,
Benson T Akingbemi,
Koji Arizono,
Scott Belcher,
Theo Colborn,
Ibrahim Chahoud,
D Andrew Crain,
Francesca Farabollini,
Louis J Guillette, [......],
Carlos Sonnenschein,
Ana M Soto, Chris E Talsness,
Julia A Taylor,
Laura N Vandenberg,
John G Vandenbergh,
Sarah Vogel,
Cheryl S Watson,
Wade V Welshons,
R Thomas Zoeller
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ABSTRACT: In their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special prominence to two industry-funded studies that adhered to standards defined by Good Laboratory Practices (GLP). These same agencies have given much less weight in risk assessments to a large number of independently replicated non-GLP studies conducted with government funding by the leading experts in various fields of science from around the world.
We reviewed differences between industry-funded GLP studies of BPA conducted by commercial laboratories for regulatory purposes and non-GLP studies conducted in academic and government laboratories to identify hazards and molecular mechanisms mediating adverse effects. We examined the methods and results in the GLP studies that were pivotal in the draft decision of the U.S. FDA declaring BPA safe in relation to findings from studies that were competitive for U.S. National Institutes of Health (NIH) funding, peer-reviewed for publication in leading journals, subject to independent replication, but rejected by the U.S. FDA for regulatory purposes.
Although the U.S. FDA and EFSA have deemed two industry-funded GLP studies of BPA to be superior to hundreds of studies funded by the U.S. NIH and NIH counterparts in other countries, the GLP studies on which the agencies based their decisions have serious conceptual and methodologic flaws. In addition, the U.S. FDA and EFSA have mistakenly assumed that GLP yields valid and reliable scientific findings (i.e., "good science"). Their rationale for favoring GLP studies over hundreds of publically funded studies ignores the central factor in determining the reliability and validity of scientific findings, namely, independent replication, and use of the most appropriate and sensitive state-of-the-art assays, neither of which is an expectation of industry-funded GLP research.
Public health decisions should be based on studies using appropriate protocols with appropriate controls and the most sensitive assays, not GLP. Relevant NIH-funded research using state-of-the-art techniques should play a prominent role in safety evaluations of chemicals.
Environmental Health Perspectives 04/2009; 117(3):309-15. · 7.04 Impact Factor
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ABSTRACT: N-methyl-2-pyrrolidone (NMP), which undergoes extensive biotransformation, has been shown in vivo to cause developmental toxicity and, especially after oral treatment, malformations in rats and rabbits. Data are lacking as to whether the original compound or one of its main metabolites is responsible for the toxic effects observed. Therefore, the relative embryotoxicity of the parent compound and its metabolites was evaluated using rat whole embryo culture (WEC) and the balb/c 3T3 cytotoxicity test. The resulting data were evaluated using two strategies; namely, one based on using all endpoints determined in the WEC and the other including endpoints from both the WEC and the cytotoxicity test. On basis of the first analysis, the substance with the highest embryotoxic potential is NMP, followed by 5-hydroxy-N-methyl-pyrrolidone (5-HNMP), 2-hydroxy-N-methylsuccinimide (2-HMSI) and N-methylsuccinimide (MSI). Specific dysmorphogeneses induced by NMP and 5-HNMP were aberrations in the head region of the embryos, abnormal development of the second visceral arches and open neural pores. The second evaluation strategy used only two endpoints of the WEC, i.e. the no observed adverse effect concentration (NOAEC(WEC)) and the lowest concentration leading to dysmorphogenesis in 100% of the cultured embryos (IC(Max WEC)). In addition to these WEC endpoints the IC(50 3T3) from the cytotoxicity test (balb/c 3T3 fibroblasts) was included in the evaluation scheme. These three endpoints were applied to a prediction model developed during a validation study of the European Centre for the Validation of Alternative Methods (ECVAM) allowing the classification of the embryotoxic potential of each compound into three classes (non-, weakly- and strongly embryotoxic). Consistent results from both evaluation strategies were observed, whereby NMP and its metabolites revealed a direct embryotoxic potential. Hereby, only NMP and 5-HNMP induced specific embryotoxic effects and were classified as weakly embryotoxic, whereas the other two metabolites, 2-HMSI and MSI, were determined to be non-embryotoxic.
Toxicology and Applied Pharmacology 04/2009; 237(2):154-67. · 4.45 Impact Factor
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Chris E Talsness
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ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental contaminants due to their long half-life and widespread use as flame retardants in several consumer products, including plastics. In addition to other actions, these compounds are characterized as thyroid hormone disruptors. Thyroid hormones affect the function of nearly all tissues via their effects on cellular metabolism and the essential roles they play in differentiation and growth. Interference with thyroid hormone homeostasis by these environmental compounds, therefore, has the potential to impact development and every system in the body. Their presence in human breast milk is particularly troubling due to exposure of nursing children. The last trimester of pregnancy up to 2 years of age corresponds to a time of rapid neurodevelopment and represents a period of vulnerability to environmental insults. Rodent studies indicate that PBDEs may act as developmental neurotoxicants and effects on the reproductive system have been reported as well. Concerns exist regarding possible impacts of exposure, in particular ones which occur during development, on human health. This paper is part of a series of articles regarding contaminants in plastic and provides an overview regarding PBDEs, a class of flame-retardant additives to plastic. PBDEs possess a similar structure to the polychlorinated biphenyls (PCBs) previously used as lubricants in electrical generators and transformers until production was prohibited approximately 25 years ago. Parallels between the two compounds will be briefly made and in particular, as more epidemiological studies on PCBs are available than on PBDEs, a few examples concerning thyroid homeostasis, cognitive function and sexually dimorphic behavior in humans will be mentioned.
Environmental Research 11/2008; 108(2):158-67. · 3.40 Impact Factor
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ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are capable of disrupting thyroid hormone homeostasis. PBDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is one of the most abundant congeners found in human breast adipose tissue and maternal milk samples.
We evaluated the effects of developmental exposure to low doses of PBDE-47 on the female reproductive system.
Pregnant Wistar rats were administered vehicle (peanut oil) or PBDE-47 [140 or 700 microg/kg body weight (bw)] on gestation day (GD) 6, or 5 mg 6-n-propyl-2-thiouracil (PTU)/L in the drinking water from GD7 through postnatal day (PND) 21.
In female offspring sacrificed on PND38, there was a significant decrease in ovarian weight after exposure to PTU or 140 microg/kg PBDE-47. Alterations in folliculogenesis were apparent: we observed a decrease in tertiary follicles and serum estradiol concentrations in the offspring exposed to either PTU or 700 microg/kg PBDE-47. PTU exposure also resulted in a decrease in primordial follicles. On PND100, persistent effects on the thyroid glands included histologic and morphometric changes after exposure to either PTU or PBDE-47. No relevant changes in reproductive indices were observed after mating the exposed F1 females with nontreated males.
Administration of PBDE-47 at doses relevant to human exposure led to changes in the rat female reproductive system and thyroid gland.
Environmental Health Perspectives 04/2008; 116(3):308-14. · 7.04 Impact Factor
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ABSTRACT: Thyroid hormone concentrations, hepatic enzyme activities and tissue concentrations of 2,2',4,4',5-pentabromodiphenyl ether (PBDE-99) were evaluated in Wistar rats (dams and offspring) after treatment by gavage on gestation day (GD) 6 with a single low dose of either 60 or 300 microg PBDE-99/kg body weight (bw), respectively. Tissue concentration analysis confirmed that PBDE-99 is persistent in rodents as significant amounts of the parent compound were detected in adipose tissue 37 days after exposure. The dose of 300 microg PBDE-99/kg bw reduced thyroxin (T4) concentration in dams at the beginning of lactation (post-gestational day [PGD] 1), and caused a slight reduction in T4 on PGD 22, although not statistically significant. In offspring, reduced T4 was observed only at PND 22, probably due to cumulative effects of PBDE-99 during lactation. PBDEs have been shown to reduce T4 concentrations in several studies, but this is the first study demonstrating endocrine disruption at low doses. The adipose tissue concentration of PBDE-99 measured in this study was close to those reported for PBDE-99 in non-occupationally exposed humans. In addition, we have previously reported permanent changes in the reproductive systems and locomotor activity of male and female offspring using these same dosages.
Toxicology 01/2008; 242(1-3):80-90. · 3.68 Impact Factor
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ABSTRACT: The organotin compound (OTC) triphenyltin (TPT) is used extensively as a herbicide, pesticide and fungicide in agriculture as well as, together with tributyltin (TBT), in marine antifouling paints. We studied the effects of in utero exposure to 2 or 6 mg triphenyltinchloride (TPTCl)/kgb.w. on pregnancy outcome and postnatal development in rat offspring. Gravid Wistar rats were treated per gavage from gestational day 6 until the end of lactation. In the 6 mg TPTCl dose group gestational mortality in dams as well as an increased incidence of anticipated and delayed parturition was observed. Furthermore, treatment resulted in a significant increase in perinatal mortality, a decrease in lactational body weight gain as well as in delayed physical maturation of offspring. Similarily, exposure to 2mg TPTCl/kgb.w. resulted in a significant increase in perinatal mortality and in delayed eye opening. Lactational body weight gain and other landmarks of physical maturation were unaffected in the low dose group. We conclude, that in utero exposure to TPTCl at the described dose levels severely affected pregnancy outcome and perinatal survival of offspring. These results were unexpected, as in two earlier studies with pubertal rats TPTCl at the same dose levels no signs of general toxicity were observed.
Toxicology 10/2007; 238(2-3):177-85. · 3.68 Impact Factor
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ABSTRACT: Di(2-ethylhexyl) phthalate (DEHP) is used in numerous consumer products, mainly imparting flexibility and durability to polyvinyl chloride (PVC) based plastics. It is a known reproductive and developmental toxicant in male rodents. However, data regarding effects of DEHP on female reproductive health are particularly sparse. We performed an extensive dose-response study following developmental exposure to DEHP and evaluated the effects on adult female reproductive function. Two wide ranges of doses, low and high, were tested. Female Wistar rats were treated daily with DEHP and peanut oil (vehicle control) by gavage from gestation day 6 to lactation day 21. The low doses were: 0.015, 0.045, 0.135, 0.405 and 1.215mgDEHP/kg/bw/day and the high doses were: 5, 15, 45, 135 and 405mg DEHP/kg/bw/day. At the doses tested, no effects on organ (liver, kidney, spleen, thymus, thyroid, ovary and uterus) or body weights were detected. Female offspring presented a normal pattern of estrous cyclicity with no hormonal alterations (serum estradiol and progesterone). A statistically significant increase in tertiary atretic follicles was observed at the highest dose (405mgDEHP/kg/day). Morphometric analysis indicated that uterus and vagina luminal epithelial cell height were unaffected by treatment. An increase in the number of ovarian atretic tertiary follicles was the only effect observed in adult female offspring exposed in utero and during lactation to DEHP.
Toxicology 02/2007; 229(1-2):114-22. · 3.68 Impact Factor
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ABSTRACT: The reproductive effects of in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP) in adult male offspring rats were investigated. The selected endpoints included reproductive organ weights, testicular function, hormonal status, sexual behaviour and fertility. Two wide ranges of doses, low and high, were tested. Female Wistar rats were treated daily with DEHP and peanut oil (vehicle control) by gavage from gestation day 6 to lactation day 21. The low-doses were 0.015, 0.045, 0.135, 0.405 and 1.215 mg DEHP/kg body weight (bw)/day, and the high-doses were 5, 15, 45, 135 and 405 mg DEHP/kg bw/day. A reduction in daily sperm production of 19-25% in relation to control was observed in animals exposed to 15, 45, 135 and 405 mg/kg/day. Quantitation of specific cell types shows that the observed effects in daily sperm production are not related to changes in the number of Sertoli cells or their capability to support early stages spermatocytes. A low incidence of cryptorchidism was observed in DEHP exposed groups with a lowest observed adverse effect level of 5mg/kg/day. Serum testosterone concentration was similar to control at most doses but was significantly increased at 0.045, 0.405 and 405 mg DEHP/kg/day. In spite of this effect, the weight of seminal vesicle with coagulating glands was significantly reduced at 405 mg/kg/day. Testis, epididymis and prostate weights were similar among groups. Fertility and sexual behaviour were not affected by DEHP treatment at any dose. Overall, our results show that in utero and lactational DEHP exposure reduces daily sperm production and has the potential to induce reproductive tract abnormalities (of which cryptorchidism seems to be the most sensitive in our rat strain) in male offspring rats. The lowest observed adverse effect levels (LOAELs) for these effects were 15 and 5 mg/kg/day, respectively. Therefore, the no observed adverse effect level (NOAEL) for this study can be set at 1.215 mg/kg/day.
Toxicology 12/2006; 228(1):85-97. · 3.68 Impact Factor
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ABSTRACT: Di-(2-ethylhexyl)-phthalate (DEHP) is a commonly used plasticizer which can act as an endocrine disruptor. It has been suggested that in addition to its antiandrogenic effects, DEHP may interfere with estrogen metabolism through suppression of aromatase enzyme activity. This enzyme catalyzes the conversion of testosterone to estradiol and plays a critical role in brain sexual differentiation. We investigated the effects of two wide ranges of DEHP doses on brain aromatase activity of male and female rat offspring. Wistar rat dams were treated daily with DEHP and peanut oil (control) by gavage from gestation day 6 to lactation day 21 at doses of 0.015, 0.045, 0.135, 0.405 and 1.215mgDEHP/kgbodyweight(bw)/day (low doses) and at 5, 15, 45, 135 and 405mgDEHP/kgbw/day (high doses). Aromatase activity was determined in hypothalamic/preoptic area (HPOA) brain sections from male and female pups on postnatal days (PNDs) 1 and 22. In males on PND 1, aromatase activity was inhibited at low doses and increased at high doses resulting in a non-monotonic dose-response profile which resembled a J-shaped curve. Inhibition was statistically significant at 0.135 and 0.405mgDEHP/kg/day, while increased activity was observed at 15, 45 and 405mg/kg/day. In contrast to findings on PND 1, aromatase activity at weaning (PND 22) was more affected in females than in males. An increase in aromatase activity was observed at only one dose in males (0.405mg/kg/day) while an increase in activity was observed at all doses in the females except for 0.045 and 5mgDEHP/kg/day. Overall, these results indicate that males and females respond differently to DEHP not only in regard to the age at which effects are manifested, but also in the shape of the dose-response curve. To our knowledge, this is the first study to report biological effects of DEHP at doses that overlap with the estimated exposure of the general human population.
Toxicology 11/2006; 227(3):185-92. · 3.68 Impact Factor
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ABSTRACT: An extensive dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP) was conducted. A wide range of low and high DEHP doses were tested. Reproductive effects were evaluated on male offspring rats. Female Wistar rats were treated daily with DEHP and peanut oil by gavage from gestation day 6 to lactation day 21 at doses of 0.015, 0.045, 0.135, 0.405 and 1.215 mg DEHP/kg body weight (bw)/day (low doses) and at 5, 15, 45, 135 and 405 mg DEHP/kg bw/day (high doses). Nipple retention and reduced anogenital distance, both sensitive markers of anti-androgenic effects during development, were only seen in males exposed to the highest dose (405 mg/kg/day). Delayed preputial separation was observed in animals exposed to 15 mg DEHP/kg/day and higher doses. Histopathological examination of the testis on postnatal days (PNDs) 1 and 22 revealed changes at 135 and 405 mg DEHP/kg/day. The most prominent finding on PND 1 was the presence of bi- and multinucleated gonocytes. On PND 22 signs of reduced germ cell differentiation in seminiferous tubules of exposed animals were observed. Testis weight on PND 22 was significantly increased at 5, 15, 45 and 135 mg/kg/day, an effect that qualitatively differs from exposure to higher doses. The current results show that DEHP acts as an anti-androgen at a high dose exposure (405 mg/kg/day). However, these results also indicate that other subtle developmental effects occur at lower DEHP doses.
Toxicology 09/2006; 225(1):64-74. · 3.68 Impact Factor
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ABSTRACT: Triphenyltin (TPT) belongs to the group of organotin compounds which have been shown to affect reproduction in mammals. It is used as a fungicide and antifouling agent and the main source of human exposure is via food. We studied the effects of 2 or 6 mg TPT/kg bw on female sexual development using a modification of the Rodent 20-Day Thyroid/Pubertal Female Assay. Moreover, the effect of TPT before the onset of puberty was investigated. Beginning at postnatal day (PND) 23 female Wistar rats were treated per gavage until either PND 33 or the first estrus after PND 53. A delay in the completion of vaginal opening (VO) was observed in the 6 mg TPT group, while the 2mg TPT group showed advanced VO. Significantly increased ovarian weights were observed in both treatment groups. Steroid hormone levels and ovarian aromatase activity were affected after exposure to 6 mg TPT/kg bw, while treatment with 2mg TPT/kg bw resulted in minor changes of these endpoints. We conclude that peripubertal exposure to 6 mg TPT/kg bw, and to a lesser extent to 2mg TPT/kg bw, affects female sexual development.
Toxicology 06/2006; 222(1-2):17-24. · 3.68 Impact Factor
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ABSTRACT: Phthalates, a class of chemicals used as plasticizers, are economically important due to several industrial applications. Di(2-ethylhexyl)phthalate (DEHP) is the most commonly used phthalate plasticizer, and it has been described as a potent antiandrogen in males. We performed an extensive dose-response study following developmental exposure to DEHP and evaluated the effects on female reproductive development. Two wide ranges of doses that included dose levels relevant for human exposure as well as high doses typically used in toxicological studies were tested. Female Wistar rats were treated daily with DEHP and peanut oil (vehicle control) by gavage from gestation day 6 to lactation day 22. The low doses were 0.015, 0.045, 0.135, 0.405, and 1.215 mg DEHP/kg body weight (bw)/day, and the high doses were 5, 15, 45, 135, and 405 mg DEHP/kg bw/day. At the dose levels tested, no signs of maternal toxicity were observed. A significant delay in the age at vaginal opening (approximately 2 days) at 15 mg DEHP/kg bw/day and above, as well as a trend for a delay in the age at first estrus at 135 and 405 mg DEHP/kg bw/day (approximately 2 days), was observed. Liver enlargement (characteristic of phthalate exposure in rats) was limited to the 135- and 405-mg DEHP/kg bw/day doses. Anogenital distance and nipple development were unaffected. Based on the results of delayed pubertal onset, the no observed adverse effect level for female reproductive development may be set at 5 mg DEHP/kg bw/day.
Toxicological Sciences 06/2006; 91(1):247-54. · 4.65 Impact Factor
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ABSTRACT: Increasing concentrations of polybrominated flame retardants, including polybrominated diphenyl ethers (PBDEs), in breast milk cause concern about possible developmental effects in nursed babies. Because previous studies in rats have indicated effects on sex steroids and sexually dimorphic behavior after maternal exposure to polychlorinated biphenyls (PCBs), our goal in the present study was to determine if developmental exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) induces similar endocrine-mediated effects. Pregnant rats were exposed to vehicle or PBDE-99 (1 or 10 mg/kg body weight, daily during gestational days 10-18). For comparison, we also included a group exposed to the technical PCB mixture Aroclor 1254 (30 mg/kg body weight, daily). PBDE exposure resulted in pronounced decreases in circulating sex steroids in male offspring at weaning and in adulthood. Female offspring were less affected. Anogenital distance was reduced in male offspring. Puberty onset was delayed in female offspring at the higher dose level, whereas a slight acceleration was detected in low-dose males. The number of primordial/primary ovarian follicles was reduced in females at the lower dose, whereas decline of secondary follicles was more pronounced at the higher dose. Sweet preference was dose-dependently increased in PBDE-exposed adult males, indicating a feminization of this sexually dimorphic behavior. Aroclor 1254 did not alter sweet preference and numbers of primordial/primary and secondary follicles but it did affect steroid concentrations in males and sexual development in both sexes. PBDE concentrations in tissues of dams and offspring were highest on gestational day 19. These results support the hypothesis that PBDEs are endocrine-active compounds and interfere with sexual development and sexually dimorphic behavior.
Environmental Health Perspectives 03/2006; 114(2):194-201. · 7.04 Impact Factor
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Critical Reviews in Toxicology 08/2005; 35(6):599-601. · 5.16 Impact Factor
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ABSTRACT: Polybrominated diphenyl ethers (PBDEs), used as flame retardants in textiles, plastics and electrical appliances, have been shown to interfere with thyroid homeostasis. We evaluated the effects of environmentally relevant concentrations (low doses) of 2,2',4, 4',5-pentabromodiphenyl ether (PBDE-99) on the female reproductive system. A single dose of either 60 microg or 300 microg PBDE-99/kg body weight (BW) was administered on gestation day 6 to gravid Wistar rats. A reference control was treated with 6-n-propyl-2-thiouracil (PTU) on gestation days 7-21. Ultrastructural changes compatible with altered mitochondrial morphology were observed in the ovaries of the F1 offspring. No statistically significant changes in ovarian follicle counts were observed. Mating of the F1 females with untreated males revealed resorption rates in the PBDE groups greater than the limits considered normal for our controls. External and skeletal anomalies were detected in offspring (F2) from two different dams (F1) with early developmental exposure to 300 microg PBDE-99/kg BW. Exposure to PBDE-99 resulted in female reproductive tract changes in the F1 generation which were apparent at adulthood.
Toxicology Letters 08/2005; 157(3):189-202. · 3.23 Impact Factor
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ABSTRACT: In utero exposure to a single low dose of 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) disrupts neurobehavioral development and causes permanent effects on the rat male reproductive system apparent in adulthood. PBDEs, a class of flame retardants, are widely used in every sector of modern life to prevent fire. They are persistent in the environment, and increasing levels of PBDEs have been found in biota and human breast milk. In the present study we assessed the effects of developmental exposure to one of the most persistent PBDE congeners (PBDE-99) on juvenile basal motor activity levels and adult male reproductive health. Wistar rat dams were treated by gavage on gestation day 6 with a single low dose of 60 or 300 microg PBDE-99/kg body weight (bw). In offspring, basal locomotor activity was evaluated on postnatal days 36 and 71, and reproductive performance was assessed in males at adulthood. The exposure to low-dose PBDE-99 during development caused hyperactivity in the offspring at both time points and permanently impaired spermatogenesis by the means of reduced sperm and spermatid counts. The doses used in this study (60 and 300 microg/kg bw) are relevant to human exposure levels, being approximately 6 and 29 times, respectively, higher than the highest level reported in human breast adipose tissue. This is the lowest dose of PBDE reported to date to have an in vivo toxic effect in rodents and supports the premise that low-dose studies should be encouraged for hazard identification of persistent environmental pollutants.
Environmental Health Perspectives 03/2005; 113(2):149-54. · 7.04 Impact Factor
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ABSTRACT: Tributyltin (TBT) and triphenyltin (TPT) induce effects in male and female reproductive organs of rodents. They also cause tumors in these organs and it is theorized that they result from endocrine disruption. We studied the effects of 40 mg methyltestosterone (MTT), 0.5 or 15 mg TBT and 2, 6 or 12 mg TPT/kg bw on the male sexual development using a modification of the Rodent 20-Day Thyroid/Pubertal Male Assay. Male Wistar rats were treated per gavage for 30 days beginning at 23 days of age. A delay in the completion of preputial separation was observed after administration of MTT and 15 mg/kg TBT. Changes in weights of one or more reproductive organs were observed in all treatment groups. Testosterone concentration was decreased in the MTT, the 15 mg TBT as well as in the 6 and 12 mg TPT groups. A decrease in luteinizing hormone (LH) concentration was observed in the MTT and 15 mg TBT groups while an increase was seen after exposure to 6 mg TPT/kg bw. We conclude that peripubertal exposure to 15 mg TBT and 6 mg TPT/kg bw clearly affected male sexual development.
Toxicology 11/2004; 202(3):145-58. · 3.68 Impact Factor
