RESUMO
Hydroxyurea (HU) is a valuable therapy for individuals with sickle cell anemia. With increased use of HU in children and throughout their lives, it is important to understand the potential effects of HU therapy on their development and fertility. Thus, studies were conducted to identify appropriate doses to examine long-term effects of prenatal and early postnatal HU exposure and to understand kinetics of HU at various life stages. Pregnant Sprague Dawley dams were administered HU (0-150 mg/kg/day) via oral gavage from gestation days 17 to 21 and during lactation. Pups were dosed with the same dose as their respective dam starting on postnatal day (PND) 10 and up to PND 34. There was minimal maternal toxicity, and no significant effects on littering at any dose of HU. Starting on ~PND 16, offspring displayed skin discoloration and alopecia at doses ≥75 mg/kg/day and lower body weight compared to controls at doses ≥100 mg/kg/day. Gestational transfer of HU was observed, but there was minimal evidence of lactational transfer. Our toxicokinetic studies suggest that the internal dose in offspring may be altered due to age, but not due to sex. The plasma area under the curve, a measure of systemic exposure, at doses tolerated by offspring was threefold to sevenfold lower than the internal therapeutic dose in humans. Therefore, strategies to establish clinically relevant exposures in animal studies are needed. Overall, these data are useful for the design of appropriate nonclinical studies in the future to evaluate the consequences of long-term HU treatment starting in childhood.
Assuntos
Antidrepanocíticos/toxicidade , Hidroxiureia/toxicidade , Toxicocinética , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Feminino , Hidroxiureia/farmacologia , Lactação/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacosRESUMO
2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in personal care products and used as an UV stabilizer. In these studies, disposition and metabolism of [14C]HMB in rats and mice was assessed following single gavage administration (10, 100, or 500 mg/kg), single IV administration (10 mg/kg), or dermal application (0.1, 1, 10, or 15 mg/kg).Following gavage administration, [14C]HMB was well absorbed and excreted mainly in urine (39-57%) and feces (24-42%) with no apparent difference between doses, species or sexes. Distribution of HMB in tissues was minimal in rats (0.36%) and mice (<0.55%).Distribution of HMB following dermal application was comparable to that following gavage administration; no differences between doses, sexes, or species were observed but absorption varied between dose vehicles. Light paraffin oil had the highest absorption and excretion (98% of the HMB dose absorbed).In rats, HMB slowly appeared in the systemic circulation (Tmax â¼2-6 h) and had poor bioavailability (F%<1).Urine metabolites for both species and all routes included HMB, HMB-glucuronide, 2,4-dihydroxybenzophenone (DHB), DHB-glucuronide, and DHB-sulfates, and novel minor dihydroxy metabolites including 2,5-dihydroxy-4-methoxybenzophenone.In vitro hepatic metabolism in mice differed from human and in vivo metabolism especially for phase II conjugates.
Assuntos
Benzofenonas/metabolismo , Protetores Solares/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-DawleyRESUMO
We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110â¯mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5â¯mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and 62.5â¯mg/kg/d from GD 8-18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5â¯mg SMV/kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5â¯mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.
Assuntos
Feto/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Sinvastatina/toxicidade , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Feto/metabolismo , Idade Gestacional , Masculino , Técnicas de Cultura de Órgãos , Organogênese/efeitos dos fármacos , Gravidez , Ratos Sprague-Dawley , Medição de Risco , Diferenciação Sexual/efeitos dos fármacos , Desenvolvimento Sexual/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/metabolismoRESUMO
Vinpocetine is being used worldwide by people of all ages, including pregnant women, for its purported multiple health benefits. However, limited data is available addressing the safety/toxicity of vinpocetine. The National Toxicology Program conducted studies to examine potential effects of vinpocetine on the developing rat. Disposition data is helpful to put the fetal findings into context and provide information on the potential risk for humans. The current study reports the systemic exposure and toxicokinetic (TK) parameters of vinpocetine and metabolite, apovincaminic acid (AVA), in pregnant Harlan Sprague Dawley rats, fetuses and amniotic fluid following oral gavage exposure of dams to 5 and 20mg/kg vinpocetine from gestational day 6 to 18. Vinpocetine was absorbed rapidly in dams with a maximum plasma concentration (Cmax) reaching ≤1.37h. Predicted Cmax and area under the concentration versus time curve (AUC) increased less than proportionally to the dose. Vinpocetine was rapidly distributed to the peripheral compartment. More importantly, significant transfer of vinpocetine from dam to fetuses was observed with fetal Cmax and AUC≥55% of dams. Vinpocetine was cleared rapidly from dam plasma with an elimination half-life of ≤4.02h with no apparent dose-related effect. Vinpocetine was rapidly and highly metabolized to AVA with AVA plasma levels in dams ≥2.7-fold higher than vinpocetine, although in the fetuses, AVA levels were much lower than vinpocetine. Comparison of current rat data with literature human data demonstrates that systemic exposure to vinpocetine in rats following repeated exposure to 5mg/kg is similar to that following a single human relevant dose of 10mg suggesting that the findings from the toxicology study may be relevant to humans.
Assuntos
Troca Materno-Fetal , Alcaloides de Vinca/farmacocinética , Líquido Amniótico/metabolismo , Animais , Área Sob a Curva , Feminino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Early deaths of young or juvenile animals (before sexual maturation is achieved) in routine regulatory safety studies present pathologists and toxicologists with the challenge of interpreting findings in the male reproductive tract. Additionally, the advent of toxicity testing regulations has resulted in a growing need for the use of juvenile animals in toxicology studies. Here, we present the reproductive toxicity findings from a 13-week inhalation toxicity study with ortho-phthalaldehyde (OPA) in male rats and mice as a case example for working through this challenging task. In this study with OPA, survival was significantly reduced in the two highest exposure concentrations of OPA tested. Early deaths and histopathological lesions in the testes and epididymides were generally also limited to these two highest exposure groups. Therefore, there was concern that peripubertal morphological features could be a confounding factor for the histopathological evaluation of exposure-related testicular and epididymal findings. Although it can be difficult to differentiate exposure-related effects from the normal morphological features defining peripubertal changes in the testes and epididymides in animals that die early in a toxicity study, the use of age-matched controls in this case study with OPA provided a reference and aided in the differentiation of these effects.
Assuntos
Envelhecimento/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Maturidade Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , o-Ftalaldeído/toxicidade , Envelhecimento/patologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Especificidade da Espécie , Contagem de Espermatozoides , Testículo/crescimento & desenvolvimento , Testículo/patologiaRESUMO
Congenital uterine wall cysts arising from paramesonephric (Müllerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and/or estrogen receptor α (ER-α), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8 and ER-α and/or PR staining. Additionally, 70% of the cysts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct.
Assuntos
Cistos/patologia , Ductos Paramesonéfricos/patologia , Doenças Uterinas/patologia , Animais , Cistos/congênito , Feminino , Ratos , Ratos Sprague-Dawley , Doenças Uterinas/congênito , Ductos Mesonéfricos/patologiaRESUMO
1. 2-Ethylhexyl-p-methoxycinnamate (EHMC) is commonly used as an ingredient in sunscreens, resulting in potential oral and dermal exposure in humans. 2. Clearance and metabolism of EHMC in hepatocytes and disposition and metabolism of EHMC in rodents following oral (8-800 mg/kg) intravenous (IV) (8 mg/kg) or dermal (0.8-80 mg/kg representing 0.1-10% formulation concentration) exposure to [14C]EHMC were investigated in rats and mice. 3. EHMC was rapidly cleared from rat and mouse hepatocytes (half-life ≤3.16 min) and less rapidly (half-life ≤48 min) from human hepatocytes. 4. [14C]EHMC was extensively absorbed and excreted primarily in urine by 72 h after oral administration to rats (65-80%) and mice (63-72%). Oral doses to rats were excreted to a lesser extent (3-8%) in feces and as CO2 (1-4%). Radioactive residues in tissues were <1% of the dose. There were no sex or species differences in disposition in rats. 5. Following dermal application, 34-42% of an 8-mg/kg dose was absorbed in rats, and 54-62% in mice in 72-h. 6. Among numerous urinary metabolites associated with hydrolysis of the ester, two potential reproductive and developmental toxicants, 2-ethylhexanol and 2-ethylhexanoic acid were produced by metabolism of EHMC.
Assuntos
Cinamatos/administração & dosagem , Cinamatos/farmacocinética , Hepatócitos/efeitos dos fármacos , Administração Intravenosa , Administração Oral , Administração Tópica , Animais , Cinamatos/metabolismo , Fezes , Feminino , Hexanóis/metabolismo , Hexanóis/farmacocinética , Humanos , Inativação Metabólica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Ratos Sprague-Dawley , Protetores Solares/administração & dosagem , Protetores Solares/metabolismo , Protetores Solares/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: 2-Hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODS: To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSION: Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats.
Assuntos
Benzofenonas/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Lactação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Reprodução/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Contagem de Células , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Espermatócitos/efeitos dos fármacos , Espermatócitos/patologia , Testosterona/sangueRESUMO
BACKGROUND: SCH 486757 is a nociceptin-1 receptor agonist that was in development as an antitussive. Studies were conducted to characterize its effects on female fertility and to examine its potential modes of action. METHODS: Female rats were administered up to 20 mg/kg SCH 486757 before/during mating through gestation day (GD) 7; female fertility and embryonic development were assessed on GD 14. In a subsequent study, pregnant rats were dosed up to 50 mg/kg SCH 486757 from GD 0 to 7. Reproductive hormones were assessed on GD 1, 3, 5, and 7, and embryonic development was assessed on GD 14. A subset of dosed dams were allowed to deliver, were subsequently re-mated, and reproductive hormones and fertility were assessed on GD 7 and 14, respectively. To determine the effects of SCH 486757 on nonpregnant rats, doses of up to 50 mg/kg SCH 486757 were administered for 4 days beginning on the day of estrus; reproductive hormones were assessed after the final dose. RESULTS: Female rats administered ≥20 mg/kg SCH 486757 exhibited abnormal estrous cycles; decreased fertility, number of corpora lutea, and implantation sites; and increased pre- and postimplantation loss. In general, administration of SCH486757 was associated with lower luteinizing hormone (LH) progesterone (P4), and estradiol (E2) levels in pregnant rats. These effects on fertility/embryonic development and reproductive hormones exhibited reversibility post dosing. Nonpregnant rats in the 50-mg/kg group exhibited apparent decreases in P4 and E2 levels, with no apparent effects on LH values. CONCLUSIONS: The SCH 486757-related effects on fertility and embryonic development were likely the result of decreases in P4, E2, and/or LH, rather than being due to decreased prolactin levels.
Assuntos
Compostos Azabicíclicos/toxicidade , Fertilidade/efeitos dos fármacos , Hormônios/sangue , Pirimidinas/toxicidade , Receptores Opioides/agonistas , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Cesárea , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Gravidez , Ratos , Receptores Opioides/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Análise de Sobrevida , Receptor de NociceptinaRESUMO
BACKGROUND: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels. METHODS: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH. RESULTS: Intact male dogs exhibited SCH 206272-related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272-related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post-dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post-dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH-containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post-dosing. CONCLUSIONS: SCH 206272-dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272-related reproductive tract findings are the result of alterations in hypothalamic-pituitary-gonadal function. However, a direct effect on the testes cannot be definitively ruled out.
Assuntos
Acetamidas/toxicidade , Hormônio Luteinizante/sangue , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/toxicidade , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-3/antagonistas & inibidores , Testículo/efeitos dos fármacos , Testosterona/sangue , Animais , Peso Corporal/efeitos dos fármacos , Cães , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Orquiectomia , RNA Mensageiro/metabolismo , Recuperação de Função Fisiológica , Testículo/metabolismoRESUMO
BACKGROUND: A series of studies were conducted to assess Polysorbate 80 (PS80), Propylene Glycol (PG), and Hydroxypropyl-ß-Cyclodextrin (HPßCD), when compared with Hydroxypropyl Methylcellulose (MC) in developmental and reproductive toxicology (DART) studies. METHODS: In the rat fertility study, 20 mg/kg MC, 10 mg/kg PS80, 1,000 mg/kg PG, 500 mg/kg HPßCD or 1,000 mg/kg HPßCD were administered orally before/during mating, and on gestation Day (GD) 0-7, followed by an assessment of embryonic development on GD 14. In the rat and rabbit teratology studies, the doses of MC, PS80, PG, and HPßCD were the same as those in the fertility study. In these teratology studies, pregnant females were dosed during the period of organogenesis, followed by an assessment of fetal external, visceral, and skeletal development. RESULTS: In the rat fertility and rat teratology studies, PS80, PG, and HPßCD did not exhibit toxicity, when compared with MC. Similarly, in the rabbit teratology study, there was no PS80 or PG-related toxicity, when compared with MC. However, individual rabbits in the 500 and 1,000 mg/kg HPßCD groups exhibited maternal toxicity, which included stool findings, decreased food consumption, and body weight gain. Furthermore, one rabbit each in the 500 and 1,000 mg/kg HPßCD groups exhibited evidence of abortion, which was considered secondary to maternal toxicity. CONCLUSIONS: Although HPßCD was not well tolerated in rabbits at doses of 500 and 1,000 mg/kg, PS80 and PG were comparable to MC and should be considered for use in developmental and reproductive toxicology studies.
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Embrião de Mamíferos/efeitos dos fármacos , Metilcelulose/análogos & derivados , Veículos Farmacêuticos/toxicidade , Polissorbatos/toxicidade , Propilenoglicol/toxicidade , Reprodução/efeitos dos fármacos , beta-Ciclodextrinas/toxicidade , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Derivados da Hipromelose , Metilcelulose/toxicidade , Gravidez , Coelhos , Ratos , Testes de Toxicidade/métodos , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND: The effects of histamine H1 antagonist chlorcyclizine on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg chlorcyclizine on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg chlorcyclizine at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with chlorcyclizine-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to chlorcyclizine. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development.
Assuntos
Fissura Palatina/induzido quimicamente , Embrião de Mamíferos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/toxicidade , Palato/efeitos dos fármacos , Piperazinas/toxicidade , Animais , Biomarcadores/metabolismo , Fissura Palatina/genética , Fissura Palatina/patologia , Embrião de Mamíferos/anormalidades , Feminino , Reabsorção do Feto/induzido quimicamente , Peso Fetal/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Exposição Materna , Análise em Microsséries , Palato/anormalidades , Palato/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Aumento de PesoRESUMO
Butylparaben (BP) is an antimicrobial agent utilized for decades as a preservative in numerous consumer products. The safety of parabens has recently come under scrutiny based on reports of estrogenic activity and suggested adverse effects upon the reproductive system. Due to the limited availability of studies that address the potential for BP exposure to induce reproductive toxicity, and clear evidence of human exposure, the National Toxicology Program conducted a multigenerational continuous breeding study to evaluate the impact of dietary BP-exposure at 0, 5000, 15,000, or 40,000â¯ppm on reproductive and developmental parameters in Hsd:Sprague Dawley SD rats. BP-exposure was not associated with adverse alterations of fertility, fecundity, pubertal attainment, or reproductive parameters in F0, F1, or F2 generations. Exposure-dependent increases in liver weights, and incidences of non-neoplastic liver lesions suggest the liver is a target organ of BP toxicity. No findings were observed that would support the purported mechanism of BP-induced endocrine disruption in perinatally-exposed rodents.
Assuntos
Anti-Infecciosos/toxicidade , Parabenos/toxicidade , Animais , Exposição Dietética , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Troca Materno-Fetal , Gravidez , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacosRESUMO
Human exposure to boron occurs primarily through diet and drinking water sources. Animal studies have found that reduced fetal weight following gestational exposure to boron (as boric acid) is the most sensitive toxicological effect. However, recent studies suggest that newborns in areas with elevated boron in drinking water may receive levels of exposure that exceed the U.S. EPA oral reference dose for B. Currently, there are no data to inform a boron risk assessment accounting for this developmental window. To address this knowledge gap, the National Toxicology Program evaluated developmental toxicity following pre- and postnatal boron exposure. Time-mated female Sprague Dawley (Hsd: Sprague Dawley SD) rats were administered 0-20 mg B/kg/day (as boric acid) via gavage from gestation day 6 to 21; offspring were dosed via gavage at the same respective dose level from postnatal day (PND) 1 to 28. There were no dose-related effects on dam bodyweight, bodyweight gain, or feed consumption. Clinical findings were limited to low incidences of umbilical hernia in the 20 mg B/kg pups which resolved by study completion. Pup plasma boron concentrations increased in dose-proportional manner and were similar between PND 4 and PND 28. Postnatal weight gain was significantly reduced at 20 mg B/kg, with male and female pups weighing 23% less than the controls on PND 28. These findings demonstrate that postnatal growth in the Sprague Dawley rat is sensitive to boron exposure and highlights the importance of evaluating the potential toxicity of agents with known human exposures during early life stages.
Assuntos
Ácidos Bóricos/toxicidade , Exposição Dietética , Animais , Animais Recém-Nascidos , Feminino , Lactação , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , ReproduçãoRESUMO
BACKGROUND: The covalent modification of interferon (IFN) alpha2b with monomethyoxy polyethylene glycol (PEG) reduces its clearance rate and increases its half-life. High doses of interferon (IFN) alpha2b have previously been shown to affect maintenance of pregnancy in rhesus monkeys. Given the role of ovarian hormones in reproductive function and pregnancy, this study was conducted to assess the effects of PEG-IFNalpha2b or IFNalpha2b (comparative control) on ovarian hormones and menstrual cyclicity in cynomolgus monkeys. In addition, the potential for reversibility of PEG-IFNalpha2b or IFNalpha2b-related observations was assessed. METHODS: Monkeys were administered 3,105 microg/m(2) human recombinant (hr) IFNalpha2b or 52, 262, or 4,239 microg/m(2) PEG-hr-IFNalpha2b every other day for one menstrual cycle, followed by a post-dose period of up to two menstrual cycles. RESULTS: Monkeys administered 3,105 microg/m(2) hr-IFNalpha2b or 52, 262, or 4,239 microg/m(2) PEG-hr-IFNalpha2b exhibited transient decreases in food consumption, leukocyte and erythrocyte parameters. Monkeys administered 3,105 microg/m(2) hr-IFNalpha2b exhibited lengthened menstrual cycles that were associated with a delay in reaching peak ovarian hormone levels and lower respective peak concentrations. Similarly, monkeys administered 4,239 microg/m(2) PEG-hr-IFNalpha2b exhibited lengthened menstrual cycles and a delay in reaching peak ovarian hormone levels and slightly lower respective peak concentrations. Post-dosing menstrual cycle length, estradiol and progesterone profiles exhibited evidence of recovery in both the hr-IFNalpha2b and the high-dose PEG-hr-IFNalpha2b groups. CONCLUSIONS: Administration of hr-IFNalpha2b or PEG-hr-IFNalpha2b at high doses to cynomolgus monkeys resulted in similar effects on menstrual cycles, estradiol and progesterone profiles, and exhibited evidence of reversibility upon cessation of dosing. These results suggest that the previously observed high-dose IFNalpha-related effects on the maintenance of pregnancy in monkeys are likely the result of altered ovarian function.
Assuntos
Antivirais/toxicidade , Interferon-alfa/toxicidade , Macaca fascicularis , Ciclo Menstrual/efeitos dos fármacos , Ovário/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Estradiol/sangue , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/farmacocinética , Leucócitos/efeitos dos fármacos , Testes de Neutralização , Ovário/metabolismo , Polietilenoglicóis , Progesterona/sangue , Proteínas Recombinantes , Recuperação de Função Fisiológica , Testes de Toxicidade , Suspensão de TratamentoRESUMO
BACKGROUND: Hexafluoropropylene oxide dimer acid [(HFPO-DA), GenX] is a member of the per- and polyfluoroalkyl substances (PFAS) chemical class, and elevated levels of HFPO-DA have been detected in surface water, air, and treated drinking water in the United States and Europe. OBJECTIVES: We aimed to characterize the potential maternal and postnatal toxicities of oral HFPO-DA in rats during sexual differentiation. Given that some PFAS activate peroxisome proliferator-activated receptors (PPARs), we sought to assess whether HFPO-DA affects androgen-dependent development or interferes with estrogen, androgen, or glucocorticoid receptor activity. METHODS: Steroid receptor activity was assessed with a suite of in vitro transactivation assays, and Sprague-Dawley rats were used to assess maternal, fetal, and postnatal effects of HFPO-DA exposure. Dams were dosed daily via oral gavage during male reproductive development (gestation days 14-18). We evaluated fetal testes, maternal and fetal livers, maternal serum clinical chemistry, and reproductive development of F1 animals. RESULTS: HFPO-DA exposure resulted in negligible in vitro receptor activity and did not impact testosterone production or expression of genes key to male reproductive development in the fetal testis; however, in vivo exposure during gestation resulted in higher maternal liver weights ([Formula: see text]), lower maternal serum thyroid hormone and lipid profiles ([Formula: see text]), and up-regulated gene expression related to PPAR signaling pathways in maternal and fetal livers ([Formula: see text]). Further, the pilot postnatal study indicated lower female body weight and lower weights of male reproductive tissues in F1 animals. CONCLUSIONS: HFPO-DA exposure produced multiple effects that were similar to prior toxicity evaluations on PFAS, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), but seen as the result of higher oral doses. The mean dam serum concentration from the lowest dose group was 4-fold greater than the maximum serum concentration detected in a worker in an HFPO-DA manufacturing facility. Research is needed to examine the mechanisms and downstream events linked to the adverse effects of PFAS as are mixture-based studies evaluating multiple PFAS. https://doi.org/10.1289/EHP4372.
Assuntos
Fluorocarbonos/efeitos adversos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Diferenciação Sexual/efeitos dos fármacos , Poluentes do Solo/efeitos adversos , Poluentes Químicos da Água/efeitos adversos , Animais , Feminino , Feto/efeitos dos fármacos , Feto/patologia , Feto/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in sunscreens and other personal care products and thus significant potential exists for human exposure. HMB was nominated to the National Toxicology Program (NTP) for testing due to its high exposure through consumer products and inadequate toxicological data at the time, which also included increasing concern for the potential effects of HMB on reproduction and development. HMB is metabolized to numerous metabolites in vivo and in vitro including 2,4-dihydroxybenzophenone (DHB), 2,3,4-trihydroxybenzophenone (THB) and 2,5-dihydroxy-4-methoxybenzophenone (2,5-DHMB) as well as their corresponding glucuronide and/or sulfate conjugates. In this study, we have developed and validated a liquid chromatography-tandem mass spectrometry method to quantitate free (unconjugated) HMB and DHB, and total (combined conjugated and unconjugated) HMB, DHB, THB and 2,5-DHMB. The method was successfully applied to quantitate these analytes in plasma from postnatal day 28 and 56 male and female Harlan Sprague Dawley rat pups following perinatal dietary exposure to 0 (control), 3,000, 10,000 and 30,000 ppm HMB beginning on gestational Day 6. All determined analyte concentrations increased with increasing dose and were significantly higher than the controls at both timepoints. All the total analytes were quantified in all plasma samples and total concentrations were considerably higher than free, suggesting extensive conjugation. Mean concentrations of total HMB and DHB were higher (~100-300-fold) than the free HMB and DHB concentrations, and total concentrations in plasma were approximately HMB≈DHB > 2,5-DHMB¼THB. Free and total analyte plasma concentrations were not sex-dependent and in general, both free and total analytes were detected in the control samples. Comparison of our rat data, using the internal dose, with human data available in the literature suggests that the rat doses used in our studies were within 4-fold of the human dose.
Assuntos
Benzofenonas/sangue , Cromatografia Líquida/métodos , Exposição Dietética , Protetores Solares/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Ratos , Ratos Sprague-DawleyRESUMO
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 AGD on PND 1 and a similar decrease was also observed on PND 56. Linuron-exposed male rats displayed an increase in areola retention on PND 13, as evidenced by 0.6 +/- 0.5 and 3.3 +/- 0.4 areolae per rat in the control and exposed groups, respectively. Male rats displayed a significant increase in nipple retention on PND 35 and 56 (collectively) of 0 +/- 0.5 and 1.7 +/- 0.3 nipples per rat in control and exposed groups, respectively. On PND 35, 4/51 rats (3/9 litters) from linuron-treated dams displayed enlarged testes in combination with malformed epididymides. Epididymal malformations were observed in 19/51 rats (6/9 litters) in the linuron-exposed dose group. On PND 56, grossly enlarged and edematous testes were seen in 16/56 linuron-exposed rats (6/9 litters). Epididymal lesions were observed in 23/58 rats (6/9 litters). Microscopically, all linuron-exposed animals that exhibited a testicular lesion on PND 56 also displayed an epididymal lesion. These lesions were not seen in control animals. Approximately 25 and 60% of the male offspring that had malformations of the epididymis and vas deferens did not exhibit either areolae on PND 13 or nipples at necropsy, respectively. These data indicate that in utero linuron exposure to 50 mg/kg/day results in permanent changes in AGD and nipple retention in male rats. Moreover, these findings indicate that linuron-induced testicular atrophy, which is observed in adult rats, is secondary to increased intratubular pressure resulting from obstruction of testicular fluid outflow subsequent to malformation of the epididymides. These data also suggest that although linuron-mediated retention of areolae on PND 13 and nipples at necropsy may be suggestive of altered testosterone-mediated reproductive development seen in adult rats, these endpoints are not predictive.
Assuntos
Canal Anal/anormalidades , Genitália Masculina/anormalidades , Herbicidas/toxicidade , Linurona/toxicidade , Mamilos/anormalidades , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Animais Recém-Nascidos , Epididimo/anormalidades , Feminino , Masculino , Exposição Materna/efeitos adversos , Pênis/anormalidades , Gravidez , Ratos , Testículo/anormalidades , Útero/efeitos dos fármacos , Útero/metabolismoRESUMO
The estrogenic isoflavone genistein is a common dietary component that has been shown to affect reproductive development in experimental animals at high doses. The objective of the present study was to examine interactions of genistein and the hormonally active pesticide methoxychlor on mammary gland development in juvenile rats. Timed-pregnant Sprague-Dawley rats were fed a soy- and alfalfa-free diet containing different combinations of genistein (300 and 800 ppm) and methoxychlor (800 ppm). Rats were fed these diets starting on gestation day (GD)1 and continuing through pregnancy and lactation until postnatal day (PND) 22, when the pups were killed. Inguinal mammary glands from both female and male pups were processed as whole-mount preparations for morphometric analysis. The total glandular area and the numbers of branch points, lateral buds, and terminal end buds in the male rats were found to be significantly greater in the groups exposed to methoxychlor than those exposed to genistein only. These effects were not observed in the female rats. In the male rats, methoxychlor had the most prominent effect on elongating the glandular ducts, while genistein enhanced the ductile branching. The 2 compounds in combination promoted the development of alveolar-lobular structure, an effect not observed with either compound alone. Immunostaining for proliferating cell nuclear antigen revealed a high percentage of immunopositive cells in the mammary epithelia of the males exposed to methoxychlor and genistein (800 ppm) compared to the controls. While no significant changes in serum levels of mammotrophic hormones were detected, increased immunostaining for insulin-like growth factor-1 receptor, estrogen receptor alpha, and progesterone receptor in the genistein + methoxychlor group suggested that local factors involved in regulating mammary growth may have played a role in propagating the endocrine effects of these two compounds. These results indicated that the mammary glands of juvenile male rather than juvenile female rats may be more sensitive to certain endocrine-active compounds and that high levels of phytoestrogens have the potential to alter the toxicological behaviors of other hormone mimics.
Assuntos
Estrogênios não Esteroides/toxicidade , Genisteína/toxicidade , Inseticidas/toxicidade , Isoflavonas , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Metoxicloro/toxicidade , Animais , Sinergismo Farmacológico , Feminino , Masculino , Glândulas Mamárias Animais/patologia , Fitoestrógenos , Preparações de Plantas , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , Fatores SexuaisRESUMO
Linuron is an herbicide with weak androgen receptor (AR) antagonist activity. Exposure to linuron from gestation days (GD) 12 to 21 perturbs androgen-dependent male reproductive development. In utero exposure to 50-mg/kg/day linuron induces malformations of the epididymis and the vas deferens. The objective of this study was to identify alterations in gene expression within the testis and epididymis associated with abnormal Wolffian duct development and to correlate changes in gene expression with the gross morphology of the affected epididymides. Pregnant Sprague-Dawley rats were administered either corn oil vehicle or linuron (50 mg/kg/day) by gavage from GD 12 to 21 (n = 3-6 controls, n = 5-10 linuron-treated dams per time point). Changes in gene expression were evaluated in testes on GD 21 and in epididymides on GD 21 and postnatal day (PND) 7, using cDNA microarrays and confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analyses. RNA was isolated from intact epididymides with reduced or no ductal coiling from the linuron groups, and epididymides with noncontiguous ducts were excluded. In the fetal testis, exposure to linuron did not result in reduced mRNA expression of the AR or that of several steroidogenic enzymes, supporting the hypothesis that linuron does not reduce fetal testosterone production. Linuron induced a significant decrease in AR mRNA expression in GD 21 epididymides. Significant changes in mRNA expression in GD 21 and PND 7 epididymides were also identified in the epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-1), bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Notch signaling pathways. These pathways are involved in tissue morphogenesis. Changes in the expression of AR and IGF-1 receptors were detected by immunostaining in malformed epididymides from linuron-exposed rats. Linuron induced changes in epididymal gene expression suggestive of altered paracrine interactions between the mesenchyme and epithelial cells during development. The EGF, Notch, IGF-1, BMP4, and FGF signaling pathways may be involved in normal testosterone-mediated development of the Wolffian duct.