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Sample records for reproductive toxicity assay

  1. A high-throughput method for assessing chemical toxicity using a Caenorhabditis elegans reproduction assay

    SciTech Connect

    Boyd, Windy A.; McBride, Sandra J.; Rice, Julie R.; Snyder, Daniel W.; Freedman, Jonathan H.

    2010-06-01

    The National Research Council has outlined the need for non-mammalian toxicological models to test the potential health effects of a large number of chemicals while also reducing the use of traditional animal models. The nematode Caenorhabditis elegans is an attractive alternative model because of its well-characterized and evolutionarily conserved biology, low cost, and ability to be used in high-throughput screening. A high-throughput method is described for quantifying the reproductive capacity of C. elegans exposed to chemicals for 48 h from the last larval stage (L4) to adulthood using a COPAS Biosort. Initially, the effects of exposure conditions that could influence reproduction were defined. Concentrations of DMSO vehicle {<=} 1% did not affect reproduction. Previous studies indicated that C. elegans may be influenced by exposure to low pH conditions. At pHs greater than 4.5, C. elegans reproduction was not affected; however below this pH there was a significant decrease in the number of offspring. Cadmium chloride was chosen as a model toxicant to verify that automated measurements were comparable to those of traditional observational studies. EC{sub 50} values for cadmium for automated measurements (176-192 {mu}M) were comparable to those previously reported for a 72-h exposure using manual counting (151 {mu}M). The toxicity of seven test toxicants on C. elegans reproduction was highly correlative with rodent lethality suggesting that this assay may be useful in predicting the potential toxicity of chemicals in other organisms.

  2. Use of an organotypic mammalian in vitro follicle growth (IVFG) assay to facilitate female reproductive toxicity screening

    PubMed Central

    Xu, Yuanming; Duncan, Francesca E.; Xu, Min; Woodruff, Teresa K.

    2015-01-01

    Screening of pharmaceutical, chemical, and environmental compounds for their effects on reproductive health relies on in vivo studies. More robust and efficient methods to assess thes effects are needed. Here we adapted and validated an organotypic in vitro follicle growth (IVFG) assay to determine the impact of compounds on markers of ovarian function. We isolated mammalian follicles and cultured them in the presence of compounds with 1) known fertotoxicity (i.e., toxicity to the reproductive system; cyclophosphamide and cisplatin); 2) no known fertotoxicity (nalbuphine); and 3) unknown fertotoxicity (Corexit EC 9500 A; CE). In each case we assayed follicle growth, hormone production, and the ability of follicle-enclosed oocytes to resume meiosis and produce a mature egg. We found that cyclophosphamide and cisplatin caused dose-dependent disruption of follicle dynamics, whereas nalbuphine did not. The reproductive toxicity of CE, an oil dispersant used heavily during the 2010 Deepwater Horizon oil spill, has never been examined in a mammalian system. We found that CE compromised follicle morphology and functional parameters. Our findings demonstrate that this IVFG assay system can be used to distinguish fertotoxic from non-toxic compounds, providing an in vitro tool for assessing effects of chemical compounds on reproductive function and health. PMID:25689754

  3. The potential of AOP networks for reproductive and developmental toxicity assay development

    EPA Science Inventory

    Historically, the prediction of reproductive and early developmental toxicity has largely relied on the use of animals. The Adverse Outcome Pathway (AOP) framework forms a basis for the development of new non-animal test methods. It also provides biological context for mechanisti...

  4. VARIATIONS IN REPRODUCTIVE TOXICANT IDENTIFICATION

    SciTech Connect

    Simmons, F

    2008-05-13

    Reproductive toxicants are a very important class of compounds. They present unique hazards to those of child bearing ages, perform their 'dirty work' using a wide variety of mechanisms on a number of different organs, and are regulatorily important. Because of all of this, properly identifying reproductive toxicants is important, but fraught with difficulty. In this paper we will describe types or reproductive toxicants, their importance, and both mistakes and good practices that people who are not experts in reproductive toxicology may use in their attempts to identify them. Additionally, this paper will focus on chemical reproductive toxicants and will not address biological agents that could affect reproductive toxicity although many principles outlined here could be applied to that endeavor.

  5. BIOMARKERS OF REPRODUCTIVE TOXICITY

    EPA Science Inventory

    Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various in situ biomarkers of repro...

  6. REPRODUCTIVE TOXICITY OF PHTHALATE ESTERS

    EPA Science Inventory

    Phthalate esters display several modes of toxicity in mammalian species. In the rat, in utero exposure at relatively low dosage levels disrupts development of the reproductive system of the male rat by altering fetal testis hormone production. This presentation is a review of t...

  7. Reproductive toxicity of phthalate esters.

    PubMed

    Martino-Andrade, Anderson Joel; Chahoud, Ibrahim

    2010-01-01

    Phthalate esters are ubiquitous environmental contaminants that in general display low-toxicity. Overall, the reproductive effects of these compounds are well characterized in adult's animals, with gonadal injury observed after high dose exposure. However, results of recent transgeneration studies indicate that the reproductive system of developing animals is particularly vulnerable to certain phthalates. The phenotypic alterations observed in male offspring rats exposed during the perinatal period have remarkable similarities with common human reproductive disorders, including cryptorchidism, hypospadias and low-sperm counts. Recent results also indicate that high phthalate doses can adversely affect adult and developing female rats. However, the main question involving phthalates is whether the current level of human exposure is sufficient to adversely affect male and/or female reproductive health. Here, we review the reproductive toxicity data of phthalates in adult and developing animals as well as possible modes of action. In addition, we briefly discuss the relevance of animal studies to humans in light of recent epidemiological data and experimental research with low (human relevant) doses. Finally, we point out some critical issues that should be addressed in order to clarify the implications of phthalates for human reproduction. PMID:19760678

  8. Assessment of Male Reproductive Toxicity##

    EPA Science Inventory

    This review covers all aspects of male reproductive toxicology. It begins with an overview of male reproductive biology and then transitions to the considerations of conducting male reproductive toxicology studies. We discuss multigenerational study as proposed in EPAs harmoniz...

  9. Phthalates as developmental reproductive toxicants

    EPA Science Inventory

    PE are a large family ofcompounds used in a wide array ofconsumer, industrial and medical products. Studies have shown that in utero treatment with PE such as diethyl hexyl phthalate (DEHP) during the critical period offetal reproductive development produced male reproductive mal...

  10. Evaluation of an alternative in vitro test battery for detecting reproductive toxicants.

    PubMed

    Piersma, A H; Bosgra, S; van Duursen, M B M; Hermsen, S A B; Jonker, L R A; Kroese, E D; van der Linden, S C; Man, H; Roelofs, M J E; Schulpen, S H W; Schwarz, M; Uibel, F; van Vugt-Lussenburg, B M A; Westerhout, J; Wolterbeek, A P M; van der Burg, B

    2013-07-01

    The application of alternative methods in developmental and reproductive toxicology is challenging in view of the complexity of mechanisms involved. A battery of complementary test systems may provide a better prediction of developmental and reproductive toxicity than single assays. We tested twelve compounds with varying mechanisms of toxic action in an assay battery including 24 CALUX transcriptional activation assays, mouse cardiac embryonic stem cell test, ReProGlo assay, zebrafish embryotoxicity assay, and two CYP17 and two CYP19 activity assays. The battery correctly detected 11/12 compounds tested, with one false negative occurring, which could be explained by the absence of the specific mechanism of action of this compound in the battery. Toxicokinetic modeling revealed that toxic concentrations were in the range expected from in vivo reproductive toxicity data. This study illustrates added value of combining assays that contain complementary biological processes and mechanisms, increasing predictive value of the battery over individual assays.

  11. Reproductive toxicity of carbon nanomaterials: a review

    NASA Astrophysics Data System (ADS)

    Vasyukova, I.; Gusev, A.; Tkachev, A.

    2015-11-01

    In the current review, we assembled the experimental evidences of an association between carbon nanomaterials including carbon black, graphite nanoplatelets, graphene, single- and multi-walled carbon nanotubes, and fullerene exposure and adverse reproductive and developmental effects, in vitro and in vivo studies. It is shown that carbon nanomaterials reveal toxic effect on reproductive system and offspring development of the animals of various system groups to a certain degree depending on carbon crystal structure. Although this paper provides initial information about the potential male and female reproductive toxicity of carbon nanomaterials, further studies, using characterized nanoparticles, relevant routes of administration, and doses closely reflecting all the expected levels of exposure are needed.

  12. Two-generation reproduction toxicity study in rats with methoxychlor.

    PubMed

    Aoyama, Hiroaki; Hojo, Hitoshi; Takahashi, Ken L; Shimizu-Endo, Naoko; Araki, Masayuki; Takeuchi-Kashimoto, Yukiko; Saka, Machiko; Teramoto, Shoji

    2012-03-01

    A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.

  13. Arsenic Toxicity in Male Reproduction and Development.

    PubMed

    Kim, Yoon-Jae; Kim, Jong-Min

    2015-12-01

    Arsenic is a toxic metalloid that exists ubiquitously in the environment, and affects global health problems due to its carcinogenicity. In most populations, the main source of arsenic exposure is the drinking water. In drinking water, chronic exposure to arsenic is associated with increased risks of various cancers including those of skin, lung, bladder, and liver, as well as numerous other non-cancer diseases including gastrointestinal and cardiovascular diseases, diabetes, and neurologic and cognitive problems. Recent emerging evidences suggest that arsenic exposure affects the reproductive and developmental toxicity. Prenatal exposure to inorganic arsenic causes adverse pregnancy outcomes and children's health problems. Some epidemiological studies have reported that arsenic exposure induces premature delivery, spontaneous abortion, and stillbirth. In animal studies, inorganic arsenic also causes fetal malformation, growth retardation, and fetal death. These toxic effects depend on dose, route and gestation periods of arsenic exposure. In males, inorganic arsenic causes reproductive dysfunctions including reductions of the testis weights, accessory sex organs weights, and epididymal sperm counts. In addition, inorganic arsenic exposure also induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and disruptions of steroidogenesis. However, the reproductive and developmental problems following arsenic exposure are poorly understood, and the molecular mechanism of arsenic-induced reproductive toxicity remains unclear. Thus, we further investigated several possible mechanisms underlying arsenic-induced reproductive toxicity. PMID:26973968

  14. Arsenic Toxicity in Male Reproduction and Development.

    PubMed

    Kim, Yoon-Jae; Kim, Jong-Min

    2015-12-01

    Arsenic is a toxic metalloid that exists ubiquitously in the environment, and affects global health problems due to its carcinogenicity. In most populations, the main source of arsenic exposure is the drinking water. In drinking water, chronic exposure to arsenic is associated with increased risks of various cancers including those of skin, lung, bladder, and liver, as well as numerous other non-cancer diseases including gastrointestinal and cardiovascular diseases, diabetes, and neurologic and cognitive problems. Recent emerging evidences suggest that arsenic exposure affects the reproductive and developmental toxicity. Prenatal exposure to inorganic arsenic causes adverse pregnancy outcomes and children's health problems. Some epidemiological studies have reported that arsenic exposure induces premature delivery, spontaneous abortion, and stillbirth. In animal studies, inorganic arsenic also causes fetal malformation, growth retardation, and fetal death. These toxic effects depend on dose, route and gestation periods of arsenic exposure. In males, inorganic arsenic causes reproductive dysfunctions including reductions of the testis weights, accessory sex organs weights, and epididymal sperm counts. In addition, inorganic arsenic exposure also induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and disruptions of steroidogenesis. However, the reproductive and developmental problems following arsenic exposure are poorly understood, and the molecular mechanism of arsenic-induced reproductive toxicity remains unclear. Thus, we further investigated several possible mechanisms underlying arsenic-induced reproductive toxicity.

  15. [Male reproductive toxicity of bisphenol A].

    PubMed

    Zhu, Wen-jiao; Qiao, Jie

    2015-11-01

    The reproductive toxicity of environmental endocrine disruptors has attracted substantial attention from researchers in recent years. Bisphenol A (BPA) is among the most prominent environmental estrogens worldwide, demonstrated to be related with the impairment of male reproductive function as well as other health problems, such as diabetes, obesity, cardiovascular diseases, and cancer. BPA acts primarily by mimicking antiandrogenic and estrogenic effects, disturbing the hypothalamic-pituitary-testicular axis and modulating gene expressions and enzyme activities in the hormone biosynthesis affecting steroids or its receptors. BPA is also involved in DNA methylation and the effects of epigenetics, resulting in dyszoospermia, oligoasthenoteratospermia/azoospermia and/or infertility in males. This review addresses the effects of BPA on male reproductive function, focusing on the mechanisms of its toxicity on spermatogenesis, semen quality, and the reproductive system. PMID:26738332

  16. Reproductive toxicity of brazilein in ICR mice.

    PubMed

    Yuan, Zhi-Yi; Lei, Fan; Chai, Yu-Shuang; Wu, Hao; Zhao, Shuang; Wang, Yu-Gang; Feng, Tian-Shi; Li, Hui-Ying; Li, Hui-Yu; Zhan, Hong-Lei; Xing, Dong-Ming; DU, Li-Jun

    2016-06-01

    Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women. PMID:27473962

  17. Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects.

    PubMed

    Chen, Jiangfei; Xiao, Yanyan; Gai, Zengxin; Li, Rong; Zhu, Zixu; Bai, Chenglian; Tanguay, Robert L; Xu, Xiaojiang; Huang, Changjiang; Dong, Qiaoxiang

    2015-12-01

    Bisphenol A (BPA), a high-volume chemical used to make polycarbonate plastic and epoxy resins, is a ubiquitous contaminant in environment and human body. To investigate the reproductive effects of long-term exposure to low concentrations of BPA, a two-generation study was conducted using the aquatic model species of zebrafish. Our findings revealed that exposure to 1nM (0.228μg/L) BPA for continuous two generations resulted in female-biased sex ratio in both F1 and F2 adult population, decreased sperm density, and decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males. Females were less sensitive to BPA exposures than males as no adverse effects were found in female gonads or gametes. Delayed hatching at 48hpf and increased malformation and mortality were found in the offspring from BPA exposed F2, but not F1 parents. Most importantly, the adverse effect on larval development and survival from BPA exposed F2 parents was paternal-specific, resulting mainly from BPA exposed males. Subsequent transcription analysis of F2 male gonads revealed dysregulated mitochondrial biogenesis and significant activation of non-canonical Wnt/planar cell polarity and Wnt/Calcium signaling pathways. Gene expression analysis of larvae from BPA exposed F2 parents showed significant reduced expression of DNA methyltransferases such as dnmt1, dnmt3, and dnmt5. In conclusion, low level BPA exposures for continuous two generations not only affects sex ratio and sperm quantity/quality in F1 and F2 adults, reproductive success in offspring from F2 parents, but also perturbs various molecular pathways potentially contributing to these BPA induced male-specific reproductive defects. PMID:26562050

  18. Reproductive and developmental toxicity of phthalates.

    PubMed

    Lyche, Jan L; Gutleb, Arno C; Bergman, Ake; Eriksen, Gunnar S; Murk, AlberTinka J; Ropstad, Erik; Saunders, Margaret; Skaare, Janneche U

    2009-04-01

    The purposes of this review are to (1) evaluate human and experimental evidence for adverse effects on reproduction and development in humans, produced by exposure to phthalates, and (2) identify knowledge gaps as for future studies. The widespread use of phthalates in consumer products leads to ubiquitous and constant exposure of humans to these chemicals. Phthalates were postulated to produce endocrine-disrupting effects in rodents, where fetal exposure to these compounds was found to induce developmental and reproductive toxicity. The adverse effects observed in rodent models raised concerns as to whether exposure to phthalates represents a potential health risk to humans. At present, di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) have been demonstrated to produce reproductive and developmental toxicity; thus, this review focuses on these chemicals. For the general population, DEHP exposure is predominantly via food. The average concentrations of phthalates are highest in children and decrease with age. At present, DEHP exposures in the general population appear to be close to the tolerable daily intake (TDI), suggesting that at least some individuals exceed the TDI. In addition, specific high-risk groups exist with internal levels that are several orders of magnitude above average. Urinary metabolites used as biomarkers for the internal levels provide additional means to determine more specifically phthalate exposure levels in both general and high-risk populations. However, exposure data are not consistent and there are indications that secondary metabolites may be more accurate indicators of the internal exposure compared to primary metabolites. The present human toxicity data are not sufficient for evaluating the occurrence of reproductive effects following phthalate exposure in humans, based on existing relevant animal data. This is especially the case for data on female reproductive toxicity, which are

  19. Benzodiazepine Synthesis and Rapid Toxicity Assay

    ERIC Educational Resources Information Center

    Fletcher, James T.; Boriraj, Grit

    2010-01-01

    A second-year organic chemistry laboratory experiment to introduce students to general concepts of medicinal chemistry is described. Within a single three-hour time window, students experience the synthesis of a biologically active small molecule and the assaying of its biological toxicity. Benzodiazepine rings are commonly found in antidepressant…

  20. The reproductive toxicity of boric acid.

    PubMed Central

    Chapin, R E; Ku, W W

    1994-01-01

    Previous studies on the reproductive toxicity of boric acid have indicated that male rodents suffer testicular atrophy after treatment. There were, however, no studies of the potential effects on female fertility or on the neonate. In addition, no study described the development of the testicular lesion, thought to be related to the mechanism of toxicity. A Reproductive Assessment by Continuous Breeding (RACB) study using mice exposed to boric acid at 1000, 4500, and 9000 ppm in the diet indicated that there are probably multiple sites of action, although male fertility appears very sensitive. Possible effects on female fertility cannot be separated from potential developmental toxicity and need additional investigation. Decrements in sperm motility were observed at all exposure levels, and testicular atrophy was confirmed in high- and middle-dose-group males. This was investigated further by timed serial-sacrifice studies using 9000 ppm in the diet of rats, which found that the first lesion seen in the testis was an inhibition of spermiation (release of mature spermatids). With continued dosing, this was followed by a disorganization of the normal ordered layering of the seminiferous epithelium, germ cell sloughing and death, and finally, atrophy. Subsequent studies using additional doses (2000, 3000, 4500, 6000, and 9000 ppm) found that it was possible to observe inhibited spermiation that did not progress to atrophy (4500 ppm and below) within the 9-week exposure period.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D PMID:7889888

  1. Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database

    EPA Science Inventory

    Multigeneration reproduction studies are used to characterize parental and offspring systemic toxicity, as well as reproductive toxicity of pesticides, industrial chemicals and pharmaceuticals. Results from 329 multigeneration studies on 316 chemicals have been digitized into sta...

  2. Reproductive and developmental toxicity testing: Examination of the extended one-generation reproductive toxicity study guideline.

    PubMed

    Saghir, Shakil A; Dorato, Michael A

    2016-08-01

    An important aspect of safety assessment of chemicals (industrial and agricultural chemicals and pharmaceuticals) is determining their potential reproductive and developmental toxicity. A number of guidelines have outlined a series of separate reproductive and developmental toxicity studies from fertilization through adulthood and in some cases to second generation. The Extended One-Generation Reproductive Toxicity Study (EOGRTS) is the most recent and comprehensive guideline in this series. EOGRTS design makes toxicity testing progressive, comprehensive, and efficient by assessing key endpoints across multiple life-stages at relevant doses using a minimum number of animals, combining studies/evaluations and proposing tiered-testing approaches based on outcomes. EOGRTS determines toxicity during preconception, development of embryo/fetus and newborn, adolescence, and adults, with specific emphasis on the nervous, immunological, and endocrine systems, EOGRTS also assesses maternal and paternal toxicity. However, EOGRTS guideline is complex, criteria for selecting doses is unclear, and monitoring systemic dose during the course of the study for better interpretation and human relevance is not clear. This paper discusses potential simplification of EOGRTS, suggests procedures for relevant dose selection and monitors systemic dose at multiple life-stages for better interpretation of data and human relevance.

  3. Protecting reproductive health and the environment: toxics use reduction.

    PubMed Central

    Geiser, K

    1993-01-01

    Toxics use reduction is a new chemical hazard management approach that has emerged in several state laws over the past years. While toxics use reduction has been promoted as a means of preventing environmental pollution, little thought has been given to its adoption as a means of managing reproductive hazards. This paper provides illustrations of use reduction approaches to conventionally recognized reproductive and developmental toxicants. These approaches will require the opening of a new dialogue between industrial designers and process managers and those most concerned about reproductive health. Several different strategies are proposed that might be adopted into state programs for promoting reduction in the use of reproductive and developmental toxicants. PMID:8243394

  4. Environmental toxicants and male reproductive function.

    PubMed

    Cheng, C Yan; Wong, Elissa W P; Lie, Pearl P Y; Li, Michelle W M; Su, Linlin; Siu, Erica R; Yan, Helen H N; Mannu, Jayakanthan; Mathur, Premendu P; Bonanomi, Michele; Silvestrini, Bruno; Mruk, Dolores D

    2011-01-01

    Environmental toxicants, such as cadmium and bisphenol A (BPA) are endocrine disruptors. In utero, perinatal or neonatal exposure of BPA to rats affect the male reproductive function, such as the blood-testis barrier (BTB) integrity. This effect of BPA on BTB integrity in immature rats is likely mediated via a loss of gap junction function at the BTB, failing to coordinate tight junction and anchoring junction function at the site to maintain the immunological barrier integrity. This in turn activates the extracellular signal-regulated kinases 1/2 (Erk1/2) downstream and an increase in protein endocytosis, destabilizing the BTB. The cadmium-induced disruption of testicular dysfunction is mediated initially via its effects on the occludin/ZO-1/focal adhesion kinase (FAK) complex at the BTB, causing redistribution of proteins at the Sertoli-Sertoli cell interface, leading to the BTB disruption. The damaging effects of these toxicants to testicular function are mediated by mitogen-activated protein kinases (MAPK) downstream, which in turn perturbs the actin bundling and accelerates the actin-branching activity, causing disruption of the Sertoli cell tight junction (TJ)-barrier function at the BTB and perturbing spermatid adhesion at the apical ectoplasmic specialization (apical ES, a testis-specific anchoring junction type) that leads to premature release of germ cells from the testis. However, the use of specific inhibitors against MAPK was shown to block or delay the cadmium-induced testicular injury, such as BTB disruption and germ cell loss. These findings suggest that there may be a common downstream p38 and/or Erk1/2 MAPK-based signaling pathway involving polarity proteins and actin regulators that is shared between different toxicants that induce male reproductive dysfunction. As such, the use of inhibitors and/or antagonists against specific MAPKs can possibly be used to "manage" the illnesses caused by these toxicants and/or "protect" industrial workers being

  5. Validation of a Fish Short-term Reproduction Assay

    EPA Science Inventory

    The Fish Short-term Reproduction Assay is an in vivo assay conducted with fathead minnows and is designed to detect changes in spawning, gross morphology, histopathology, and specific biochemical endpoints that reflect disturbances in the hypothalamic-pituitary-gonadal (HPG) axis...

  6. Phthalate Esters and Reproductive Toxicity** Presentation requested by State of Mass Use Reductions Committee-TURI

    EPA Science Inventory

    Phthalate esters and reproductive toxicity the presentation described the uses of phthalates, the toxicity to mammals with a focus on reproductive toxicity and the potency of these chemicals to disrupt mammalian reproductive development in utero

  7. Assaying Environmental Nickel Toxicity Using Model Nematodes

    PubMed Central

    Rudel, David; Douglas, Chandler D.; Huffnagle, Ian M.; Besser, John M.; Ingersoll, Christopher G.

    2013-01-01

    Although nickel exposure results in allergic reactions, respiratory conditions, and cancer in humans and rodents, the ramifications of excess nickel in the environment for animal and human health remain largely undescribed. Nickel and other cationic metals travel through waterways and bind to soils and sediments. To evaluate the potential toxic effects of nickel at environmental contaminant levels (8.9-7,600 µg Ni/g dry weight of sediment and 50-800 µg NiCl2/L of water), we conducted assays using two cosmopolitan nematodes, Caenorhabditis elegans and Pristionchus pacificus. We assayed the effects of both sediment-bound and aqueous nickel upon animal growth, developmental survival, lifespan, and fecundity. Uncontaminated sediments were collected from sites in the Midwestern United States and spiked with a range of nickel concentrations. We found that nickel-spiked sediment substantially impairs both survival from larval to adult stages and adult longevity in a concentration-dependent manner. Further, while aqueous nickel showed no adverse effects on either survivorship or longevity, we observed a significant decrease in fecundity, indicating that aqueous nickel could have a negative impact on nematode physiology. Intriguingly, C. elegans and P. pacificus exhibit similar, but not identical, responses to nickel exposure. Moreover, P. pacificus could be tested successfully in sediments inhospitable to C. elegans. Our results add to a growing body of literature documenting the impact of nickel on animal physiology, and suggest that environmental toxicological studies could gain an advantage by widening their repertoire of nematode species. PMID:24116204

  8. Assaying environmental nickel toxicity using model nematodes

    USGS Publications Warehouse

    Rudel, David; Douglas, Chandler; Huffnagle, Ian; Besser, John M.; Ingersoll, Christopher G.

    2013-01-01

    Although nickel exposure results in allergic reactions, respiratory conditions, and cancer in humans and rodents, the ramifications of excess nickel in the environment for animal and human health remain largely undescribed. Nickel and other cationic metals travel through waterways and bind to soils and sediments. To evaluate the potential toxic effects of nickel at environmental contaminant levels (8.9-7,600 µg Ni/g dry weight of sediment and 50-800 µg NiCl2/L of water), we conducted assays using two cosmopolitan nematodes, Caenorhabditis elegans and Pristionchus pacificus. We assayed the effects of both sediment-bound and aqueous nickel upon animal growth, developmental survival, lifespan, and fecundity. Uncontaminated sediments were collected from sites in the Midwestern United States and spiked with a range of nickel concentrations. We found that nickel-spiked sediment substantially impairs both survival from larval to adult stages and adult longevity in a concentration-dependent manner. Further, while aqueous nickel showed no adverse effects on either survivorship or longevity, we observed a significant decrease in fecundity, indicating that aqueous nickel could have a negative impact on nematode physiology. Intriguingly, C. elegansand P. pacificus exhibit similar, but not identical, responses to nickel exposure. Moreover, P. pacificus could be tested successfully in sediments inhospitable to C. elegans. Our results add to a growing body of literature documenting the impact of nickel on animal physiology, and suggest that environmental toxicological studies could gain an advantage by widening their repertoire of nematode species.

  9. GENE EXPRESSION PROFILING TO IDENTIFY BIOMARKERS OF REPRODUCTIVE TOXICITY

    EPA Science Inventory

    SOT 2005 SESSION ABSTRACT

    GENE EXPRESSION PROFILING TO IDENTIFY BIOMARKERS OF REPRODUCTIVE TOXICITY

    David J. Dix. National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle...

  10. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF ARSENIC IN RODENTS: A REVIEW

    EPA Science Inventory

    Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal...

  11. Economic benefits of using adaptive predictive models of reproductive toxicity in the context of a tiered testing program

    EPA Science Inventory

    A predictive model of reproductive toxicity, as observed in rat multigeneration reproductive (MGR) studies, was previously developed using high throughput screening (HTS) data from 36 in vitro assays mapped to 8 genes or gene-sets from Phase I of USEPA ToxCast research program, t...

  12. MECHANISMS OF MALE REPRODUCTIVE TOXICITY: BED, BATH AND BEYOND

    EPA Science Inventory

    Male reproductive function depends upon the integration of a great number of highly complex biological processes and their endocrine support. Therefore it is not surprising that male reproductive health can be impaired by exposures to drugs and environmental toxicants that impact...

  13. Zebrafish models for assessing developmental and reproductive toxicity.

    PubMed

    He, Jian-Hui; Gao, Ji-Min; Huang, Chang-Jiang; Li, Chun-Qi

    2014-01-01

    The zebrafish is increasingly used as a vertebrate animal model for in vivo drug discovery and for assessing chemical toxicity and safety. Numerous studies have confirmed that zebrafish and mammals are similar in their physiology, development, metabolism and pathways, and that zebrafish responses to toxic substances are highly predictive of mammalian responses. Developmental and reproductive toxicity assessments are an important part of new drug safety profiling. A significant number of drug candidates have failed in preclinical tests due to their adverse effect on development and reproductivity. Compared to conventional mammal testing, zebrafish testing for assessing developmental and reproductive toxicity offers several compelling experimental advantages, including transparency of embryo and larva, higher throughput, shorter test period, lower cost, smaller amount of compound required, easier manipulation and direct compound delivery. Toxicity and safety assessments using zebrafish have also been accepted by the FDA and EMEA for investigative new drug (IND) approval.

  14. A Different Approach to Validating Screening Assays for Developmental Toxicity

    EPA Science Inventory

    BACKGROUND: There continues to be many efforts around the world to develop assays that are shorter than the traditional embryofetal developmental toxicity assay, or use fewer or no mammals, or use less compound, or have all three attributes. Each assay developer needs to test th...

  15. Nickel nanoparticles exposure and reproductive toxicity in healthy adult rats.

    PubMed

    Kong, Lu; Tang, Meng; Zhang, Ting; Wang, Dayong; Hu, Ke; Lu, Weiqi; Wei, Chao; Liang, Geyu; Pu, Yuepu

    2014-01-01

    Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E2) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions. PMID:25407529

  16. Nickel Nanoparticles Exposure and Reproductive Toxicity in Healthy Adult Rats

    PubMed Central

    Kong, Lu; Tang, Meng; Zhang, Ting; Wang, Dayong; Hu, Ke; Lu, Weiqi; Wei, Chao; Liang, Geyu; Pu, Yuepu

    2014-01-01

    Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E2) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions. PMID:25407529

  17. Developmental and reproductive toxicity evaluation of toluene vapor in the rat. I. Reproductive toxicity.

    PubMed

    Roberts, L G; Bevans, A C; Schreiner, C A

    2003-01-01

    The reproductive toxicity of toluene was evaluated in a 2-generation test in which male and female Sprague-Dawley rats, parental (F0) and first generation (F1), were exposed to toluene via whole body inhalation, 6 h/day, 7 days/week for 80 days premating and 15 days of mating at concentrations of 0, 100, 500 and 2000 ppm (0, 375, 1875 and 7500 mg/m(3)). Toluene was administered at 2000 ppm to both sexes, or to females or males only to be mated with untreated partners. Pregnant females at all dose levels were exposed from gestation day (GD) 1-20 and lactation day (LD) 5-21. At LD5, females were removed from their litters for daily exposure and returned when 6 h of exposure was completed. F1 pups selected to produce the F2 generation were treated for 80 days beginning immediately after weaning (LD21) and initially mated at a minimum of 100 days of age. F2 pups were not exposed to toluene by inhalation. Toluene exposure did not induce adverse effects on fertility, reproductive performance, or maternal/pup behaviors during the lactation period in males and females of the parental or first generation, but did inhibit growth in F1 and F2 offspring in the 2000 ppm (both sexes treated) and 2000 ppm (females only treated) groups. Caesarean section of selected 2000 ppm (both sexes treated) dams at GD20 showed reduced fetal body weight and skeletal variations. Exposure to toluene caused decreased pup weights throughout lactation in F1 and F2 2000 ppm (both sexes treated), and 2000 ppm (females only treated) groups. Exposure at 2000 ppm to male parents only did not induce similar weight inhibition in offspring. The toluene offspring NOAEL is 500 ppm in groups in which maternal animals were exposed, and 2000 ppm for male only treated groups. PMID:14613816

  18. Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice

    PubMed Central

    Zhang, Jia-Qing; Gao, Bin-Wen; Wang, Jing; Wang, Xian-Wei; Ren, Qiao-Ling; Chen, Jun-Feng; Ma, Qiang; Xing, Bao-song

    2016-01-01

    Diquat is a bipyridyl herbicide that has been widely used as a model chemical for in vivo studies of oxidative stress due to its generation of superoxide anions, and cytotoxic effects. There is little information regarding the toxic effects of diquat on the female reproductive system, particularly ovarian function. Thus, we investigated the reproductive toxic effects of diquat on female mice. Chronic exposure to diquat reduced ovary weights, induced ovarian oxidative stress, resulted in granulosa cell apoptosis, and disrupted oocyte developmental competence, as shown by reactive oxygen species (ROS) accumulation, decreased polar body extrusion rates and increased apoptosis-related genes expression. Additionally, after diquat treatment, the numbers of fetal mice and litter sizes were significantly reduced compared to those of control mice. Thus, our results indicated that chronic exposure to diquat induced reproductive toxicity in female mice by promoting the ROS production of gruanousa cells and ooctyes, impairing follicle development, inducing apoptosis, and reducing oocyte quality. In conclusion, our findings indicate that diquat can be used as a potent and efficient chemical for in vivo studies of female reproductive toxicity induced by oxidative stress. Moreover, the findings from this study will further enlarge imitative research investigating the effect of ovarian damage induced by oxidative stress on reproductive performance and possible mechanisms of action in large domestic animals. PMID:26785375

  19. Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice.

    PubMed

    Zhang, Jia-Qing; Gao, Bin-Wen; Wang, Jing; Wang, Xian-Wei; Ren, Qiao-Ling; Chen, Jun-Feng; Ma, Qiang; Xing, Bao-Song

    2016-01-01

    Diquat is a bipyridyl herbicide that has been widely used as a model chemical for in vivo studies of oxidative stress due to its generation of superoxide anions, and cytotoxic effects. There is little information regarding the toxic effects of diquat on the female reproductive system, particularly ovarian function. Thus, we investigated the reproductive toxic effects of diquat on female mice. Chronic exposure to diquat reduced ovary weights, induced ovarian oxidative stress, resulted in granulosa cell apoptosis, and disrupted oocyte developmental competence, as shown by reactive oxygen species (ROS) accumulation, decreased polar body extrusion rates and increased apoptosis-related genes expression. Additionally, after diquat treatment, the numbers of fetal mice and litter sizes were significantly reduced compared to those of control mice. Thus, our results indicated that chronic exposure to diquat induced reproductive toxicity in female mice by promoting the ROS production of gruanousa cells and ooctyes, impairing follicle development, inducing apoptosis, and reducing oocyte quality. In conclusion, our findings indicate that diquat can be used as a potent and efficient chemical for in vivo studies of female reproductive toxicity induced by oxidative stress. Moreover, the findings from this study will further enlarge imitative research investigating the effect of ovarian damage induced by oxidative stress on reproductive performance and possible mechanisms of action in large domestic animals. PMID:26785375

  20. Chronic Exposure to Diquat Causes Reproductive Toxicity in Female Mice.

    PubMed

    Zhang, Jia-Qing; Gao, Bin-Wen; Wang, Jing; Wang, Xian-Wei; Ren, Qiao-Ling; Chen, Jun-Feng; Ma, Qiang; Xing, Bao-Song

    2016-01-01

    Diquat is a bipyridyl herbicide that has been widely used as a model chemical for in vivo studies of oxidative stress due to its generation of superoxide anions, and cytotoxic effects. There is little information regarding the toxic effects of diquat on the female reproductive system, particularly ovarian function. Thus, we investigated the reproductive toxic effects of diquat on female mice. Chronic exposure to diquat reduced ovary weights, induced ovarian oxidative stress, resulted in granulosa cell apoptosis, and disrupted oocyte developmental competence, as shown by reactive oxygen species (ROS) accumulation, decreased polar body extrusion rates and increased apoptosis-related genes expression. Additionally, after diquat treatment, the numbers of fetal mice and litter sizes were significantly reduced compared to those of control mice. Thus, our results indicated that chronic exposure to diquat induced reproductive toxicity in female mice by promoting the ROS production of gruanousa cells and ooctyes, impairing follicle development, inducing apoptosis, and reducing oocyte quality. In conclusion, our findings indicate that diquat can be used as a potent and efficient chemical for in vivo studies of female reproductive toxicity induced by oxidative stress. Moreover, the findings from this study will further enlarge imitative research investigating the effect of ovarian damage induced by oxidative stress on reproductive performance and possible mechanisms of action in large domestic animals.

  1. An amphibian model for studies of developmental reproductive toxicity.

    PubMed

    Berg, Cecilia

    2012-01-01

    The developmental programming of the reproductive system is vulnerable to chemical exposure. It is therefore important to evaluate long-term consequences of early life-stage exposure to endocrine disrupting chemicals. The African clawed frog Xenopus tropicalis has several characteristics which facilitates studies of developmental reproductive toxicity. Here, I present a X. tropicalis test protocol, including study design, exposure regime, and endpoints for chemical disruption of sex differentiation, reproductive organ development, the thyroxin-regulated metamorphosis, oestrogen synthesis (activity of the CYP19 aromatase enzyme), and fertility. PMID:22669660

  2. Predicting the risk of developmental toxicity from in vitro assays

    SciTech Connect

    Spielmann, Horst . E-mail: spielmann.zebet@bfr.bund.de

    2005-09-01

    Reproductive toxicity refers to the adverse effects of a substance on any aspect of the reproductive cycle, including the impairment of reproductive function, the induction of adverse effects in the embryo, such as growth retardation, malformations, and death. Due to the complexity of the mammalian reproductive cycle, it is impossible to model the whole cycle in a single in vitro system in order to detect chemical effects on mammalian reproduction. However, the cycle can be broken down in its biological components which may be studied individually or in combination. This approach has the advantage that the target tissue/organ of a developmental toxicant can be identified. In specific areas of developmental toxicity, a number of useful and promising in vitro models are already available. The individual tests may be used as building blocks of a tiered testing strategy. So far, research has focused on developing and validating tests covering only a few components of the reproductive cycle, in particular organogenesis of the embryo, reflecting important concerns for teratogenic chemicals. During the last three decades, a number of established models and promising new developments have emerged that will be discussed, e.g. culture of mammalian embryos and embryonic cells and tissues and the use of embryonic stem cells.

  3. Reproductive toxicity: Male and female reproductive systems as targets for chemical injury

    SciTech Connect

    Mattison, D.R.; Plowchalk, D.R.; Meadows, M.J.; Al-Juburi, A.Z.; Gandy, J.; Malek, A. )

    1990-03-01

    On the basis of current knowledge of reproductive biology and toxicology, it is apparent that chemicals affecting reproduction may elicit their effects at a number of sites in both the male and the female reproductive system. This multiplicity of targets is attributable to the dynamic nature of the reproductive system, in which the hypothalamic-pituitary-gonadal axis is controlled by precise positive and negative feedback mechanisms among its components. Interference by a xenobiotic at any level in either the male or the female reproductive system may ultimately impair hypothalamic or pituitary function. Normal gonadal processes such as spermatogenesis or oogenesis, ejaculation or ovulation, hormone production by Leydig or granulosa cells, and the structure or function of the accessory reproductive structures (e.g., epididymis, fallopian tube) also appear vulnerable to xenobiotics. The reproductive system is a complex one that requires local and circulating hormones for control. This brief review illustrates a system for characterizing the mechanism of action of reproductive toxicants, as well as for defining the sites available for disruption of reproduction. Unfortunately, at present, data addressing the actual vulnerability of reproduction are sorely lacking. However, when experiments have been conducted and combined with epidemiologic data or clinical observation, it has been possible to demonstrate impairment of reproductive processes by xenobiotics. The role of environmental exposure to xenobiotics in the increase in infertility that has been observed remains to be defined. 87 references.

  4. Reproductive toxicity: male and female reproductive systems as targets for chemical injury.

    PubMed

    Mattison, D R; Plowchalk, D R; Meadows, M J; al-Juburi, A Z; Gandy, J; Malek, A

    1990-03-01

    On the basis of current knowledge of reproductive biology and toxicology, it is apparent that chemicals affecting reproduction may elicit their effects at a number of sites in both the male and the female reproductive system. This multiplicity of targets is attributable to the dynamic nature of the reproductive system, in which the hypothalamic-pituitary-gonadal axis is controlled by precise positive and negative feedback mechanisms among its components. Interference by a xenobiotic at any level in either the male or the female reproductive system may ultimately impair hypothalamic or pituitary function. Normal gonadal processes such as spermatogenesis or oogenesis, ejaculation or ovulation, hormone production by Leydig or granulosa cells, and the structure or function of the accessory reproductive structures (e.g., epididymis, fallopian tube) also appear vulnerable to xenobiotics. The reproductive system is a complex one that requires local and circulating hormones for control. This brief review illustrates a system for characterizing the mechanism of action of reproductive toxicants, as well as for defining the sites available for disruption of reproduction. Unfortunately, at present, data addressing the actual vulnerability of reproduction are sorely lacking. However, when experiments have been conducted and combined with epidemiologic data or clinical observation, it has been possible to demonstrate impairment of reproductive processes by xenobiotics. The role of environmental exposure to xenobiotics in the increase in infertility that has been observed remains to be defined.

  5. Cadmium inhalation and male reproductive toxicity.

    PubMed

    Ragan, H A; Mast, T J

    1990-01-01

    Cadmium is a highly toxic element that is cumulative and has a long biological half-life in mammals. The severe toxicity of cadmium in man has been known for more than 100 years. Despite the knowledge that cadmium is toxic, only 20 human cases of poisoning via ingestion were recorded prior to 1941, whereas in the ensuing five-year period more than 680 cases of cadmium poisonings from accidental oral ingestion of this metal were documented. Some of the recorded effects of exposure to cadmium in laboratory animals include renal tubular damage, placental and testicular necrosis, structural and functional liver damage, osteomalacia, testicular tumors, teratogenic malformations, anemia, hypertension, pulmonary edema, chronic pulmonary emphysema, and induced deficiencies of iron, copper, and zinc. Some of these effects have also been observed in human after accidental exposures to cadmium oxide fumes and are characteristic of the syndrome described in Japan as Itai Itai disease in which ingestion of cadmium is the inciting chemical.

  6. Reproductive and Developmental Toxicity of Dioxin in Fish1

    PubMed Central

    King-Heiden, Tisha C.; Mehta, Vatsal; Xiong, Kong M.; Lanham, Kevin A.; Antkiewicz, Dagmara S.; Ganser, Alissa; Heideman, Warren

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is a global environmental contaminant and the prototypical ligand for investigating aryl hydrocarbon receptor (AHR)-mediated toxicity. Environmental exposure to TCDD results in developmental and reproductive toxicity in fish, birds and mammals. To resolve the ecotoxicological relevance and human health risks posed by exposure to dioxin-like AHR agonists, a vertebrate model is needed that allows for toxicity studies at various levels of biological organization, assesses adverse reproductive and developmental effects and establishes appropriate integrative correlations between different levels of effects. Here we describe the reproductive and developmental toxicity of TCDD in feral fish species and summarize how using the zebrafish model to investigate TCDD toxicity has enabled us to characterize the AHR signaling in fish and to better understand how dioxin-like chemicals induce toxicity. We propose that such studies can be used to predict the risks that AHR ligands pose to feral fish populations and provide a platform for integrating risk assessments for both ecologically relevant organisms and humans. PMID:21958697

  7. Semiautomated Motility Assay For Determining Toxicity

    NASA Technical Reports Server (NTRS)

    Noever, David A.; Cronise, Raymond

    1996-01-01

    Improved method of assessing toxicities of various substances based on observation of effects of those substances on motilities of manageably small number of cells of protozoan species Tetrahema pyriformis. Provides repeatable, standardized tests with minimal handling by technicians and with minimal exposure of technicians to chemicals. Rapid and economical alternative to Draize test.

  8. Reproductive toxicity of monocrotophos to bobwhite quail

    USGS Publications Warehouse

    Stromborg, K.L.

    1986-01-01

    Pairs of 1st-year breeding bobwhites were fed constant or decreasing concentrations of monocrotophos for 15 days. In addition, a control diet was used in a pair-fed group matched with the pairs in the constant group. Dietary concentrations for the constant group were logarithmically spaced at .100, .178, .316, .562, 1.000 ppm of actual insecticide and also at 0 ppm (control) for five pairs at each concentration. The beginning concentrations for the decreasing pairs were identical to the constant group but regularly decreased to reach 25% of the starting concentrations by Day 13. Food consumption, egg production, hatchability of eggs under artificial incubation, and survival of hatched chicks for 2 weeks were recorded pairwise during 15-day treatment and 14-day posttreatment periods. Mortality was high at the greatest constant concentration and in the associated pair-fed group. Food consumption and egg production rates were negatively dose-related during the treatment period in the constant and decreasing groups. The laying rate of pair-fed hens was reduced to the same extent as in the constant group. Reproductive inhibition was not permanent, and pairs resumed laying after a dose-related recovery interval. No dose-related effects on hatchability or chick survival were detected. There was no evidence of a pesticide effect on reproduction other than that exerted through pesticide-induced anorexia.

  9. Toxic substances and reproductive disorders in Baltic fish and crustaceans.

    PubMed

    Breitholtz, M; Hill, C; Bengtsson, B E

    2001-08-01

    In the Baltic Sea ecosystem reproductive disorders have occurred in top consumers such as seals and some fish-eating birds, due to biomagnification of toxic substances, e.g. DDT and PCBs. Reproductive disturbances have also affected fish during the last 25 years. However, there is no strong evidence that toxic substances have caused these problems. Rather, the disorders seem to result from a combination of two or more biotic or abiotic factors. The M74 syndrome, which kills fry of salmon and sea trout, is characterized by a deficiency of thiamine (vitamin B1). Several factors may contribute to the thiamine deficiency, including the diet of salmon in the sea and halogenated organic compounds. Cod do not develop M74, and poor cod recruitment is mainly due to poor oxygen conditions in the spawning areas in combination with overfishing. Toxic compounds in pulp-mill effluents retard gonadal development in perch, but the mechanisms and the active substances have not been identified. Recruitment problems in perch in the coastal waters outside some pulp mills may also be explained by a lack of food items for juvenile fish, rather than reproductive failure. There are very limited data on reproductive disorders in crustaceans from the Baltic Sea. Most data come from studies of the benthic amphipod Monoporeia affinis, which has been used in monitoring programs. Several signs of reproductive disorder have been reported in this amphipod, e.g. malformation and death of embryos, and asynchronous maturation of males and females.

  10. Cadmium inhalation and male reproductive toxicity

    SciTech Connect

    Ragan, H.A.; Mast, T.J. )

    1990-01-01

    Cadmium is a highly toxic element that is cumulative and has a long biological half-life in mammals. The severe toxicity of cadmium in man has been known for more than 100 years. Despite the knowledge that cadmium is toxic, only 20 human cases of poisoning via ingestion were recorded prior to 1941, whereas in the ensuing five-year period more than 680 cases of cadmium poisonings from accidental oral ingestion of this metal were documented. Some of the recorded effects of exposure to cadmium in laboratory animals include renal tubular damage, placental and testicular necrosis, structural and functional liver damage, osteomalacia, testicular tumors, teratogenic malformations, anemia, hypertension, pulmonary edema, chronic pulmonary emphysema, and induced deficiencies of iron, copper, and zinc. Some of these effects have also been observed in human after accidental exposures to cadmium oxide fumes and are characteristic of the syndrome described in Japan as Itai Itai disease in which ingestion of cadmium is the inciting chemical.134 references.

  11. GENE EXPRESSION PROFILING TO IDENTIFY MECHANISMS OF MALE REPRODUCTIVE TOXICITY

    EPA Science Inventory

    Gene Expression Profiling to Identify Mechanisms of Male Reproductive Toxicity
    David J. Dix
    National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711, USA.
    Ab...

  12. PROSPECTIVE PREGNANCY STUDY DESIGNS FOR ASSESSING REPRODUCTIVE AND DEVELOPMENTAL TOXICANTS

    EPA Science Inventory

    Prospective Pregnancy Study Designs for Assessing Reproductive and Developmental Toxicants
    Germaine M. Buck,1 Courtney D. Johnson,1 Joseph Stanford,2 Anne Sweeney,3 Laura Schieve,4 John Rockett,5 Sherry G. Selevan,6 Steve Schrader 7

    Abstract
    The origin of successfu...

  13. REPRODUCTIVE TOXICITY OF ANDROGENIC GROWTH PROMOTORS IN THE FATHEAD MINNOW

    EPA Science Inventory

    Reproductive Toxicity of Androgenic Growth Promoters in the Fathead Minnow. Jensen, KM*, Kahl, MD, Makynen, EA, Hornung, MW, Ankley, GT. U.S. Environmental Protection Agency, Duluth, MN. Trenbolone acetate is a synthetic steroid which is extensively used in the US as a growth pro...

  14. Early indicators of male reproductive toxicity

    SciTech Connect

    Overstreet, J.W.; Samuels, S.J.; Day, P.; Hendrickx, A.G.; Prahalada, S.; Mast, T.; Katz, D.F.; Sakai, C.

    1988-03-01

    Longitudinal data were analyzed for seminal characteristics of rhesus monkeys and beagles. The monkeys were exposed to DBCP; the beagles were exposed to acute or chronic whole body gamma irradiation. The semen was analyzed for volume and sperm concentration. Sperm were measured for percent motility, swimming speed, and head dimensions. Abnormalities of the sperm tail were also noted. All treatments resulted in measurable effects on the semen parameters. Sperm production, as evaluated by seminal sperm concentration or total sperm numbers in the ejaculate, was as informative of testicular toxicity as any other parameter or combination of parameters. A consistent finding was that changes in sperm output occurred concomitantly with changes in sperm motility.

  15. Comparative toxicant sensitivity of sexual and asexual reproduction in the rotifer Brachionus calyciflorus

    SciTech Connect

    Snell, T.W.; Carmona, M.J.

    1995-03-01

    Cyclically parthenogenetic zooplankters like rotifers are important tools for assessing toxicity in aquatic environments. Sexual reproduction is an essential component of rotifer life cycles, but current toxicity tests utilize only asexual reproduction. The authors compared the effects of four toxicants on asexual and sexual reproduction of the rotifer Brachionus calyciflorus. Toxicants had a differential effect on sexual and asexual reproduction, with sexual reproduction consistently the most sensitive. Concentrations of 0.2 {mu}g/ml PCP (sodium pentachlorophenate) had no effect on the asexual reproductive rate, but significantly reduced sexual reproduction. Likewise, chlorpyrifos concentrations of 0.3 {mu}g/ml had no significant effect on asexual reproduction, but sexual reproduction was significantly reduced. There was no difference in NOECs, LOECs, and chronic values for asexual and sexual reproduction for cadmium and naphthol tests. However, comparison of toxicant effect levels revealed that sexual reproduction was more strongly reduced at each toxicant concentration. The four toxicants tested inhibited sexual reproduction 2 to 68 times more than asexual reproduction at the lowest observed effect concentrations. Toxicants inhibited sexual reproduction in its initial step: sexual female production. Because sexual reproduction is more sensitive, toxicity tests based exclusively on asexual reproduction may not be protective of rotifer life cycles.

  16. 76 FR 59142 - Guidance for Industry on Reproductive and Developmental Toxicities-Integrating Study Results To...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-23

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Reproductive and Developmental... a guidance for industry entitled ``Reproductive and Developmental Toxicities--Integrating Study... developmental or reproductive risks associated with drug or biological product exposure when a...

  17. Developmental and reproductive toxicity testing of vaccines.

    PubMed

    Barrow, Paul

    2012-03-01

    The majority of new preventative and therapeutic vaccines are now assessed for developmental toxicity according to guidelines issued by the FDA in 2006. Despite the absence of confirmed effects in humans, vaccines are frequently suspected of having adverse side-effects on the development of children. Such suspicions are perhaps unavoidable considering the extremely widespread use of vaccines. The preclinical developmental toxicology studies are designed to assess possible influences of each component of the vaccine formulation-and the induced antibodies-on the development of the conceptus, neonate and suckling organism. Immune modulation by a vaccine or an adjuvant could, for instance, affect the outcome of pregnancy by interfering with the natural shift in immune balance of the mother during gestation. Maternal immunoglobulins are transferred from the mother to the offspring in order to confer passive immunity during early life. This maternal antibody transport is prenatal in humans and monkeys, but tends to be delayed until after birth in other species. Therefore, a suitable model species needs to be chosen for preclinical studies in order to ensure exposure of the foetus to the induced maternal antibodies following vaccination. Rabbits are the best laboratory model for prenatal immunoglobulin transfer, but rodents are more practical for the necessary postnatal investigations. Non-human primates are the only appropriate models for the testing of vaccines that are not immunogenic in lower species. It is advisable to test new adjuvants separately according to the ICH S5(R2) guidelines. Preclinical paediatric investigations are not currently required for vaccines, even though most vaccines are given to children. Other areas of regulatory concern include developmental immunotoxicity and effects on the preimplantation embryo. Because of the limitations of the available animal models for developmental toxicity testing, pharmacovigilance is essential.

  18. [Thought and method of reproductive toxicity research in traditional Chinese medicine].

    PubMed

    Han, Jia-Yin; Yan, Yi; Liang, Ai-hua; Zhang, Yu-shi; Li, Chun-ying; Zhao, Yong; Lu, Yu-ting; Cui, Hong-yu; Li, Gui-qin

    2014-11-01

    Reproductive toxicity research takes an important place in traditional Chinese medicine pre-clinical safety evaluation. Modern reproductive toxicity experiment includes drug-related miscarriage, fetal death, teratism, and adverse effects on fertility, genital system, embryonic development and fetus, which is different from contraindicated in pregnancy in traditional Chinese medicine theory. Now the three-phases reproductive toxicity study is the method mainly applied in traditional Chinese medicine reproductive toxicity evaluation. Besides that, alternative methods of whole embryos culture and embryonic stem cell test are also used in traditional Chinese medicine embryo toxicity evaluation. This article reviews research progress and pre-clinical evaluation on reproductive toxicity of traditional Chinese medicine.

  19. Impacts of environmental toxicants on male reproductive dysfunction.

    PubMed

    Wong, Elissa W P; Cheng, C Yan

    2011-05-01

    Male infertility caused by exposure to environmental toxicants such as cadmium, mercury, bisphenol A (BPA) and dioxin is a global problem, particularly in industrialized countries. Studies in the testis and other organs have illustrated the importance of environmental toxicant-induced oxidative stress in mediating disruption to cell junctions. This, in turn, is regulated by the activation of PI3K/c-Src/FAK and MAPK signaling pathways, with the involvement of polarity proteins. This leads to reproductive dysfunction such as reduced sperm count and reduced quality of semen. In this review, we discuss how these findings can improve understanding of the modes of action of environmental toxicants in testicular dysfunction. Thus, specific inhibitors and/or antagonists against signaling molecules in these pathways may be able to 'reverse' and/or 'block' the disruptive effects of toxicant-induced damage. Additional studies comparing high-level acute exposure versus low-level chronic exposure to environmental toxicants are also needed to fully elucidate the underlying molecular mechanism(s) by which these toxicants disrupt male reproductive function. PMID:21324536

  20. Regulation of priority carcinogens and reproductive or developmental toxicants

    SciTech Connect

    Hooper, K.; LaDou, J.; Rosenbaum, J.S.; Book, S.A. )

    1992-01-01

    In California, 370 carcinogens and 112 reproductive/developmental toxicants have been identified as a result of the State's Safe Drinking Water and Toxic Enforcement Act of 1986. They include pesticides, solvents, metals, industrial intermediates, environmental mixtures, and reactive agents. Occupational, environmental, and consumer product exposures that involve these agents are regulated under the Act. At levels of concern, businesses must provide warnings for and limit discharges of those chemicals. The lists of chemicals were compiled following systematic review of published data, including technical reports from the U.S. Public Health Service--National Toxicology Program (NTP), and evaluation of recommendations from authoritative bodies such as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (USEPA). Given the large number of chemicals that are carcinogens or reproductive/developmental toxicants, regulatory concerns should focus on those that have high potential for human exposure, e.g., widely distributed or easily absorbed solvents, metals, environmental mixtures, or reactive agents. In this paper, we present a list of 33 potential priority carcinogens and reproductive/developmental toxicants, including alcoholic beverages, asbestos, benzene, chlorinated solvents, formaldehyde, glycol ethers, lead, tobacco smoke, and toluene.

  1. Regulation of priority carcinogens and reproductive or developmental toxicants.

    PubMed

    Hooper, K; LaDou, J; Rosenbaum, J S; Book, S A

    1992-01-01

    In California, 370 carcinogens and 112 reproductive/developmental toxicants have been identified as a result of the State's Safe Drinking Water and Toxic Enforcement Act of 1986. They include pesticides, solvents, metals, industrial intermediates, environmental mixtures, and reactive agents. Occupational, environmental, and consumer product exposures that involve these agents are regulated under the Act. At levels of concern, businesses must provide warnings for and limit discharges of those chemicals. The lists of chemicals were compiled following systematic review of published data, including technical reports from the U.S. Public Health Service--National Toxicology Program (NTP), and evaluation of recommendations from authoritative bodies such as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (USEPA). Given the large number of chemicals that are carcinogens or reproductive/developmental toxicants, regulatory concerns should focus on those that have high potential for human exposure, e.g., widely distributed or easily absorbed solvents, metals, environmental mixtures, or reactive agents. In this paper, we present a list of 33 potential priority carcinogens and reproductive/developmental toxicants, including alcoholic beverages, asbestos, benzene, chlorinated solvents, formaldehyde, glycol ethers, lead, tobacco smoke, and toluene. PMID:1463026

  2. Toxic effects on survival and reproduction, a process oriented approach

    SciTech Connect

    Bedaux, J.J.M.; Kooijman, S.A.L.M.

    1995-12-31

    The authors present a new analysis of survival and reproduction data from toxicity tests. The analysis is based on the Dynamic Energy Budget theory for feeding, growth and reproduction, and a one-compartment kinetics for the toxic compound. The toxic effect size depends on the internal concentration. Effects on survival occur via the hazard rate, which is set equal to the killing rate times the internal concentration that exceeds a threshold value. Effects on reproduction depend on the mode of action of the toxicant: direct effects (mortality during oogenesis or energy costs per egg), or indirect effects (via growth, maintenance or assimilation). The effects on energetic parameters are quantified by the ratio between the internal concentration that exceeds a threshold value, and the tolerance concentration. The process-based models quantify effects as functions of exposure time and (external) concentration on a mechanistic basis. The parameters (no effect concentration, killing rate, tolerance concentration and elimination rate) are independent from the chosen exposure time of the toxicity test. The standard log-logistic models are purely descriptive, have more parameters and are sensitive to the chosen exposure time. The estimation of no-effect concentrations (NOEC`s as well as parametric NEC`S) in standard statistical analyses is problematic. Application to ring test data for chronic tests on Daphnia magna and other toxicity data reveals that these problems do not occur with the analysis, due to the absence of free gradient parameters. It is possible to obtain estimates for the standard model parameters from the new parameters, but not vice versa. The authors believe that the analysis provides a better basis for risk assessment and QSAR studies than the standard one.

  3. Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results.

    PubMed

    Duydu, Yalçın; Başaran, Nurşen; Ustündağ, Aylin; Aydın, Sevtap; Undeğer, Ulkü; Ataman, Osman Yavuz; Aydos, Kaan; Düker, Yalçın; Ickstadt, Katja; Waltrup, Brita Schulze; Golka, Klaus; Bolt, Hermann Maximilian

    2016-01-01

    Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandırma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 ± 69.49 ng/g) of the high exposure group workers in Bandırma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child). PMID:26511087

  4. Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results.

    PubMed

    Duydu, Yalçın; Başaran, Nurşen; Ustündağ, Aylin; Aydın, Sevtap; Undeğer, Ulkü; Ataman, Osman Yavuz; Aydos, Kaan; Düker, Yalçın; Ickstadt, Katja; Waltrup, Brita Schulze; Golka, Klaus; Bolt, Hermann Maximilian

    2016-01-01

    Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandırma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 ± 69.49 ng/g) of the high exposure group workers in Bandırma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child).

  5. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    PubMed Central

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-01-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations. PMID:27669995

  6. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    NASA Astrophysics Data System (ADS)

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-09-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations.

  7. Assessing Reproductive Toxicity of Two Environmental Toxicants with a Novel in vitro Human Spermatogenic Model

    PubMed Central

    Easley, Charles A.; Bradner, Joshua M.; Moser, Amber; Rickman, Chelsea A.; McEachin, Zachary T.; Merritt, Megan M.; Hansen, Jason M.; Caudle, W. Michael

    2015-01-01

    Environmental influences and insults by reproductive toxicant exposure can lead to impaired spermatogenesis or infertility. Understanding how toxicants disrupt spermatogenesis is critical for determining how environmental factors contribute to impaired fertility. While current animal models are available, understanding of the reproductive toxic effects on human fertility requires a more robust model system. We recently demonstrated that human pluripotent stem cells can differentiate into spermatogonial stem cells/spermatogonia, primary and secondary spermatocytes, and haploid spermatids; a model that mimics many aspects of human spermatogenesis. Here, using this model system, we examine the effects of 2-bromopropane (2-BP) and 1–2, Dibromo-3-chloropropane (DBCP) on in vitro human spermatogenesis. 2-BP and DBCP are non-endocrine disrupting toxicants that are known to impact male fertility. We show that acute treatment with either 2-BP or DBCP induces a reduction in germ cell viability through apoptosis. 2-BP and DBCP affect viability of different cell populations as 2-BP primarily reduces spermatocyte viability whereas DBCP exerts a much greater effect on spermatogonia. Acute treatment with 2-BP or DBCP also reduces the percentage of haploid spermatids. Both 2-BP and DBCP induce reactive oxygen species (ROS) formation leading to an oxidized cellular environment. Taken together, these results suggest that acute exposure with 2-BP or DBCP causes human germ cell death in vitro by inducing ROS formation. This system represents a unique platform for assessing human reproductive toxicity potential of various environmental toxicants in a rapid, efficient, and unbiased format. PMID:25863443

  8. Validation of an LDH Assay for Assessing Nanoparticle Toxicity

    PubMed Central

    Han, Xianglu; Gelein, Robert; Corson, Nancy; Wade-Mercer, Pamela; Jiang, Jingkun; Biswas, Pratim; Finkelstein, Jacob N.; Elder, Alison; Oberdörster, Günter

    2014-01-01

    Studies showed that certain cytotoxicity assays were not suitable for assessing nanoparticle (NP) toxicity. We evaluated a lactate dehydrogenase (LDH) assay for assessing copper (Cu-40, 40 nm), silver (Ag-35, 35 nm; Ag-40, 40 nm), and titanium dioxide (TiO2-25, 25 nm) NPs by examining their potential to inactivate LDH and interference with β-nicotinamide adenine dinucleotide (NADH), a substrate for the assay. We also performed a dissolution assay for some of the NPs. We found that the copper NPs, because of their high dissolution rate, could interfere with the LDH assay by inactivating LDH. Ag-35 could also inactivate LDH probably because of the carbon matrix used to cage the particles during synthesis. TiO2-25 NPs were found to adsorb LDH molecules. In conclusion, NP interference with the LDH assay depends on the type of NPs and the suitability of the assay for assessing NP toxicity should be examined case by case. PMID:21722700

  9. SCREENING FOR TOXIC INDUSTRIAL CHEMICALS USING SEMIPERMEABLE MEMBRANE DEVICES WITH RAPID TOXICITY ASSAYS

    EPA Science Inventory

    A time-integrated sampling device interfaced with two toxicity-based assays is reported for monitoring volatile toxic industrial chemicals (TICs). Semipermeable membrane devices (SPMDs) using dimethylsulfoxide (DMSO) as the fill solvent accumulated each of 17 TICs from the vapor...

  10. Mutation assays involving blood cells that metabolize toxic substances

    DOEpatents

    Crespi, Charles L.; Thilly, William G.

    1985-01-01

    A line of human blood cells which have high levels of oxidative activity (such as oxygenase, oxidase, peroxidase, and hydroxylase activity) is disclosed. Such cells grow in suspension culture, and are useful to determine the mutagenicity of xenobiotic substances that are metabolized into toxic or mutagenic substances. Mutation assays using these cells, and other cells with similar characteristics, are also disclosed.

  11. Indium acetate toxicity in male reproductive system in rats.

    PubMed

    Lee, Kuo-Hsin; Chen, Hsiu-Ling; Leung, Chung-Man; Chen, Hsin-Pao; Hsu, Ping-Chi

    2016-01-01

    Indium, a rare earth metal characterized by high plasticity, corrosion resistance, and a low melting point, is widely used in the electronics industry, but has been reported to be an environmental pollutant and a health hazard. We designed a study to investigate the effects of subacute exposure of indium compounds on male reproductive function. Twelve-week old male Sprague-Dawley rats were randomly divided into test and control groups, and received weekly intraperitoneal injections of indium acetate (1.5 mg/kg body weight) and normal saline, respectively, for 8 weeks. Serum indium levels, cauda epididymal sperm count, motility, morphology, chromatin DNA structure, mitochondrial membrane potential, oxidative stress, and testis DNA content were investigated. The indium acetate-treated group showed significant reproductive toxicity, as well as an increased percentage of sperm morphology abnormality, chromatin integrity damage, and superoxide anion generation. Furthermore, positive correlations among sperm morphology abnormalities, chromatin DNA damage, and superoxide anion generation were also noted. The results of this study demonstrated the toxic effect of subacute low-dose indium exposure during the period of sexual maturation on male reproductive function in adulthood, through an increase in oxidative stress and sperm chromatin DNA damage during spermiogenesis, in a rodent model.

  12. Developmental toxicity assay using high content screening of zebrafish embryos

    PubMed Central

    Lantz-McPeak, Susan; Guo, Xiaoqing; Cuevas, Elvis; Dumas, Melanie; Newport, Glenn D.; Ali, Syed F.; Paule, Merle G.; Kanungo, Jyotshna

    2016-01-01

    Typically, time-consuming standard toxicological assays using the zebrafish (Danio rerio) embryo model evaluate mortality and teratogenicity after exposure during the first 2 days post-fertilization. Here we describe an automated image-based high content screening (HCS) assay to identify the teratogenic/embryotoxic potential of compounds in zebrafish embryos in vivo. Automated image acquisition was performed using a high content microscope system. Further automated analysis of embryo length, as a statistically quantifiable endpoint of toxicity, was performed on images post-acquisition. The biological effects of ethanol, nicotine, ketamine, caffeine, dimethyl sulfoxide and temperature on zebrafish embryos were assessed. This automated developmental toxicity assay, based on a growth-retardation endpoint should be suitable for evaluating the effects of potential teratogens and developmental toxicants in a high throughput manner. This approach can significantly expedite the screening of potential teratogens and developmental toxicants, thereby improving the current risk assessment process by decreasing analysis time and required resources. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID:24871937

  13. [Evaluation of ivermectin's reproductive toxicity to male Carassius auratus].

    PubMed

    Wang, Di; Li, Shao-wu; Geng, Long-wu; Liu, Tong-yan

    2015-10-01

    As a new type of antiparasitic drugs, ivermectin (IVM) has been widely applied in agriculture, stock raising and aquaculture in China because of its broad spectrum and high efficiency. In order to evaluate the IVM' s reproductive toxicity to male Crucian carp (Carassius auratus), IVM was orally given to the experimental fish with different dosages and the gonadosomatic index (GSI), sexual hormone contents (including testosterone and estradiol) in serum and testis, γ-aminobutyric acid content in serum and brain tissues, ultra-structure of spermatozoa and gonadal tissue in fish were determined in this study. The experimental fish were classified into A, B, C and D groups corresponding to the different dosages of IVM (0, 0.3, 0.9 and 1.5 mg . kg-1, respectively once a day for 3 days continuously). Several indices in fish were detected after 8 days self-purification. The results indicated that GSI gradually decreased with the increase of drug dosage, and GSI in groups C and D was significantly lower than that in group A. The contents of testosterone, estradiol and y-aminobutyric acid exhibited a trend of first increasing and then decreasing and reached the peak at group B. Sperm longevity gradually decreased and the motion time also decreased in II, III and IV level sperms with the increasing dosage of IVM, which appeared to be especially obvious in group C and D. No obvious differences were found in the ultra-structure of spermatozoa and gonadal tissues. In conclusion, this study suggested that IVM had no obvious reproductive toxicity to male Crucian carp at the normal therapeutic dosage but could cause serious potential reproductive toxicity to fish at a high concentration. PMID:26995928

  14. Rutin Ameliorates Cyclophosphamide-induced Reproductive Toxicity in Male Rats

    PubMed Central

    Abarikwu, S. O.; Otuechere, C. A.; Ekor, M.; Monwuba, K.; Osobu, D.

    2012-01-01

    Cyclophosphamide (CYC) as an anticancer alkylating agent has been known as a male reproductive toxicant. This study was aimed to evaluate the protective effect of rutin (RUT) on CYC-induced reproductive toxicity. Sexually mature Wistar rats (weighing 199 ± 10 g with five animals in each group) were given CYC (15 mg/kg) and/or RUT (30 mg/kg) twice a week via gavage for 4 weeks. The sperm counts, sperm motility, sperm morphology, daily sperm production (DSP), testicular, and epididymal antioxidant systems: superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and testicular steroidogenic enzymes (3β-hydroxysteroid dehydrogenase and 17β-HSD and spermatogenesis marker enzymes (lactate dehydrogenase (LDH), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) in the testes, epididymis and seminal vesicles were investigated at the end of the fourth week. By the end of the fourth week, RUT prevented lower sperm counts, sperm motility, DSP, and higher abnormal sperm numbers induced by CYC. In testes, RUT decreased SOD, LDH, and SDH and increased CAT, 3β-HSD, 17β-HSD, ALP, and ACP induced by CYC. In epididymis, RUT increased SOD, CAT, GSH, GSH-Px, GR, GST SDH, ALP and ACP and decreased MDA and LDH induced by CYC. In seminal vesicles, marker enzymes were unchanged in rats given CYC alone or in combination with RUT. It appears that RUT ameliorates CYC reproductive toxicity at the investigated dose. PMID:22778522

  15. An epigenetic signal encoded protection mechanism is activated by graphene oxide to inhibit its induced reproductive toxicity in Caenorhabditis elegans.

    PubMed

    Zhao, Yunli; Wu, Qiuli; Wang, Dayong

    2016-02-01

    Although many studies have suggested the adverse effects of engineered nanomaterials (ENMs), the self-protection mechanisms for organisms against ENMs toxicity are still largely unclear. Using Caenorhabditis elegans as an in vivo assay system, our results suggest the toxicity of graphene oxide in reducing reproductive capacity by inducing damage on gonad development. The observed reproductive toxicity of GO on gonad development was due to the combinational effect of germline apoptosis and cell cycle arrest, and DNA damage activation might act as an inducer for this combinational effect. For the underlying molecular mechanism of reproductive toxicity of GO, we raised a signaling cascade of HUS-1/CLK-2-CEP-1-EGL-1-CED-4-CED-3 to explain the roles of core apoptosis signaling pathway and DNA damage checkpoints. Moreover, we identified a miRNA regulation mechanism activated by GO to suppress its induced reproductive toxicity. A mir-360 regulation mechanism was activated by GO to suppress its induced DNA damage-apoptosis signaling cascade through affecting component of CEP-1. Our identified epigenetic signal encoded protection mechanism activated by GO suggests a novel self-protection mechanism for organisms against the ENMs toxicity.

  16. Mutation assays involving blood cells that metabolize toxic substances

    DOEpatents

    Crespi, C.L.; Thilly, W.G.

    1999-08-10

    The present invention pertains to a line of human blood cells which have high levels of oxidative activity (such as oxygenase, oxidase, peroxidase, and hydroxylase activity). Such cells grow in suspension culture, and are useful to determine the mutagenicity of xenobiotic substances that are metabolized into toxic or mutagenic substances. The invention also includes mutation assays using these cells, and other cells with similar characteristics. 3 figs.

  17. Mutation assays involving blood cells that metabolize toxic substances

    DOEpatents

    Crespi, Charles L.; Thilly, William G.

    1999-01-01

    The present invention pertains to a line of human blood cells which have high levels of oxidative activity (such as oxygenase, oxidase, peroxidase, and hydroxylase activity). Such cells grow in suspension culture, and are useful to determine the mutagenicity of xenobiotic substances that are metabolized into toxic or mutagenic substances. The invention also includes mutation assays using these cells, and other cells with similar characteristics.

  18. Toxicity Assays in Nanodrops Combining Bioassay and Morphometric Endpoints

    PubMed Central

    Reboud, Julien; Papine, Alexandre; Angulo, Jesus; Pointu, Hervé; Diaz-Latoud, Chantal; Lajaunie, Christian; Chatelain, François; Arrigo, André-Patrick; Schaack, Béatrice

    2007-01-01

    Background Improved chemical hazard management such as REACH policy objective as well as drug ADMETOX prediction, while limiting the extent of animal testing, requires the development of increasingly high throughput as well as highly pertinent in vitro toxicity assays. Methodology This report describes a new in vitro method for toxicity testing, combining cell-based assays in nanodrop Cell-on-Chip format with the use of a genetically engineered stress sensitive hepatic cell line. We tested the behavior of a stress inducible fluorescent HepG2 model in which Heat Shock Protein promoters controlled Enhanced-Green Fluorescent Protein expression upon exposure to Cadmium Chloride (CdCl2), Sodium Arsenate (NaAsO2) and Paraquat. In agreement with previous studies based on a micro-well format, we could observe a chemical-specific response, identified through differences in dynamics and amplitude. We especially determined IC50 values for CdCl2 and NaAsO2, in agreement with published data. Individual cell identification via image-based screening allowed us to perform multiparametric analyses. Conclusions Using pre/sub lethal cell stress instead of cell mortality, we highlighted the high significance and the superior sensitivity of both stress promoter activation reporting and cell morphology parameters in measuring the cell response to a toxicant. These results demonstrate the first generation of high-throughput and high-content assays, capable of assessing chemical hazards in vitro within the REACH policy framework. PMID:17235363

  19. Baker's yeast assay procedure for testing heavy metal toxicity

    SciTech Connect

    Bitton, G.; Koopman, B.; Wang, H.D.

    1984-01-01

    Baker's yeast (Saccharomyces cerevisiae) is microorganism which is commercially available and sold as packaged dry pellets in any food store at low cost. Studies have been undertaken on the effects of organic xenobiotics as well as heavy metals on yeast metabolism. This type of study has been generally useful in examining the mechanism(s) of chemical toxicity. However, a rapid and quantitative toxicity test using S. cerevisiae as the test organism has not been developed. The purpose of this study was to develop a toxicity assay for heavy metals, using commercial dry yeast as the test microorganism. This rapid and simple procedure is based on the reduction of 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium chloride (INT) to INT-formazan by the yeast electron transport system. The scoring of active cells following exposure to heavy metals was undertaken according to the MINT (malachite green-INT) method developed by Bitton and Koopman.

  20. Evaluating the male and female reproductive toxicity of high-boiling petroleum substances.

    PubMed

    Murray, F Jay; Gray, Thomas M; Roberts, Linda G; Roth, Randy N; Nicolich, Mark J; Simpson, Barry J

    2013-11-01

    To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary.

  1. Historical control data in reproductive and developmental toxicity studies.

    PubMed

    Mylchreest, Eve; Harris, Stephen B

    2013-01-01

    Reproductive and developmental toxicity studies in laboratory animals are conducted as part of the process of evaluating the risk of pharmaceuticals and chemicals to human reproduction and development. In these studies, comparison of data from groups dosed with the test article to a concurrent control group is considered the most relevant approach for the interpretation of adverse effects. However, differences between the concurrent control and treated groups may arise by chance alone, and in some instances may even appear to be dose-related. These limitations of the concurrent control group are of particular concern when interpreting fetal malformation data because malformations are rare events that can be better characterized when incidences in both concurrent control and treated groups are compared to a larger set of control values. Historical control data can be useful not only to understand the range of normal for a given endpoint but also to monitor the biological variability over time due to various external factors (e.g., genetic changes in a strain, changes at the breeding facility). It can also serve to track the performance of the laboratory and identify any changes in the data that may be the result of internal factors at the performing laboratory due to modification in animal diet, seasonal changes, or even the proficiency of the technicians in handling animals and recording fetal and offspring observations. This chapter will provide the reader with guidance on building a laboratory historical control database and applying it to the scientific interpretation of reproductive and developmental toxicity data. Information on sources of external historical control data will be provided and some perspective given on the utility of this data. A discussion of the presentation of historical control data with descriptive statistics will be accompanied by examples of tabulation of the data. Supernumerary rib will be used as an example of how historical control

  2. Historical control data in reproductive and developmental toxicity studies.

    PubMed

    Mylchreest, Eve; Harris, Stephen B

    2013-01-01

    Reproductive and developmental toxicity studies in laboratory animals are conducted as part of the process of evaluating the risk of pharmaceuticals and chemicals to human reproduction and development. In these studies, comparison of data from groups dosed with the test article to a concurrent control group is considered the most relevant approach for the interpretation of adverse effects. However, differences between the concurrent control and treated groups may arise by chance alone, and in some instances may even appear to be dose-related. These limitations of the concurrent control group are of particular concern when interpreting fetal malformation data because malformations are rare events that can be better characterized when incidences in both concurrent control and treated groups are compared to a larger set of control values. Historical control data can be useful not only to understand the range of normal for a given endpoint but also to monitor the biological variability over time due to various external factors (e.g., genetic changes in a strain, changes at the breeding facility). It can also serve to track the performance of the laboratory and identify any changes in the data that may be the result of internal factors at the performing laboratory due to modification in animal diet, seasonal changes, or even the proficiency of the technicians in handling animals and recording fetal and offspring observations. This chapter will provide the reader with guidance on building a laboratory historical control database and applying it to the scientific interpretation of reproductive and developmental toxicity data. Information on sources of external historical control data will be provided and some perspective given on the utility of this data. A discussion of the presentation of historical control data with descriptive statistics will be accompanied by examples of tabulation of the data. Supernumerary rib will be used as an example of how historical control

  3. Restraint stress exacerbates alcohol-induced reproductive toxicity in male rats.

    PubMed

    Priya, P Hari; Girish, B P; Reddy, P Sreenivasula

    2014-12-01

    Cumulative exposure to multiple stresses may lead to aggravating the toxicity of each stress, qualitatively or quantitatively altering biological responses because of toxicological interaction. In this study, we intended to determine the possible effects of restraint stress on reproductive toxicity due to ethanol usage in male rats. Early pubertal male Wistar rats were subjected to either restraint stress (5 h/day) or alcohol intoxication (2 mg/kg body weight) or both for 60 days. Body weights of control and experimental rats were similar during the 60 days of this study. Testes were harvested, weighed, and prepared for enzyme assays, and cauda epididymides were isolated for the determination of density, motility, and viability of stored spermatozoa. Restraint stress or alcohol treatment significantly reduced testis weight and caused significant reductions in steroidogenesis and spermatogenesis. Mean density, motility, and viability of stored spermatozoa were reduced in experimental rats. Plasma testosterone concentrations in rats subjected to restraint stress or alcohol were decreased compared with those of controls, concomitant with increased concentrations of LH and FSH in experimental rats. These data suggest that sub-chronic exposure to restraint stress or alcohol contribute to reduce testicular and epididymal function in exposed rats. The study also suggests that restraint stress exacerbates alcohol-induced reproductive toxicity in rats.

  4. Microcystis aeruginosa toxin: cell culture toxicity, hemolysis, and mutagenicity assays.

    PubMed Central

    Grabow, W O; Du Randt, W C; Prozesky, O W; Scott, W E

    1982-01-01

    Crude toxin was prepared by lyophilization and extraction of toxic Microcystis aeruginosa from four natural sources and a unicellular laboratory culture. The responses of cultures of liver (Mahlavu and PCL/PRF/5), lung (MRC-5), cervix (HeLa), ovary (CHO-K1), and kidney (BGM, MA-104, and Vero) cell lines to these preparations did not differ significantly from one another, indicating that toxicity was not specific for liver cells. The results of a trypan blue staining test showed that the toxin disrupted cell membrane permeability within a few minutes. Human, mouse, rat, sheep, and Muscovy duck erythrocytes were also lysed within a few minutes. Hemolysis was temperature dependent, and the reaction seemed to follow first-order kinetics. Escherichia coli, Streptococcus faecalis, and Tetrahymena pyriformis were not significantly affected by the toxin. The toxin yielded negative results in Ames/Salmonella mutagenicity assays. Microtiter cell culture, trypan blue, and hemolysis assays for Microcystis toxin are described. The effect of the toxin on mammalian cell cultures was characterized by extensive disintegration of cells and was distinguishable from the effects of E. coli enterotoxin, toxic chemicals, and pesticides. A possible reason for the acute lethal effect of Microcystis toxin, based on cytolytic activity, is discussed. Images PMID:6808921

  5. Predicting chronic copper and nickel reproductive toxicity to Daphnia pulex-pulicaria from whole-animal metabolic profiles.

    PubMed

    Taylor, Nadine S; Kirwan, Jennifer A; Johnson, Craig; Yan, Norman D; Viant, Mark R; Gunn, John M; McGeer, James C

    2016-05-01

    The emergence of omics approaches in environmental research has enhanced our understanding of the mechanisms underlying toxicity; however, extrapolation from molecular effects to whole-organism and population level outcomes remains a considerable challenge. Using environmentally relevant, sublethal, concentrations of two metals (Cu and Ni), both singly and in binary mixtures, we integrated data from traditional chronic, partial life-cycle toxicity testing and metabolomics to generate a statistical model that was predictive of reproductive impairment in a Daphnia pulex-pulicaria hybrid that was isolated from an historically metal-stressed lake. Furthermore, we determined that the metabolic profiles of organisms exposed in a separate acute assay were also predictive of impaired reproduction following metal exposure. Thus we were able to directly associate molecular profiles to a key population response - reproduction, a key step towards improving environmental risk assessment and management. PMID:26854702

  6. Predicting chronic copper and nickel reproductive toxicity to Daphnia pulex-pulicaria from whole-animal metabolic profiles.

    PubMed

    Taylor, Nadine S; Kirwan, Jennifer A; Johnson, Craig; Yan, Norman D; Viant, Mark R; Gunn, John M; McGeer, James C

    2016-05-01

    The emergence of omics approaches in environmental research has enhanced our understanding of the mechanisms underlying toxicity; however, extrapolation from molecular effects to whole-organism and population level outcomes remains a considerable challenge. Using environmentally relevant, sublethal, concentrations of two metals (Cu and Ni), both singly and in binary mixtures, we integrated data from traditional chronic, partial life-cycle toxicity testing and metabolomics to generate a statistical model that was predictive of reproductive impairment in a Daphnia pulex-pulicaria hybrid that was isolated from an historically metal-stressed lake. Furthermore, we determined that the metabolic profiles of organisms exposed in a separate acute assay were also predictive of impaired reproduction following metal exposure. Thus we were able to directly associate molecular profiles to a key population response - reproduction, a key step towards improving environmental risk assessment and management.

  7. Reproductive toxicity of DDT in adult male rats.

    PubMed

    Ben Rhouma, K; Tébourbi, O; Krichah, R; Sakly, M

    2001-08-01

    The reproductive toxicity of DDT was investigated in adult male rats exposed to 50 and 100 mg/kg body weight (b.wt) day(-1) for 10 successive days. Compared with control animals, administration of DDT led to a dose-dependent reduction of testicular weight and the number as well as the percentage of motile spermatozoa in the epididymis. Testicular histological observations revealed also a marked loss of gametes in the lumen of seminiferous tubules. In DDT-treated rats, the seminal vesicles weights dropped significantly, resulting from a decrease of testosterone production by testes, whereas serum LH and FSH increased after pesticide exposure. This increase of gonadotrophin levels may be related to an impairment of the negative feedback exerted by the steroid on the hypothalamic--pituitary axis. It is concluded that DDT induced adverse effects on male rat fertility by acting directly on the testes and altering the neuroendocrine function.

  8. Reproductive toxicity in acrylamide-treated female mice.

    PubMed

    Wei, Quanwei; Li, Jian; Li, Xingmei; Zhang, Lei; Shi, Fangxiong

    2014-07-01

    We investigated the reproductive toxicity of acrylamide in female mice. The results from immunohistochemistry provided evidence that nitric oxide synthase (NOS) signaling was involved in the process of follicular development and atresia. Oral administration of acrylamide to female mice led to significantly reduced body weights, organ weights and the number of corpora lutea (P<0.05). Serum progesterone concentrations were significantly reduced (P<0.05) concomitant with the increasing doses of acrylamide; however, 17β-estradiol (E2) concentrations were unchanged with treatment. Measurement of NOS activities indicated that total NOS (TNOS), iNOS and eNOS activities were significantly increased (P<0.05) with increasing doses of acrylamide. The results from in vitro study indicated that acrylamide reduced the viability of mouse granulosa cells in a dose-dependent manner. In summary, acrylamide affected bodily growth and development, as well as reproductive organs, the number of corpora lutea and progesterone production in female mice, possibly acting through the NOS signaling pathway.

  9. Validating potential toxicity assays to assess petroleum hydrocarbon toxicity in polar soil.

    PubMed

    Harvey, Alexis Nadine; Snape, Ian; Siciliano, Steven Douglas

    2012-02-01

    Potential microbial activities are commonly used to assess soil toxicity of petroleum hydrocarbons (PHC) and are assumed to be a surrogate for microbial activity within the soil ecosystem. However, this assumption needs to be evaluated for frozen soil, in which microbial activity is limited by liquid water (θ(liquid)). Influence of θ(liquid) on in situ toxicity was evaluated and compared to the toxicity endpoints of potential microbial activities using soil from an aged diesel fuel spill at Casey Station, East Antarctica. To determine in situ toxicity, gross mineralization and nitrification rates were determined by the stable isotope dilution technique. Petroleum hydrocarbon-contaminated soil (0-8,000 mg kg(-1)), packed at bulk densities of 1.4, 1.7, and 2.0 g cm(-3) to manipulate liquid water content, was incubated at -5°C for one, two, and three months. Although θ(liquid) did not have a significant effect on gross mineralization or nitrification, gross nitrification was sensitive to PHC contamination, with toxicity decreasing over time. In contrast, gross mineralization was not sensitive to PHC contamination. Toxic response of gross nitrification was comparable to potential nitrification activity (PNA) with similar EC25 (effective concentration causing a 25% effect in the test population) values determined by both measurement endpoints (400 mg kg(-1) for gross nitrification compared to 200 mg kg(-1) for PNA), indicating that potential microbial activity assays are good surrogates for in situ toxicity of PHC contamination in polar regions.

  10. Tests for oil/dispersant toxicity: In situ laboratory assays

    SciTech Connect

    Wright, D.A.; Coelho, G.M.; Aurand, D.V.

    1995-12-31

    As part of its readiness program in oil spill response, the Marine Pollution Control Unit (MPCU), Department of Transport, U.K. conducts annual field trials in the North Sea, approximately 30 nautical miles from the southeast coast of England. The trials take the form of controlled releases of crude oil or Medium Fuel/Gas Oil mix (MFO), with and without the application of Corexit 9527 dispersant. In 1994 and 1995 the authors conducted a series of in situ toxicity bioassays in association with these spills with included 48h LC50 tests for turbot (Scophthalmus maximus) and oyster (Crassostrea gigas) larvae, a 48 h oyster (C. gigas) embryonic development test and two full life-cycle assays using the copepods Acartia tonsa and Tisbe battagliai. Tests were also conducted in the Chesapeake Bay laboratory using estuarine species including the copepod Eurytemora affinis and the inland silverside Menidia beryllina. Here, the authors report on the results of these assays, together with 1996 in situ toxicity data resulting from Norwegian field trials in the northern North Sea.

  11. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... addition, it can be used to provide initial information on possible effects on male and female reproductive... tests for repeated dose toxicity as described in § 799.9305 of this part and reproductive/developmental... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The...

  12. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... addition, it can be used to provide initial information on possible effects on male and female reproductive... tests for repeated dose toxicity as described in § 799.9305 of this part and reproductive/developmental... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The...

  13. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... addition, it can be used to provide initial information on possible effects on male and female reproductive... tests for repeated dose toxicity as described in § 799.9305 of this part and reproductive/developmental... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The...

  14. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... addition, it can be used to provide initial information on possible effects on male and female reproductive... tests for repeated dose toxicity as described in § 799.9305 of this part and reproductive/developmental... in 40 CFR Part 792—Good Laboratory Practice Standards apply to this section. The...

  15. Development of an in vitro test system for assessment of male, reproductive toxicity.

    PubMed

    Habas, Khaled; Anderson, Diana; Brinkworth, Martin

    2014-02-10

    There is a need for improved reproductive toxicology assays that do not require large numbers of animals but are sensitive and informative. Therefore, Staput velocity-sedimentation separation followed by culture of specific mouse testicular cells was used as such a system. The specificity of separation was assessed using immunocytochemistry to identify spermatids, spermatocytes and spermatogonia. The efficacy of the system to detect toxicity was then evaluated by analysing the effects of hydrogen peroxide (H2O2) by the terminal uridine-deoxynucleotide end-labelling (TUNEL) assay to show the rate of apoptosis induced among the different types of germ cells. We found that 2 h of treatment at both 1 and 10 μM induced increases of over ∼10-fold in the percentage of apoptotic cells (p≤0.001), confirming that testicular germ cells are prone to apoptosis at very low concentrations of H2O2. It was also demonstrated for the first time for this compound that spermatogonia are significantly more susceptible than spermatocytes, which are more affected than spermatids. This reflects the proportion of actively dividing cells in these cell types, suggesting a mechanism for the differential sensitivity. The approach should thus form the basis of a useful test system for reproductive and genetic toxicology in the future.

  16. SCREENING LEVEL REPRODUCTION ASSAY WITH THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

    EPA Science Inventory

    There has been recent concern for the potential effects of endocrine disrupting chemicals (EDCs) on reproduction and development of humans and wildlife species. The U.S. Environment Protection Agency (EPA) has identified EDC issues as one of six high priority research areas. Furt...

  17. Evaluation of the male reproductive toxicity of gallium arsenide.

    PubMed

    Bomhard, Ernst M; Cohen, Samuel M; Gelbke, Heinz-Peter; Williams, Gary M

    2012-10-01

    Gallium arsenide is an important semiconductor material marketed in the shape of wafers and thus is not hazardous to the end user. Exposure to GaAs particles may, however, occur during manufacture and processing. Potential hazards require evaluation. In 14-week inhalation studies with small GaAs particles, testicular effects have been reported in rats and mice. These effects occurred only in animals whose lungs showed marked inflammation and also had hematologic changes indicating anemia and hemolysis. The time- and concentration-dependent progressive nature of the lung and blood effects together with bioavailability data on gallium and arsenic lead us to conclude that the testicular/sperm effects are secondary to hypoxemia resulting from lung damage rather than due to a direct chemical effect of gallium or arsenide. Conditions leading to such primary effects are not expected to occur in humans at production and processing sites. This has to be taken into consideration for any classification decision for reproductive toxicity; especially a category 1 according to the EU CLP system is not warranted.

  18. Abnormal secretion of reproductive hormones and antioxidant status involved in quinestrol-induced reproductive toxicity in adult male rat.

    PubMed

    Li, Jian; Wang, Hongwei; Zhang, Jiliang; Zhou, Bianhua; Si, Lifang; Wei, Lan; Li, Xiang

    2014-02-01

    This study aimed to evaluate the effects of quinestrol, a synthetic oestrogen homologue with reproductive toxicity, on the secretion of reproductive hormones and antioxidant status in adult male rat. Our results showed that quinestrol exposure significantly decreased the weight of the testis, epididymides, seminal vesicle, and prostate, as well as the sperm counts in the cauda epididymis of rats. Quinestrol significantly reduced the size of seminiferous tubules and the total number of spermatogenic cells. Serum testosterone, follitropin, and lutropin were also significantly reduced in a dose-related manner after quinestrol exposure. Meanwhile, the activity of superoxide dismutase, glutathione peroxidase, and total antioxide capacity significantly decreased, whereas the malondialdehyde and nitric oxide concentrations significantly increased in the testes. These findings revealed that endocrine disorders of reproductive hormones and oxidative stress may be involved in reproductive toxicity induced by quinestrol in adult male rats. PMID:24183492

  19. The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals.

    PubMed

    van der Burg, Bart; Wedebye, Eva Bay; Dietrich, Daniel R; Jaworska, Joanna; Mangelsdorf, Inge; Paune, Eduard; Schwarz, Michael; Piersma, Aldert H; Kroese, E Dinant

    2015-08-01

    There is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible.

  20. Economic benefits of using adaptive predictive models of reproductive toxicity in the context of a tiered testing program.

    PubMed

    Martin, Matthew T; Knudsen, Thomas B; Judson, Richard S; Kavlock, Robert J; Dix, David J

    2012-02-01

    A predictive model of reproductive toxicity, as observed in rat multigeneration reproductive (MGR) studies, was previously developed using high throughput screening (HTS) data from 36 in vitro assays mapped to 8 genes or gene-sets from Phase I of USEPA ToxCast research program, the proof-of-concept phase in which 309 toxicologically well characterized chemicals were testing in over 500 HTS assays. The model predicted the effects on male and female reproductive function with a balanced accuracy of 80%. In a theoretical examination of the potential impact of the model, two case studies were derived representing different tiered testing scenarios to: 1) screen-out chemicals with low predicted probability of effect; and 2) screen-in chemicals with a high probability of causing adverse reproductive effects. We define 'testing cost efficiency' as the total cost divided by the number of positive chemicals expected in the definitive guideline toxicity study. This would approach $2.11 M under the current practice. Under case study 1, 22% of the chemicals were screened-out due to low predicted probability of adverse reproductive effect and a misclassification rate of 12%, yielding a test cost efficiency of $1.87 M. Under case study 2, 13% of chemicals were screened-in yielding a testing cost efficiency of $1.13 M per test-positive chemical. Applying the model would also double the total number of positives identified. It should be noted that the intention of the case studies is not to provide a definitive mechanism for screening-in or screening-out chemicals or account for the indirect costs of misclassification. The case studies demonstrate the customizability of the model as a tool in chemical testing decision-making. The predictive model of reproductive toxicity will continue to evolve as new assays become available to fill recognized biological gaps and will be combined with other predictive models, particularly models of developmental toxicity, to form an initial tier

  1. [Progress in studies of the male reproductive toxicity of pyrethroid insecticides].

    PubMed

    Yao, Ke-Wen; Wang, Jie-Dong

    2008-03-01

    As a new type of pesticides and because of their high performance and low toxicity, pyrethroid insecticides are widely used in place of organochlorine insecticides both in agriculture and in the home. In the recent years, more and more evidence indicates that pyrethroid insecticides can reduce sperm count and motility, cause deformity of the sperm head, increase the count of abnormal sperm, damage sperm DNA and induce its aneuploidy rate, as well as affect sex hormone levels and produce reproductive toxicity. The present article reviews the advances in the studies of male reproductive toxicity of pyrethroid pesticides by experiment in animals and human population, discusses the mechanism of male reproductive toxicity of pesticides and raises some problems concerning the evaluation of human reproductive hazards.

  2. Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals

    EPA Science Inventory

    The mode of action for the reproductive toxicity of triazole antifungals have been previously characterized by an observed increased in serum testosterone, hepatotoxicity, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these m...

  3. Toxicity benchmarks for antimony, barium, and beryllium determined using reproduction endpoints for Folsomia candida, Eisenia fetida, and Enchytraeus crypticus.

    PubMed

    Kuperman, Roman G; Checkai, Ronald T; Simini, Michael; Phillips, Carlton T; Speicher, Jason A; Barclift, David J

    2006-03-01

    The U.S. Environmental Protection Agency is developing ecological soil screening levels (Eco-SSLs) for the ecological risk assessment of contaminants at Superfund sites. The Eco-SSLs for several soil contaminants have been developed from toxicity benchmarks for soil invertebrates in the existing literature. Insufficient information to generate Eco-SSLs for Sb, Ba, and Be necessitated toxicity testing to fill the data gaps. We used standardized toxicity tests with the earthworm Eiseniafetida, enchytraeid Enchytraeus crypticus, and collembolan Folsomia candida in the present study. These tests were selected on the basis of their ability to measure chemical toxicity to ecologically relevant test species during chronic assays and their inclusion of at least one reproduction component among the measurement endpoints. Tests were conducted in Sassafras Sandy Loam soil, which supports relatively high bioavailability of metals. Weathering and aging procedures for metals in amended soil were incorporated into these studies to better reflect exposure conditions in the field. The relative toxicity of metals to the soil invertebrates tested was Be > Sb > Ba based on the median effective concentration values for reproduction. These studies produced toxicological data that can contribute to the development of Eco-SSLs for Sb, Ba, and Be for soil invertebrates.

  4. Toxic effects of bisphenol A on sexual and asexual reproduction in Hydra oligactis.

    PubMed

    Fukuhori, N; Kitano, M; Kimura, H

    2005-05-01

    Hydra oligactis, an evolutionarily primitive invertebrate, produced eggs or testes (sexual reproduction) when starved at 10 degrees C, and produced buds (asexual reproduction) when fed at 20 degrees C. Bisphenol A (BPA) at 2-4 mg/L given to male or female hydra had adverse effects on both sexual and asexual reproduction. Despite the estrogenic nature of BPA, testis formation and egg formation were similarly affected. The doses causing these acute toxicities were comparable to those reported earlier in aquatic invertebrates and were much higher than environmentally detected doses, at which the disruption of the endocrine system has been reported in fishes. All these facts indicate that the adverse effects are the results of general toxicity and may not be due to the estrogenic function of the compound. On the other hand, we found that BPA at 1 mg/L (a dose still much higher than environmental doses) stimulated asexual reproduction. No such stimulation of sexual reproduction was seen. When male hydras were fed at 10 degrees C, they produced both buds and testes simultaneously. BPA at 0.5 and 1 mg/L under this condition also stimulated asexual reproduction, whereas it suppressed sexual reproduction more severely than BPA at 2-3 mg/L. There may be some interaction between processes involved in sexual and asexual reproduction under this condition, and the stimulation of asexual reproduction by BPA may cause suppression of sexual reproduction.

  5. Review of the reproductive biology of amphipods and their endocrine regulation: identification of mechanistic pathways for reproductive toxicants.

    PubMed

    Hyne, Ross V

    2011-12-01

    The reproductive biology of amphipods is reviewed to update the knowledge of the male and female reproductive processes of oogenesis and spermatogenesis as well as the endocrine systems of amphipods with the aim of advancing studies of reproductive toxicology. The ovarian and reproduction cycles of female gammaridean amphipods are closely correlated with the molt cycle, which is under direct control by the steroid hormone 20-hydroxyecdysone. The ability of males to copulate and subsequently for females to ovulate is restricted to the early postmolt period of the females. New developments in our understanding of the molt cycle and the endocrine regulatory pathways for reproduction using genomics techniques on other crustacean species are also discussed. The arthropod sterol ponasterone A or xenobiotics such as the fungicide fenarimol have been shown to elicit endocrine disruption in some crustaceans by acting as an agonist for 20-hydroxyecdysone at the ecdysone receptor or by inhibiting the synthesis of 20-hydroxyecdysone, respectively, resulting in disruption of molting and reproduction. Recent studies suggest that cadmium can inhibit secondary vitellogenesis in amphipods. Experimental approaches for examining the metabolic pathways associated with ecdysteroid hormonal signaling or metabolism, exoskeleton maintenance and molting, and the regulation of vitellogenin in amphipods are discussed. This information should aid in the identification of useful biomarkers for reproductive toxicity.

  6. QSAR models for reproductive toxicity and endocrine disruption in regulatory use – a preliminary investigation†

    PubMed Central

    Jensen, G.E.; Niemelä, J.R.; Wedebye, E.B.; Nikolov, N.G.

    2008-01-01

    A special challenge in the new European Union chemicals legislation, Registration, Evaluation and Authorisation of Chemicals, will be the toxicological evaluation of chemicals for reproductive toxicity. Use of valid quantitative structure–activity relationships (QSARs) is a possibility under the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data and epidemiological human studies), dominant lethal effect in rodents (in vivo) and Drosophila melanogaster sex-linked recessive lethal effect. A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened. A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models. The chemicals predicted positive for reproductive toxicity will be submitted to the Danish Environmental Protection Agency as scientific input for a future updated advisory classification list with advisory classifications for concern for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption. PMID:19061080

  7. Potato (Solanum tuberosum) greenhouse tuber production as an assay for asexual reproduction effects from herbicides

    EPA Science Inventory

    The present study determined whether young potato plants can be used as an assay to indicate potential effects of pesticides on asexual reproduction. Solanum tuberosum (Russet Burbank) plants were grown from seed pieces in a mineral soil in pots under greenhouse conditions. Plant...

  8. GENDER BASED DIFFERENCES IN ENDOCRINE AND REPRODUCTIVE TOXICITY

    EPA Science Inventory

    Basic differences in male versus female reproductive physiology lead to differentials in their respective susceptibilities to chemical insult as evidenced by a variety of observations. As individuals undergo maturation from prenatal sex differentiation through pubertal developme...

  9. PRIORITIZATION OF NTP REPRODUCTIVE TOXICANTS FOR FIELD STUDIES

    EPA Science Inventory

    Population studies evaluate human reproductive impairment are time consuming,
    expensive, logistically difficult and with limited resources must be prioritized to
    effectivelyprevent the adverse health effects in humans. Interactions among
    health scientists, unions,a...

  10. Current Development in Reproductive Toxicity Testing of Pesticides

    EPA Science Inventory

    A protocol to evaluate the potential developmental and reproductive effects of test chemicals has been developed by the Life Stages Task Force of the International Life Sciences Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical Safety Asses...

  11. Dissecting the assays to assess microbial tolerance to toxic chemicals in bioprocessing.

    PubMed

    Zingaro, Kyle A; Nicolaou, Sergios A; Papoutsakis, Eleftherios T

    2013-11-01

    Microbial strains are increasingly used for the industrial production of chemicals and biofuels, but the toxicity of components in the feedstock and product streams limits process outputs. Selected or engineered microbes that thrive in the presence of toxic chemicals can be assessed using tolerance assays. Such assays must reasonably represent the conditions the cells will experience during the intended process and measure the appropriate physiological trait for the desired application. We review currently used tolerance assays, and examine the many parameters that affect assay outcomes. We identify and suggest the use of the best-suited assays for each industrial bioreactor operating condition, discuss next-generation assays, and propose a standardized approach for using assays to examine tolerance to toxic chemicals.

  12. Acute, chronic and reproductive toxicity of complex cyanobacterial blooms in Daphnia magna and the role of microcystins.

    PubMed

    Smutná, Marie; Babica, Pavel; Jarque, Sergio; Hilscherová, Klára; Maršálek, Blahoslav; Haeba, Maher; Bláha, Ludek

    2014-03-01

    Toxic cyanobacterial blooms are a global threat to human health and aquatic biota. While the ecotoxicity of cyanobacterial toxins such as microcystins has been studied extensively, little is known about the risks they pose in the wild, i.e. within complex biomasses. In this work, crustaceans (Daphnia magna) were exposed to varying concentrations (0-405 mg d.w L(-1)) of eight complex cyanobacterial water bloom samples in a series of acute (48 h) and chronic (21 day) toxicity experiments. Further acute and chronic exposure assays were performed using aqueous extracts of the crude biomass samples and two fractions prepared by solid phase extraction (SPE) of the aqueous extracts. The cyanobacterial biomasses differed with respect to their dominant cyanobacterial species and microcystin contents. High acute toxicity was observed for 6 of the 8 crude biomass samples. Chronic exposure assays were performed using one complex biomass sample and its various subsamples/fractions. The complex biomass, the crude aqueous extract, and the microcystin-free SPE permeate all elicited similar and significant lethal effects, with LC50 values of around 35.6 mg biomass d.w L(-1) after 21 days. The cyanobacterial biomass samples also affected reproductive health, significantly increasing the time to the first brood (LOEC = 45 mg d.w L(-1) exposure) and inhibiting fecundity by 50% at 15 mg d.w L(-1). Conversely, the microcystin-containing C18-SPE eluate fraction had only weak effects in the chronic assay. These results indicate that cyanobacterial water blooms are highly toxic to zooplankton (both acutely and chronically) at environmentally relevant concentrations. However, the effects observed in the acute and chronic assays were independent of the samples' microcystin contents. Our results thus point out the importance of other cyanobacterial components such as lipopolysaccharides, various peptides and depsipeptides, polar alkaloid metabolites or other unidentified metabolites in the

  13. Photoenhanced toxicity of a weathered oil on Ceriodaphnia dubia reproduction

    USGS Publications Warehouse

    Calfee, R.D.; Little, E.E.; Cleveland, L.; Barron, M.G.

    1999-01-01

    Traditionally, the toxic effects of petroleum have been investigated by conducting studies in the absence of ultraviolet radiation (UV). Photomediated toxicity is often not considered, and the toxic effects of an oil spill can be grossly underestimated. The toxicity of a weathered oil collected from a monitoring well at an abandoned oil field to Ceriodaphnia dubia was examined in the presence of UV. A solar simulator equipped with UVB, UVA, and cool white lamps was used to generate environmentally comparable solar radiation intensities. C. dubia were exposed to six concentrations of water accommodated fractions (WAD of weathered oil in conjunction with three levels of laboratory simulated UV (Reference = < 0.002 ??W/cm2 UVB; 3.0 ??W/cm2 UVA; Low = 0.30 ??W/cm2 UVB; 75.0 ??W/cm2 UVA; High = 2.0 ??W/cm2UVB; 340.0 ??W/cm2 UVA) and visible light. Seven day static renewal bioassays were used to characterize WAF/UV toxicity. WAF toxicity significantly (p < 0.05) increased when the organisms were exposed to WAF in the presence of UV. The photoenhanced toxicity of the WAF increased with WAF concentration within each UV regime. Relative to the reference light regime, the average number of neonates from adults exposed to 1.6 mg TPH/L decreased significantly by 20% within the low light regime, and by 60% within the high light regime. These results indicate that organisms exposed to dissolved-phase weathered oil in the presence of environmentally realistic solar radiation, exhibit 1.3-2.5 times greater sensitivity, relative to organisms exposed under traditional laboratory fluorescent lighting.

  14. Evaluation of an alternative in vitro test battery for detecting reproductive toxicants in a grouping context.

    PubMed

    Kroese, E Dinant; Bosgra, Sieto; Buist, Harrie E; Lewin, Geertje; van der Linden, Sander C; Man, Hai-yen; Piersma, Aldert H; Rorije, Emiel; Schulpen, Sjors H W; Schwarz, Michael; Uibel, Frederik; van Vugt-Lussenburg, Barbara M A; Wolterbeek, Andre P M; van der Burg, Bart

    2015-08-01

    Previously we showed a battery consisting of CALUX transcriptional activation assays, the ReProGlo assay, and the embryonic stem cell test, and zebrafish embryotoxicity assay as 'apical' tests to correctly predict developmental toxicity for 11 out of 12 compounds, and to explain the one false negative [7]. Here we report on applying this battery within the context of grouping and read across, put forward as a potential tool to fill data gaps and avoid animal testing, to distinguish in vivo non- or weak developmental toxicants from potent developmental toxicants within groups of structural analogs. The battery correctly distinguished 2-methylhexanoic acid, monomethyl phthalate, and monobutyltin trichloride as non- or weak developmental toxicants from structurally related developmental toxicants valproic acid, mono-ethylhexyl phthalate, and tributyltin chloride, respectively, and, therefore, holds promise as a biological verification model in grouping and read across approaches. The relevance of toxicokinetic information is indicated.

  15. The Epigenetic Consequences of Paternal Exposure to Environmental Contaminants and Reproductive Toxicants.

    PubMed

    Estill, Molly S; Krawetz, Stephen A

    2016-09-01

    Human populations are exposed to a wide spectrum of environmental contaminants, some of which are considered reproductive toxins. The influence of such toxins on the male reproductive system has been investigated extensively in animal models, while epidemiological studies seek to understand the effect of human exposures. The basic tenant of epidemiological studies in male human reproduction is to infer how one or more substances alter the hormonal profile, seminal characteristics, or both. Determining if a substance alters semen quality may not always provide the underlying mechanism. The mechanisms by which toxins may alter human sperm and semen quality are typically examined as a function of hormonal changes and cellular damage. The possibility that more subtle epigenetic alterations underlie some of the reproductive changes has, until recently, received little attention. In this review, we discuss the roles of epigenetics in human spermatogenesis, while considering the impact of reproductive toxicants on the epigenome. PMID:27357567

  16. Reproductive toxicity of low-level lead exposure in men

    SciTech Connect

    Telisman, Spomenka Colak, Bozo; Pizent, Alica; Jurasovic, Jasna; Cvitkovic, Petar

    2007-10-15

    Parameters of semen quality, seminal plasma indicators of secretory function of the prostate and seminal vesicles, sex hormones in serum, and biomarkers of lead, cadmium, copper, zinc, and selenium body burden were measured in 240 Croatian men 19-52 years of age. The subjects had no occupational exposure to metals and no known other reasons suspected of influencing male reproductive function or metal metabolism. After adjusting for age, smoking, alcohol, blood cadmium, and serum copper, zinc, and selenium by multiple regression, significant (P<0.05) associations of blood lead (BPb), {delta}-aminolevulinic acid dehydratase (ALAD), and/or erythrocyte protoporphyrin (EP) with reproductive parameters indicated a lead-related increase in immature sperm concentration, in percentages of pathologic sperm, wide sperm, round sperm, and short sperm, in serum levels of testosterone and estradiol, and a decrease in seminal plasma zinc and in serum prolactin. These reproductive effects were observed at low-level lead exposure (BPb median 49 {mu}g/L, range 11-149 {mu}g/L in the 240 subjects) common for general populations worldwide. The observed significant synergistic effect of BPb and blood cadmium on increasing serum testosterone, and additive effect of a decrease in serum selenium on increasing serum testosterone, may have implications on the initiation and development of prostate cancer because testosterone augments the progress of prostate cancer in its early stages.

  17. Environmental toxicants: hidden players on the reproductive stage.

    PubMed

    Giudice, Linda C

    2016-09-15

    A growing body of evidence suggests that environmental contaminants, including natural gas, endocrine-disrupting chemicals, and air pollution, are posing major threats to human reproductive health. Many chemicals are in commonly used personal care products, linings of food containers, pesticides, and toys, as well as in discarded electronic waste, textile treatments, and indoor and outdoor air and soil. They travel across borders through trade, food, wind, and water. Reproductive and other health effects can be incurred by exposures in utero, in the neonatal or adolescent periods, or in adulthood and can have transgenerational effects. Most chemicals do not undergo the level of evaluation for harm that pharmaceuticals, e.g., do, and they are rarely seen or seriously considered as a danger to human health. Herein, the burden of exposures, challenges in assessing data and populations at risk, models for evaluating harm, and mechanisms of effects are briefly reviewed, ending with a call to action for reproductive health care professionals to advocate for further research, education, and chemical policy reform for the health of this and future generations. PMID:27545021

  18. A simple, rapid, inexpensive assay for toxic chemicals using a bacterial indicator

    SciTech Connect

    Botsford, J.L.; Hillaker, T.; Robertson, B.; Gonzales, M.; Benavidez, M.; Jones, B.; Baker, R.; Steen, W.; Pacheco, F.; Homer, V.; Lucero, O.; Matthews, M.; Koehler, V.

    1996-12-31

    A simple test for toxic chemicals has been developed. Rhizobium meliloti is combined with the toxic chemical. A tetrazolium dye, MTT (3-[4,5-Dimethylthiazol-2-yl]2,5-diphenyl-tetrazolium bromide) is added. The bacterium reduces this dye, causing the optical absorbance to increase dramatically. The increase can be determined with a simple spectrophotometer. Toxic chemicals and minerals inhibit the reduction of the dye. Presumably the dye serves as a terminal electron acceptor for electron transport. Toxic substances presumably damage the electron transport system. The results compare favorably with published results of tests using the Microtox{trademark} assay and with the Polytox{trademark} assay. This assay is simpler and requires no specialized equipment. It should be possible to use this assay in a third world situation.

  19. Ethyl t-butyl ether: review of reproductive and developmental toxicity.

    PubMed

    de Peyster, Ann

    2010-06-01

    Ethyl t-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. Knowledge of developmental and reproductive toxicity potential of ETBE is critical for making informed decisions about acceptance and regulations. This review discusses toxicology studies providing information about effects on reproduction and the conceptus. Seven GLP-compliant studies following widely accepted protocols have focused specifically on developmental and reproductive toxicity (DART) in rats and rabbits exposed to ETBE by gavage with doses up to 1,000 mg/kg body weight/day, the limit specified in standardized test guidelines. Other repeat-dose general toxicology studies have administered ETBE to rodents for up to 180 days, and included reproductive organ weights, histology, or other indications of reproductive system structure or function. DART potential of the main ETBE metabolite t-butyl alcohol and class-related MTBE has also been studied. More GLP-compliant studies exist for evaluating ETBE using well-established, currently recommended protocols than are available for many other chemicals used today. The database for determining ETBE DART potential is adequate, although not all study details are currently easily accessible for peer-review. ETBE does not appear to be selectively toxic to reproduction or embryofetal development in the absence of other manifestations of general toxicity. Studies using recommended methods for sample preservation and analysis have shown no targeted effect on the reproductive system. No embryofetal effects were observed in rabbits. Early postnatal rat pup deaths show no clear dose-response and have largely been attributed to total litter losses with accompanying evidence of maternal neglect or frank maternal morbidity. PMID:20544807

  20. Toxicity of 8-Hydroxyquinoline in Cryprinus carpio Using the Acute Toxicity Test, Hepatase Activity Analysis and the Comet Assay.

    PubMed

    Yan, Shuaiguo; Chen, Lili; Dou, Xiaofei; Qi, Meng; Du, Qiyan; He, Qiaoqiao; Nan, Mingge; Chang, Zhongjie; Nan, Ping

    2015-08-01

    To evaluate the environmental toxicity of 8-hydroxyquinoline (8-HOQ), an important industrial raw material found in China's major ornamental fish, Cryprinus carpio, using the acute toxicity test, hepatase activity analysis and the comet assay. The results indicated that 8-HOQ had significant acute toxicity in adult C. carpio with a 96 h-LC50 of 1.15 and 0.22 mg L(-1) hepatic quinoline residues as assessed by HPLC. 8-HOQ also induced genotoxicity in the form of strand breaks in the DNA of hepatic cells as shown by the comet assay. With regard to physiological toxicity, 8-HOQ induced a decrease in the activities of hepatic GOT and GPT with increased exposure concentration and time. These data suggest that 8-HOQ may be toxic to the health of aquatic organisms when accidentally released into aquatic ecosystems. The data also suggest that the comet assay may be used in biomonitoring to determine 8-HOQ genotoxicity and hepatic GPT and GOT activities may be potential biomarkers of physiological toxicity.

  1. Toxicity of 8-Hydroxyquinoline in Cryprinus carpio Using the Acute Toxicity Test, Hepatase Activity Analysis and the Comet Assay.

    PubMed

    Yan, Shuaiguo; Chen, Lili; Dou, Xiaofei; Qi, Meng; Du, Qiyan; He, Qiaoqiao; Nan, Mingge; Chang, Zhongjie; Nan, Ping

    2015-08-01

    To evaluate the environmental toxicity of 8-hydroxyquinoline (8-HOQ), an important industrial raw material found in China's major ornamental fish, Cryprinus carpio, using the acute toxicity test, hepatase activity analysis and the comet assay. The results indicated that 8-HOQ had significant acute toxicity in adult C. carpio with a 96 h-LC50 of 1.15 and 0.22 mg L(-1) hepatic quinoline residues as assessed by HPLC. 8-HOQ also induced genotoxicity in the form of strand breaks in the DNA of hepatic cells as shown by the comet assay. With regard to physiological toxicity, 8-HOQ induced a decrease in the activities of hepatic GOT and GPT with increased exposure concentration and time. These data suggest that 8-HOQ may be toxic to the health of aquatic organisms when accidentally released into aquatic ecosystems. The data also suggest that the comet assay may be used in biomonitoring to determine 8-HOQ genotoxicity and hepatic GPT and GOT activities may be potential biomarkers of physiological toxicity. PMID:26067700

  2. Multigeneration Reproduction and Male Developmental Toxicity Studies on Atrazine in Rats

    PubMed Central

    DeSesso, John M; Scialli, Anthony R; White, Tacey E K; Breckenridge, Charles B

    2014-01-01

    BACKGROUND Reproductive toxicity of Atrazine (ATR) was evaluated in two rat multigenerational studies. Development of male reproductive parameters was evaluated in separate studies after prenatal or postnatal exposure. METHODS In multigenerational studies, rats received dietary concentrations of 0, 10, 50, 100 or 500 ppm ATR. In separate studies in female rats, ATR was administered by gavage at 0, 1, 5, 25 or 125 mg/kg/day during pregnancy (GD6–21) or lactation (LD2–21). Plasma testosterone concentration, testicular and epididymal weights, and sperm counts were measured in male offspring on PND70 and 170. RESULTS In the multigenerational studies, parental systemic toxicity occurred at 500 ppm (38.7 mg/kg/day), but reproductive endpoints were unaffected. In the prenatal study, maternal toxicity and embryo-fetal mortality occurred at 125 mg/kg/day. In male offspring, testosterone levels and sperm counts were unaffected, although the percentage of abnormal sperm increased at 125 mg/kg/day (PND 70) and 25 mg/kg/day (PND170). In the postnatal study, maternal toxicity and reduced body weights of male offspring occurred at 125 mg/kg/day. Additionally, reduced testicular (PND70, PND170) and epididymal (PND70) weights and increased numbers of abnormal sperm (PND70, PND170) were seen, but no changes in plasma testosterone or sperm counts. CONCLUSIONS Dietary administration of ATR did not affect rat reproduction up to a parentally toxic dose of 38.7 mg/kg/day. Some effects on male reproductive system development occurred after high dose, bolus administration to dams, but doses were much higher than expected under normal use conditions. Thus, oral RfDs for ATR would be protective for reproductive effects PMID:24797874

  3. Rapid aquatic toxicity assay utilizing labeled thymidine incorporation in sea urchin embryos

    SciTech Connect

    Jackim, E.; Nacci, D.

    1984-01-01

    Aquatic toxicity was evaluated in the sea urchin embryo (Arbacea punctulata) by the inhibition of tritiated thymidine incorporation after a brief exposure to toxic chemicals. Arbacia is a useful surrogate species for assay: well-studied, easily cultured and fertile virtually year round. The simplicity and speed of this test system lends itself to screening large numbers of compounds, mixtures or water samples.

  4. A FLUORESCENCE BASED ASSAY FOR DNA DAMAGE INDUCED BY TOXIC INDUSTRIAL CHEMICALS

    EPA Science Inventory

    One of the reported effects for exposure to many of the toxic industrial chemicals is DNA damage. The present study describes a simple, rapid and innovative assay to detect DNA damage resulting from exposure of surrogate DNA to toxic industrial chemicals (acrolein, allylamine, ch...

  5. VAPOR SAMPLING DEVICE FOR INTERFACE WITH MICROTOX ASSAY FOR SCREENING TOXIC INDUSTRIAL CHEMICALS

    EPA Science Inventory

    A time-integrated sampling system interfaced with a toxicity-based assay is reported for monitoring volatile toxic industrial chemicals (TICs). Semipermeable membrane devices (SPMDs) using dimethyl sulfoxide (DMSO) as the fill solvent accumulated each of 17 TICs from the vapor...

  6. A Call for Nominations of Quantitative High-Throughput Screening Assays from Relevant Human Toxicity Pathways

    EPA Science Inventory

    The National Research Council of the United States National Academies of Science has recently released a document outlining a long-range vision and strategy for transforming toxicity testing from largely whole animal-based testing to one based on in vitro assays. “Toxicity Testin...

  7. Predictive Signatures from ToxCast Data for Chronic, Developmental and Reproductive Toxicity Endpoints

    EPA Science Inventory

    The EPA ToxCast program is using in vitro assay data and chemical descriptors to build predictive models for in vivo toxicity endpoints. In vitro assays measure activity of chemicals against molecular targets such as enzymes and receptors (measured in cell-free and cell-based sys...

  8. Perspectives on Validation of High-Throughput Assays Supporting 21st Century Toxicity Testing

    EPA Science Inventory

    In vitro high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. ...

  9. STRESS PATHWAY-BASED REPORTER ASSAYS TO ASSESS TOXICITY OF ENVIRONMENTAL CHEMICALS.

    EPA Science Inventory

    There is an increasing need for assays for the rapid and efficient assessment of toxicities of large numbers of environmental chemicals. To meet this need, we are developing cell-based reporter assays that measure the activation of key molecular stress pathways. We are using pro...

  10. Reproductive toxicity of trenbolone acetate in embryonically exposed Japanese quail.

    PubMed

    Quinn, Michael J; Lavoie, Emma T; Ottinger, Mary Ann

    2007-01-01

    This study was conducted to assess the effects of a one time embryonic exposure to trenbolone acetate on reproductive development and function in Japanese quail (Coturnix japonica). Embryos were exposed to either 0.05, 0.5, 5, or 50microg trenbolone or a sesame oil vehicle control at embryonic day 4. Onset of puberty, gonadal histopathology, sperm motility, cloacal gland size, and male copulatory behavior were assessed in adults. Trenbolone delayed onset of puberty in males, inhibited cloacal gland development, and reduced male reproductive behaviors. Industry laboratories have shown trenbolone acetate to be non-teratogenic in mammalian studies. Our study, however, shows that this one time in ovo exposure delayed onset of puberty in and suppressed adult copulatory behavior in quail males. These results suggest that this one time embryonic exposure to trenbolone may have disrupted development of either the central nervous system or the hypothalamic-pituitary-gonadal axis. This is the first study to demonstrate a demasculinizing effect on copulatory behavior in Japanese quail from embryonic exposure to a non-aromatizable androgenic chemical. More studies are needed to determine the mechanisms behind the observed effects.

  11. Zebrafish reproductive toxicity induced by chronic perfluorononanoate exposure.

    PubMed

    Zhang, Wei; Sheng, Nan; Wang, Minhui; Zhang, Hongxia; Dai, Jiayin

    2016-06-01

    Perfluoroalkyl acids (PFAAs) are a group of anthropogenic compounds that have been widely used in consumer products for over 50 years. One of the most dominant PFAAs is perfluorononanoate (PFNA), a compound detected ubiquitously in aquatic ecosystems. While PFNA is suspected of being an endocrine disruptor, the mechanisms behind PFNA-induced reproductive disorders are poorly understood. The aim of this study was to investigate the reproduction-related effects and possible mechanisms of PFNA on adult zebrafish (Danio rerio) following 180 days of exposure at different concentrations (0.01, 0.1, 1mg/L). PFNA concentration in the gonads of zebrafish was tested by HPLC-MS/MS after chronic exposure to study possible inconsistent accumulation between the genders. The results showed that the accumulation of PFNA in the male gonads was almost one-fold higher than that in the female gonads, indicating a possible higher PFAA gonad burden for male zebrafish. Significant reductions in the male gonadosomatic index (GSI) and female egg production were observed. In addition, the decreased 72h hatching rate displayed an evident dosage effect, indicating that maternal exposure to PFNA might impair offspring developmental success. To investigate how PFNA exposure affects the hypothalamic-pituitary-gonadal-liver axis (HPGL axis), the transcriptional levels of genes were measured by real-time PCR. The disrupted expression of genes, such as ERα, ERβ, FSHR, LHR, StAR, and 17βHSD, indicated the possible interference of PFNA on the HPGL axis function and sex hormone synthesis. Furthermore, testosterone (T) and estradiol (E2) levels in serum and VTG content in the liver were detected to clarify the influences of PFNA on sex hormone levels. Except for the increase in serum estrogen levels, as an estrogen analogue, PFNA also induced the synthesis of biomarker protein vitellogenin (VTG) in the adult male liver. The results of this study indicate that chronic exposure to PFNA can lead to

  12. Studies on the male reproductive toxicity of Freon 22.

    PubMed

    Lee, I P; Suzuki, K

    1981-01-01

    Freons have been used extensively as refrigerants and as propellants in household products, and yet their possible effects on male reproduction have received little attention. In the present study, adult male Sprague-Dawley rats (nine weeks of age) were exposed to 50 000 ppm Freon 22, five hrs per day for eight weeks. The control group received filtered air at an identical flow rate. At the end of the eight week exposure period, body and organ weights, hematology, blood chemistry, plasma gonadotropins, and fertility parameters were not significantly different from controls, with the exception of serum cholesterol levels, which were slightly higher, and glucose and triglyceride levels which were lower. The weight of coagulating glands was also lower than those of controls, but did not interfere with fertility function.

  13. Nonclinical reproductive toxicity testing requirements for drugs, pesticides, and industrial chemicals in India and China.

    PubMed

    Rao, K S; Dong, Jing

    2013-01-01

    India and China have booming chemical, agrochemical, and pharmaceutical industries. Both countries also represent expanding markets for foreign chemical and healthcare companies. All such products require reproductive toxicity testing before marketing. The ICH testing guidelines for medicinal products are not applicable in China and India. Nonetheless, reproductive toxicity studies designed and run to ICH principles are generally acceptable for submission. The Chinese guidelines take into consideration traditional Chinese medicines, which are usually mixtures. Likewise, the specific recommendations of India and China for the reproductive toxicity testing of chemicals and pesticides differ from those of the OECD and the USEPA. Again, studies performed in accordance with internationally recognized principles are usually acceptable for submission in both countries. The Chinese guideline for the reproductive toxicity testing of agrochemicals is currently under revision; the new version is expected to resemble more closely the requirements of the OECD and the USEPA. As a member of the OECD, India has conducted Good Laboratory Practice (GLP) inspection, accreditation, and monitoring activities since 2004. China has made several attempts to join the Council Decisions on Mutual Acceptance of Data in the Assessment of Chemicals since 2005. Currently 47 laboratories in China have been certified by the national GLP authorities. Several laboratories in China have also been recently been certified by OECD member countries as GLP compliant. In India, there are currently 23 GLP-Certified laboratories; about six of these are also AALAC accredited. The specific study designs specified in the guidelines of China and India for reproductive toxicity studies are described in detail in this chapter. PMID:23138892

  14. Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of hydrodesulfurized kerosine.

    PubMed

    Schreiner, C; Bui, Q; Breglia, R; Burnett, D; Koschier, F; Podhasky, P; Lapadula, L; White, R; Feuston, M; Krueger, A; Rodriquez, S

    1997-10-24

    Hydrodesulfurized kerosine (HDS kerosine), applied dermally, was tested for reproductive and developmental toxicity in Sprague-Dawley rats, using a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening Protocol. A preliminary acute dermal irritancy test demonstrated that dilution of HDS kerosine in either a light (100 Saybolt universal seconds, SUS) or moderate viscosity (340 SUS) USP mineral oil reduced irritation of the neat material comparably. Similar dermal absorption was observed in vitro for neat HDS kerosine or diluted in either of the mineral oils. HDS kerosine diluted to 494 (60%), 330 (40%), or 165 (20%) mg/kg/day in Squibb mineral oil (340 SUS) was applied daily at 1 ml/kg to the shaved backs of rats for 7 wk (premating, mating to d 19 of gestation) to females and 8 wk to males. Dams and litters were sacrificed on postpartum d 4 and males were sacrificed within the following week. HDS kerosine produced slight to moderate skin irritation at the highest dose in both sexes but no apparent maternal, reproductive, or developmental toxicity. No clinical signs of toxicity and no effects on body weight, food consumption, or absolute organ weights were observed. Relative kidney weights were heavier in male rats at the high dose. Skin changes were observed microscopically in male rats in all groups and in females at the high dose. No microscopic changes were observed in reproductive organs of parental animals. There were no differences in mean number of corpora lutea, implantation sites, and live pups per litter, and no gross anomalies were observed. Pups born from treated dams showed comparable body weights and weight gains to controls. The viability index on postpartum d 4 was > or = 93%. In conclusion, the no observable adverse effect level (NOAEL) for HDS kerosine for reproductive and developmental toxicity in rats is 494 mg/kg/d.

  15. A Systematic Review of the Molecular Mechanisms of Uranium -Induced Reproductive Toxicity.

    PubMed

    Asghari, Mohammad Hossein; Saeidnia, Soodabeh; Rezvanfar, Mohammad Amin; Abdollahi, Mohammad

    2015-01-01

    Uranium is the heaviest metal known as nuclear fuel, and employed in the production of glass tinting compounds, ceramic glazes, gyroscope wheels, chemical catalysts and X-ray tube targets. Inhalation and ingestion are two of the most usual ways of exposure. Uranium may be released into drinking water through the mining leading to contamination. Uranium is able to damage the DNA by generation of free radicals and acting as a catalyst in the Fenton reactions causing oxidative stress. In fact, reproductive system contains high amount of polyunsaturated fatty acids, and therefore it is highly vulnerable to reactive oxygen species (ROS) and sensitive to uranium toxicity. Toxic effects of uranium are generally reported through different mechanisms of action including inflammation, degeneration of testis, vacuolization of Leydig cells, spermatocytes necrosis, and oocyte dysmorphism. The present article provides a comprehensive review of the recent findings mostly about the molecular and biochemical toxicity of uranium on the reproductive system. PMID:26728775

  16. Revision of the ICH guideline on detection of toxicity to reproduction for medicinal products: SWOT analysis.

    PubMed

    Barrow, Paul

    2016-09-01

    SWOT analysis was used to gain insights and perspectives into the revision of the ICH S5(R2) guideline on detection of toxicity to reproduction for medicinal products. The current ICH guideline was rapidly adopted worldwide and has an excellent safety record for more than 20 years. The revised guideline should aim to further improve reproductive and developmental (DART) safety testing for new drugs. Alternative methods to animal experiments should be used whenever possible. Modern technology should be used to obtain high quality data from fewer animals. Additions to the guideline should include considerations on the following: limit dose setting, maternal toxicity, biopharmaceuticals, vaccines, testing strategies by indication, developmental immunotoxicity, and male-mediated developmental toxicity. Emerging issues, such as epigenetics and the microbiome, will most likely pose challenges to DART testing in the future. It is hoped that the new guideline will be adopted even outside the ICH regions. PMID:27046733

  17. Revision of the ICH guideline on detection of toxicity to reproduction for medicinal products: SWOT analysis.

    PubMed

    Barrow, Paul

    2016-09-01

    SWOT analysis was used to gain insights and perspectives into the revision of the ICH S5(R2) guideline on detection of toxicity to reproduction for medicinal products. The current ICH guideline was rapidly adopted worldwide and has an excellent safety record for more than 20 years. The revised guideline should aim to further improve reproductive and developmental (DART) safety testing for new drugs. Alternative methods to animal experiments should be used whenever possible. Modern technology should be used to obtain high quality data from fewer animals. Additions to the guideline should include considerations on the following: limit dose setting, maternal toxicity, biopharmaceuticals, vaccines, testing strategies by indication, developmental immunotoxicity, and male-mediated developmental toxicity. Emerging issues, such as epigenetics and the microbiome, will most likely pose challenges to DART testing in the future. It is hoped that the new guideline will be adopted even outside the ICH regions.

  18. A sensitive, rapid and inexpensive way to assay pesticide toxicity based on electrochemical biosensor.

    PubMed

    Yong, Daming; Liu, Chang; Yu, Dengbin; Dong, Shaojun

    2011-03-15

    We reported a rapid toxicity assay method using electrochemical biosensor for pesticides, Escherichia coli (E. coli) was taken as a model microorganism for test. In this method, we adopted ferricyanide instead of natural electron acceptor O(2), and then microbial oxidation was substantially accelerated. Toxicity assays measured the effect of toxic materials on the metabolic activity of microorganisms. The current signal of ferrocyanide produced from the metabolism was proven to be directly related to the toxicity, which could be amplified by ultramicroelectrode array (UMEA). The ratio of the electrochemical signals, recorded in the presence and absence of toxin, provided an index of inhibition. Accordingly, a direct toxicity assessment (DTA) based on chronoamperometry was proposed to detect the effect of toxic chemicals on microorganisms. 3,5-Dichlorophenol (DCP) was taken as the reference toxicant, its IC50 was estimated to be 8.0mg/L. Three pesticides were examined using this method. IC50 values of 6.5mg/L for Ametryn, 22 mg/L for Fenamiphos and 5.7 mg/L for Endosulfan were determined and in line with EC50 values reported in the literature. Atomic force microscopy (AFM) was also used for morphology characterization of E. coli induced by three pesticides. These results confirmed the present electrochemical method used is reliable. In addition, the electrochemical method is a sensitive, rapid and inexpensive way for toxicity assays of pesticides. PMID:21315890

  19. Application of the FETAX developmental toxicity assay for evaluating the success of bioremediation

    SciTech Connect

    Bantle, J.A.; Rayburn, J.R.; Hull, M.A.; Hutchins, S.; Wilson, J.

    1995-12-31

    A ten-year-old subsurface spill of JP-4 jet fuel at Eglin Air Force Base (FL) was remediated using nitrate application. The authors used the Frog Embryo Teratogenesis Assay-Xenopus (FETAX) before, during and after remediation to detect whether toxicity was altered. FETAX is a 96-hr whole embryo developmental toxicity assay used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. FETAX developmental toxicity assays were performed on soil samples and extracts throughout remediation. They chose FETAX because development is a weak link in the life cycle of living organisms and indicative of chronic effects. Environmental chemistry was also performed to quantify TPH and BTEX concentrations in the soil. Preliminary FETAX experiments with pure JP-4 showed that JP-4 was more fetotoxic than teratogenic and metabolic activation did not greatly alter the development toxicity of pure JP-4. The newly developed technique of direct exposure was more successful with Eglin soil samples than aqueous extraction in this study because the direct exposure technique is better for hydrophobic materials such as JP-4. Using the direct exposure technique, there was a correlation noted between TPH and BTEX concentrations in the soil samples and developmental toxicity. A general decrease in developmental toxicity in both control and nitrate-treated plots was observed throughout the study. FETAX proved sensitive enough to detect this toxicity and useful in determining when sufficient bioremediation had occurred.

  20. ASSESSMENT OF A FATHEAD MINNOW REPRODUCTION ASSAY FOR IDENTIFYING ENDOCRINE-DISRUPTING CHEMICALS WITH DIVERSE MODES OF ACTION

    EPA Science Inventory

    The US EPA has developed a short-term reproduction test with the fathead minnow to identify potential endocrine disrupting chemicals (EDCs). The assay is initiated by collecting baseline spawning data from reproductively-active adult fathead minnows for 21 d, followed by a 21 d e...

  1. CHARACTERIZATION OF RESPONSES TO THE ANTIANDROGEN FLUTAMIDE IN A SHORT-TERM REPRODUCTION ASSAY WITH THE FATHEAD MINNOW

    EPA Science Inventory

    A short-term reproduction assay with the fathead minnow has been developed to detect chemicals with the potential to disrupt reproductive endocrine functions controlled by estrogen- and androgen-mediated pathways. The objective of this study was to characterize the responses of t...

  2. Alleviative effects of quercetin and onion on male reproductive toxicity induced by diesel exhaust particles.

    PubMed

    Izawa, Hiromi; Kohara, Machiko; Aizawa, Koichi; Suganuma, Hiroyuki; Inakuma, Takahiro; Watanabe, Gen; Taya, Kazuyoshi; Sagai, Masaru

    2008-05-01

    Diesel exhaust particles (DEPs) are particulate matter from diesel exhaust that contain many toxic compounds, such as polyaromatic hydrocarbons (PAHs). Some toxicities of PAH are thought to be expressed via aryl hydrocarbon receptors (AhRs). The male reproductive toxicity of DEPs might depend on AhR activation induced by PAHs. We hypothesized that AhR antagonists protect against the male reproductive toxicity of DEPs. Quercetin is a flavonoid and a well-known AhR antagonist, while onion contains many flavonoids, including quercetin. Hence, we examined whether quercetin and onion have alleviative effects against the male reproductive toxicity induced by DEPs. BALB/c male mice were fed quercetin- or onion-containing diets and received 10 injections of DEP suspension or vehicle into the dorsal subcutaneous layer over 5 weeks. The mice were euthanized at 2 weeks, after the last treatment, and their organs were collected. Daily sperm production and total incidence of sperm abnormalities were significantly affected in the DEP groups as compared with the vehicle group, but the total incidence of sperm abnormalities in the quercetin + DEP-treated mice was significantly reduced as compared with the DEP-treated mice. The numbers of Sertoli cells were significantly decreased in DEP-treated mice as compared with the vehicle-treated mice, but, the numbers of Sertoli cells were significantly increased in the quercetin and the onion + DEP-treated mice as compared with the DEP-treated mice. These results clearly indicate alleviative effects of quercetin and onion against the male reproductive toxicity induced by DEP.

  3. An evaluation of 2,4-dichlorophenoxyacetic acid in the Amphibian Metamorphosis Assay and the Fish Short-Term Reproduction Assay.

    PubMed

    Coady, Katherine; Marino, Troy; Thomas, Johnson; Sosinski, Lindsay; Neal, Barbara; Hammond, Larry

    2013-04-01

    2,4-Dichlorophenoxyacetic acid (2,4-D) was evaluated in both the Amphibian Metamorphosis Assay (AMA) and the Fish Short Term Reproduction Assay (FSTRA). In the AMA, tadpoles were exposed to mean measured 2,4-D concentrations of 0 (water control), 0.273, 3.24, 38.0 and 113 mg acid equivalents (ae)/L for either seven or 21 days. In the FSTRA, fathead minnows were exposed to mean measured 2,4-D concentrations of 0 (water control), 0.245, 3.14, 34.0, and 96.5 mg ae/L for 21 days. The respective concentrations of 2,4-D were not overtly toxic to either Xenopus laevis tadpoles or fathead minnows (Pimephales promelas). In the AMA, there were no signs of either advanced or delayed development, asynchronous development, or significant histopathological effects of the thyroid gland among 2,4-D exposed tadpoles evaluated on either day seven or day 21 of the exposure. Therefore, following the AMA decision logic, 2,4-D is considered "likely thyroid inactive" in the AMA with a No Observable Effect Concentration (NOEC) of 113 mg ae 2,4-D/L. In the FSTRA, there were no significant differences between control and 2,4-D exposed fish in regard to fertility, wet weight, length, gonado-somatic indices, tubercle scores, or blood plasma concentrations of vitellogenin. Furthermore, there were no treatment-related histopathologic changes in the testes or ovaries in any 2,4-D exposed group. The only significant effect was a decrease in fecundity among fish exposed to 96.5 mg ae 2,4-D/L. The cause of the reduced fecundity at the highest concentration of 2,4-D tested in the assay was most likely due to a generalized stress response in the fish, and not due to a specific endocrine mode of action of 2,4-D. Based on fish reproduction, the NOEC in the FSTRA was 34.0 mg ae 2,4-D/L.

  4. Reproductive toxicities of methoxychlor based on estrogenic properties of the compound and its estrogenic metabolite, hydroxyphenyltrichloroethane.

    PubMed

    Aoyama, Hiroaki; Chapin, Robert E

    2014-01-01

    Methoxychlor is an organochlorine pesticide having a weak estrogenicity, which is estimated to be approximately 1000- to 14,000-fold less potent to a natural ligand, 17β-estradiol. However, its active metabolite, hydroxyphenyltrichloroethane, has much more potent estrogenic activity and probably acts in the target organs of animals exposed to methoxychlor at least 100 times stronger than the parent compound. A variety of in vivo reproductive toxicity studies have shown that treatment with methoxychlor exerts typical endocrine-disrupting effects manifest as estrogenic effects, such as formation of cystic ovaries resulting in ovulation failures, uterine hypertrophy, hormonal imbalances, atrophy of male sexual organs, and deteriorations of sperm production in rats and/or mice, through which it causes serious reproductive damages in both sexes of animals at sufficient dose levels. However, methoxychlor is not teratogenic. The no-observed-adverse-effect level of methoxychlor among reliable experimental animal studies in terms of the reproductive toxicity is 10 ppm (equivalent to 0.600 mg/kg/day) in a two-generation reproduction toxicity study.

  5. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity

    NASA Astrophysics Data System (ADS)

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  6. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity

    PubMed Central

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-01-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered. PMID:27585557

  7. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

    PubMed

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-02

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  8. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

    PubMed

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-01-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered. PMID:27585557

  9. Human environmental and occupational exposures to boric acid: reconciliation with experimental reproductive toxicity data.

    PubMed

    Bolt, Hermann M; Başaran, Nurşen; Duydu, Yalçın

    2012-01-01

    The reproductive toxicity of boric acid and borates is a matter of current regulatory concern. Based on experimental studies in rats, no-observed-adverse-effect levels (NOAELs) were found to be 17.5 mg boron (B)/kg body weight (b.w.) for male fertility and 9.6 mg B/kg b.w. for developmental toxicity. Recently, occupational human field studies in highly exposed cohorts were reported from China and Turkey, with both studies showing negative results regarding male reproduction. A comparison of the conditions of these studies with the experimental NOAEL conditions are based on reported B blood levels, which is clearly superior to a scaling according to estimated B exposures. A comparison of estimated daily B exposure levels and measured B blood levels confirms the preference of biomonitoring data for a comparison of human field studies. In general, it appears that high environmental exposures to B are lower than possible high occupational exposures. The comparison reveals no contradiction between human and experimental reproductive toxicity data. It clearly appears that human B exposures, even in the highest exposed cohorts, are too low to reach the blood (and target tissue) concentrations that would be required to exert adverse effects on reproductive functions.

  10. Multigeneration reproductive and developmental toxicity study of bar gene inserted into genetically modified potato on rats.

    PubMed

    Rhee, Gyu Seek; Cho, Dae Hyun; Won, Yong Hyuck; Seok, Ji Hyun; Kim, Soon Sun; Kwack, Seung Jun; Lee, Rhee Da; Chae, Soo Yeong; Kim, Jae Woo; Lee, Byung Mu; Park, Kui Lea; Choi, Kwang Sik

    2005-12-10

    Each specific protein has an individual gene encoding it, and a foreign gene introduced to a plant can be used to synthesize a new protein. The identification of potential reproductive and developmental toxicity from novel proteins produced by genetically modified (GM) crops is a difficult task. A science-based risk assessment is needed in order to use GM crops as a conventional foodstuff. In this study, the specific characteristics of GM food and low-level chronic exposure were examined using a five-generation animal study. In each generation, rats were fed a solid pellet containing 5% GM potato and non-GM potato for 10 wk prior to mating in order to assess the potential reproductive and developmental toxic effects. In the multigeneration animal study, there were no GM potato-related changes in body weight, food consumption, reproductive performance, and organ weight. Polymerase chain reaction (PCR) was carried out using extracted genomic DNA to examine the possibility of gene persistence in the organ tissues after a long-term exposure to low levels of GM feed. In each generation, the gene responsible for bar was not found in any of the reproductive organs of the GM potato-treated male and female rats, and the litter-related indexes did not show any genetically modified organism (GMO)-related changes. The results suggest that genetically modified crops have no adverse effects on the multigeneration reproductive-developmental ability.

  11. Multigeneration reproductive and developmental toxicity study of bar gene inserted into genetically modified potato on rats.

    PubMed

    Rhee, Gyu Seek; Cho, Dae Hyun; Won, Yong Hyuck; Seok, Ji Hyun; Kim, Soon Sun; Kwack, Seung Jun; Lee, Rhee Da; Chae, Soo Yeong; Kim, Jae Woo; Lee, Byung Mu; Park, Kui Lea; Choi, Kwang Sik

    2005-12-10

    Each specific protein has an individual gene encoding it, and a foreign gene introduced to a plant can be used to synthesize a new protein. The identification of potential reproductive and developmental toxicity from novel proteins produced by genetically modified (GM) crops is a difficult task. A science-based risk assessment is needed in order to use GM crops as a conventional foodstuff. In this study, the specific characteristics of GM food and low-level chronic exposure were examined using a five-generation animal study. In each generation, rats were fed a solid pellet containing 5% GM potato and non-GM potato for 10 wk prior to mating in order to assess the potential reproductive and developmental toxic effects. In the multigeneration animal study, there were no GM potato-related changes in body weight, food consumption, reproductive performance, and organ weight. Polymerase chain reaction (PCR) was carried out using extracted genomic DNA to examine the possibility of gene persistence in the organ tissues after a long-term exposure to low levels of GM feed. In each generation, the gene responsible for bar was not found in any of the reproductive organs of the GM potato-treated male and female rats, and the litter-related indexes did not show any genetically modified organism (GMO)-related changes. The results suggest that genetically modified crops have no adverse effects on the multigeneration reproductive-developmental ability. PMID:16326439

  12. Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats.

    PubMed

    Wolterbeek, André; Oosterwijk, Thies; Schneider, Steffen; Landsiedel, Robert; de Groot, Didima; van Ee, Renz; Wouters, Mariëlle; van de Sandt, Han

    2015-08-15

    Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-LRI project, NM-200 was tested in a two-generation reproduction toxicity study according to OECD guideline 416. Male and female rats were treated by oral gavage with NM-200 at dose levels of 0, 100, 300 and 1000mg/kg bw/day for two generations. Body weight and food consumption were measured throughout the study. Reproductive and developmental parameters were measured and at sacrifice (reproductive) organs and tissues were sampled for histopathological analysis. Oral administration of NM-200 up to 1000mg/kg bw/day had no adverse effects on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations. The NOAEL was 1000mg/kg body weight per day.

  13. Mechanisms of phthalate ester toxicity in the female reproductive system.

    PubMed Central

    Lovekamp-Swan, Tara; Davis, Barbara J

    2003-01-01

    Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation. PMID:12573895

  14. Xenopus tropicalis as a test system for developmental and reproductive toxicity.

    PubMed

    Berg, Cecilia; Gyllenhammar, Irina; Kvarnryd, Moa

    2009-01-01

    The usefulness of Xenopus tropicalis as a model species to investigate endocrine disruption and developmental reproductive toxicity was assessed. In our test system tadpoles were exposed to test substances from shortly after hatching until metamorphosis, including the period of gonadal differentiation. Effects on the sex hormone and thyroid hormone axes were evidenced as skewed sex ratios, malformations of reproductive organs, altered cytochrome (CYP19) (aromatase) activity, and gene expression in gonads and brain, as well as changed thyroid histology and time to metamorphosis. Reproductive toxicity was evaluated at sexual maturity. Male-to-female sex reversal was implied at concentrations as low as 6 pM (1.8 ng/L) ethynylestradiol (EE2), which is comparable to EE2 levels observed in the environment. EE2-exposed males that were not sex reversed had significantly reduced fertility and a reduced amount of spermatozoa in testes compared with control males. This indicates that reproduction in wild frogs might be impaired by estrogenic environmental pollutants. Aromatase activity in brain and testes of adult frogs was not affected by larval EE2 exposure. Preliminary results indicate that exposure to the environmentally relevant pharmaceutical clotrimazole modulated aromatase activity in brain and gonads during sex differentiation, which warrants further investigation. The susceptibility to estrogen-induced sex reversal of X. tropicalis was comparable to that of other frog species and fish. Similarities between the reproductive effects in X. tropicalis and those reported in fish, birds, and mammals after developmental exposure to estrogens make X. tropicalis promising model for research on endocrine disruption and developmental reproductive toxicity. PMID:19184736

  15. A COMPARISON OF MULTIPLE TOXICITIES FOLLOWING DEVELOPMENTAL EXPOSURE TO PESTICIDES: NEUROTOXICITY, IMMUNOTOXICITY, AND REPRODUCTIVE TOXICITY.

    EPA Science Inventory

    The NAS report (Pesticides in the Diets of Infants and Children, 1993) called for significant research effort into the long-term effects of perinatal pesticide exposure on the nervous, immune, and reproductive systems. In response, the US EPA and NIEHS collaborated on a series o...

  16. Latex laboratory-gloves: an unexpected pitfall in amphibian toxicity assays with tadpoles.

    PubMed

    Gutleb, A C; Bronkhorst, M; van den Berg, J H; Murk, A J

    2001-07-01

    This study examined the unexpected toxic effects of protective latex laboratory gloves on developing amphibians. Mortality after exposure to rinsing water from the outside of the gloves was observed in Xenopus laevis and Rana temporaria, with R. temporaria being more sensitive. This phenomenon was further confirmed using the microtiter-version of the Microtox-Assay, an in vitro assay for general toxicity. Latex gloves from the specific brand used in the experiment, in which the toxicity to tadpoles was observed for the first time, showed the highest toxicity of all materials and brands tested. Due to the high responsiveness of amphibian tadpoles to latex-glove contaminated rinsing water, special care is necessary when cleaning aquaria during toxicological experiments with amphibians as otherwise results may be biased.

  17. Toxicity of hydroxylated polychlorinated biphenyls (HO-PCBs) using the bioluminescent assay Microtox(®).

    PubMed

    Bhalla, Renu; Tehrani, Rouzbeh; Van Aken, Benoit

    2016-09-01

    Hydroxylated polychlorinated biphenyls (HO-PCBs) are toxic contaminants which are produced in the environment by biological or abiotic oxidation of PCBs. The toxicity of a suite of 23 mono-hydroxylated derivatives of PCBs and 12 parent PCBs was determined using the bacterial bioluminescent assay Microtox(®). All HO-PCBs tested exhibited higher toxicity than the corresponding parent PCB, with effect concentration 50 % (EC50) ranging from 0.07 to 133 mg L(-1). The highest toxicities were recorded with 4-hydroxylated derivatives of di-chlorinated biphenyls (EC50 = 0.07-0.36 mg L(-1)) and 2-hydroxylated derivatives of tri-chlorinated biphenyls carrying a chlorine substituent on the phenolic ring (EC50 = 0.34-0.48 mg L(-1)). The toxicity of HO-PCBs generally decreased when the degree of chlorination increased. Consistently with this observation, a significant positive correlation was measured between toxicity (measured by EC50) and octanol-water partition coefficient (pK ow) for the HO-PCBs under study (Pearson's correlation coefficient, r = 0.74), which may be explained by the lower solubility and bioavailability generally associated with higher hydrophobicity. This study is the first one which assessed the toxicity of a suite of PCBs and HO-PCBs using the bioluminescent assay Microtox(®), showing an inverse correlation between toxicity and hydrophobicity. PMID:27411941

  18. Dye labelled monoclonal antibody assay for detection of Toxic Shock Syndrome Toxin -1 from Staphylococcus aureus

    PubMed Central

    Javid, Khojasteh V; Foster, HA

    2011-01-01

    Objective The aim of study was to develop a rapid assay, dye labelled monoclonal antibody assay (DLMAA), using non-radioactive organic synthetic dyes for identification of Toxic Shock Syndrome Toxin-1 (TSST-1) producing strains of Staphylococcus aureus. Materials and Methods The assay protocol required only two simple steps; addition of TSST-1 antigen to a nitrocellulose membrane and then adding a colloidal dye labelled antibody (D/A) suspension detection reagent. Results The sensitivity and specificity of the assay was determined relative to positive and negative strains compared to an ELISA assay. Overall 100% agreement was found between both assays. The sensitivity for detection of TSST-1 was 30 ng. Conclusion The DLMAA did not require handling and disposal of radioactive materials. It is a rapid qualitative technique for detection of TSST-1 toxin at room temperature within a short time. PMID:22530084

  19. Reproductive toxicity of 2,4-toluenediamine in the rat. 1. Effect on male fertility

    SciTech Connect

    Thysen, B.; Varma, S.K.; Bloch, E.

    1985-01-01

    Effects of 2,4-toluenediamine (TDA) on reproduction in adult male Sprague-Dawley rats were evaluated. Diets containing 0, 0.01 and 0.03% TDA were fed ad libitum to experimental animals for 10 wk. No signs of toxicity were found. Exposure to the high dose resulted in decreased mating frequency and an increase in infertile matings. Light-microscopic examination of the testes revealed reduced numbers of sperm in the seminiferous tubules and cauda epididymides. These results indicate that TDA is capable of reducing fertility and of exerting an inhibitory or toxic effect on spermatogenesis in the rat.

  20. Assessment of phenolic herbicide toxicity and mode of action by different assays.

    PubMed

    Bettiol, Cinzia; De Vettori, Stefania; Minervini, Giovanni; Zuccon, Elisa; Marchetto, Davide; Ghirardini, Annamaria Volpi; Argese, Emanuele

    2016-04-01

    A phytotoxicity assay based on seed germination/root elongation has been optimized and used to evaluate the toxic effects of some phenolic herbicides. The method has been improved by investigating the influence of experimental conditions. Lepidium sativum was chosen as the most suitable species, showing high germinability, good repeatability of root length measurements, and low sensitivity to seed pretreatment. DMSO was the most appropriate solvent carrier for less water-soluble compounds. Three dinitrophenols and three hydroxybenzonitriles were tested: dinoterb, DNOC, 2,4-dinitrophenol, chloroxynil, bromoxynil, and ioxynil. Toxicity was also determined using the Vibrio fischeri Microtox® test, and a highly significant correlation was found between EC50 values obtained by the two assays. Dinoterb was the most toxic compound. The toxicity of hydroxybenzonitriles followed the order: ioxynil >bromoxynil >chloroxynil; L. sativum exhibited a slightly higher sensitivity than V. fischeri to these compounds. A QSAR analysis highlighted the importance of hydrophobic, electronic, and hydrogen-bonding interactions, in accordance with a mechanism of toxic action based on protonophoric uncoupling of oxidative phosphorylation. The results suggest that the seed germination/root elongation assay with L. sativum is a valid tool for the assessment of xenobiotic toxicity and can be recommended as part of a test battery. PMID:26695414

  1. Reproductive toxicity in male mice exposed to Nanjing City tap water.

    PubMed

    Zhao, Dayong; Chen, Yajun; Zhou, Kemei; Cheng, Shupei; Ma, Ting; Jiang, Cuiling; Yan, Wenming; Zhu, Liqin; Gu, Xijun; Zhu, Xiaohua; Wu, Bing; Zhang, Yan; Zhang, Xuxiang

    2011-07-01

    End points of reproductive toxicity were investigated in male mice (Mus musculus, ICR) fed Nanjing City tap water for 90 days. There was no significant alteration in body weights between treatment and control mice. In treated mice, flow cytometry analysis of testicular tissue indicated that the relative percentage of the elongated spermatid (HC) decreased significantly (P < 0.05). Also slight increases in the relative percentage of round spermatids (1C) and primary spermatocytes (4C) were noted. The ratios of 4C:2C (diploid germ cells) and 1C:2C increased, and testicular histopathology indicated an expansion of interstitial space and a decreased number and size of Leydig cells in treated mice. The current study suggests that Nanjing City tap water is toxic to the reproductive system of mice and additional study to evaluate its effects on other species, including human beings, would be warranted. PMID:21431922

  2. Classification of reproductive toxicants with diverse mechanisms in the embryonic stem cell test.

    PubMed

    Riebeling, Christian; Fischer, Kristin; Luch, Andreas; Seiler, Andrea E M

    2015-12-01

    The embryonic stem cell test (EST) is a promising system to detect embryotoxicity in vitro. Recent studies have pointed out some limitations of the EST and suggest that the applicability domain of the EST and its prediction model have to be better defined. Here, eight substances of known reproductive toxicity were tested in the EST under blind conditions. We applied the prediction model to the data of the EST after classifying the substances according to the published criteria. In addition, a simplified classification of the EST results into two classes as an approach to hazard assessment was compared to the European Union Classification, Labelling and Packaging (CLP) Regulation labels of the substances. With one exception, substances that are labeled as reproductive toxicants according to the CLP Regulation were detected as embryotoxic in the EST while substances without label were found to be non-embryotoxic according to the EST. PMID:26558462

  3. Reproductive toxicity evaluation of methylethyl ketoxime by gavage in CD rats.

    PubMed

    Tyl, R W; Gerhart, J M; Myers, C B; Marr, M C; Brine, D R; Gilliam, A F; Seely, J C; Derelanko, M J; Rinehart, W E

    1996-06-01

    Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime), an antioxidant agent used in paints, resins, and adhesives, was tested for reproductive toxicity in a two-generation study with CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group (F0) were administered MEKO in water, by gavage, at 0, 10, 100, or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/week for 10 weeks with vaginal cytology evaluation (VCE) of F0 females during the last 3 weeks of the prebreed period. Animals were mated within groups for 3 weeks with dosing during mating, gestation, and lactation for 7 days/week. F0 parents and F1 weanlings, 10/sex/dose, were necropsied (after a 2-week postwean VCE in F0 females) with hematologic evaluation (including methemoglobin) and histology of adult livers, spleens, and reproductive organs. F1 weanlings, 30/sex/dose, were dosed for 11 weeks and mated as described above. Because of poor reproductive performance, not treatment related, F1 animals with no F2a litters were rebred to produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose, were necropsied and evaluated as described above. Inguinal mammary glands were examined histologically from all nonselected F1 and F2 (a and b) female weanlings. Adult toxicity was observed in both generations and both sexes at all doses. Treatment-related parental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day, parents exhibited dose-related reduced body weights and weight gains, reduced feed consumption, clinical signs of toxicity, and anemia with concomitant extramedullary hematopoiesis and hemosiderosis in livers and spleens (and increased spleen weights). At 10 mg/kg/day, only adult liver and spleen histologic effects were present. There was no evidence of reproductive organ or mammary glad pathology or of reproductive or postnatal toxicity at any dose tested. There was no adult "no observable adverse effect level" (NOAEL) established; the NOAEL for reproductive and postnatal

  4. A microsystem-based assay for studying pollen tube guidance in plant reproduction

    NASA Astrophysics Data System (ADS)

    Yetisen, A. K.; Jiang, L.; Cooper, J. R.; Qin, Y.; Palanivelu, R.; Zohar, Y.

    2011-05-01

    We present a novel microsystem-based assay to assess and quantify pollen tube behavior in response to pistil tissues. During plant reproduction, signals from female tissues (pistils) guide the sperm-carrying pollen tube to the egg cell to achieve fertilization and initiate seed development. Existing pollen tube guidance bioassays are performed in an isotropically diffusive environment (for example, a semi in vivo assay in petri dishes) instead of anisotropically diffusive conditions required to characterize guidance signal gradients. Lack of a sensitive pollen tube guidance bioassay has therefore compounded the difficulties of identifying and characterizing the guidance signals that are likely produced in minute quantities by the ovules. We therefore developed a novel microsystem-based assay that mimics the in vivo micro-environment of ovule fertilization by pollen tubes in the model research plant Arabidopsis thaliana. In this microdevice, the pollen tube growth rate, length and ovule targeting frequencies were similar to those obtained using a semi in vivo plate assay. As a direct measure of the microdevice's utility in monitoring pollen tube guidance, we demonstrated that in this device, pollen tubes preferentially enter chambers with unfertilized ovules, suggesting that the pollen tubes sense the concentration gradient and respond to the chemoattractants secreted by unfertilized ovules.

  5. Reproductive and developmental toxicity of amitraz in sprague-dawley rats.

    PubMed

    Lim, Jeong-Hyeon; Kim, Sung-Hwan; Kim, Kang-Hyeon; Park, Na-Hyeong; Shin, In-Sik; Moon, Changjong; Park, Soo-Hyun; Kim, Sung-Ho; Kim, Jong-Choon

    2010-03-01

    The present study was conducted to obtain information on the effects of amitraz on reproductive and developmental parameters in rats. The test chemical was administered via the drinking water containing 0, 40, 120, and 360 ppm to male rats from 2 weeks before mating to the end of 14-day mating period and to females from 2 weeks before mating, throughout mating, gestation and up to lactational day 4. During the study period, clinical signs, body weights, food intake, organ weights, reproductive and littering findings, necropsy findings, sperm parameters, and histopathology were examined. At 360 ppm, decreases in the body weight gain, food consumption, and the number of live pups and an increase in the post-implantation loss were observed. In addition, decreases in the seminal vesicle weight and sperm motility were found in males. At 120 ppm, a decrease in the food consumption was found transiently in both males and females, but no reproductive and developmental toxicity was observed in both sexes. There were no signs of either general or reproductive and developmental toxicity in the 40 ppm group. Based on these results, it was concluded that the repeated oral administration of amitraz to rats resulted in a decrease in the food consumption at 120 ppm and decreases in the seminal vesicle weight, sperm motility, and the number of live pups and an increase in the post-implantation loss at 360 ppm in rats. Under these experimental conditions, the no-observed-adverse-effect level (NOAEL) of amitraz for general and reproduction/developmental toxicity was believed to be 120 ppm, and the no-observed-effect level (NOEL) of amitraz was believed to be 40 ppm in rats.

  6. Lutein alleviates arsenic-induced reproductive toxicity in male mice via Nrf2 signaling.

    PubMed

    Li, S G; Xu, S Z; Niu, Q; Ding, Y S; Pang, L J; Ma, R L; Jing, M X; Wang, K; Ma, X M; Feng, G L; Liu, J M; Zhang, X F; Xiang, H L; Li, F

    2016-05-01

    This study aims to investigate the mechanisms involved in the action of lutein (LU) alleviating arsenic-induced reproductive toxicity using mice model. Forty male Kunming mice were received following treatments by gavage: normal saline solution (control), arsenic trioxide (ATO; 5 mg/kg/day), LU (40 mg/kg/day), and ATO + LU (5 mg/kg/day + 40 mg/kg/day). At the end, the mice were killed by cervical dislocation and weighed. Pathological examination was done on the testis. The biomedical parameters including superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. The messenger RNA (mRNA) and protein expression of Nrf2, heme oxygenase 1 (HO-1), glutathione S-transferase (GST), nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1) in testis were detected by real-time polymerase chain reaction and Western blot. We found that there was a decrease in sperm count; testis somatic index; the activities of SOD, GSH, total antioxidative capacity (p < 0.01, respectively) in ATO-treated mice, while there was an increase in the levels of sperm abnormalities, MDA, and 8-OHdG than control (p < 0.01, respectively). The groups treated with ATO + LU showed recovery of the measured parameters between those of ATO or saline-treated group. The antagonized interaction between ATO and LU was statistically significant (p < 0.01). Mice treated with ATO + LU also showed greater mRNA expression of Nrf2, HO-1, NQO1, and GST than ATO or saline-treated groups. These findings suggest that LU alleviates reproductive toxicity induced by arsenic in male mice via Nrf2 signaling, which implicates a possible mechanism of LU in preventing the reproductive injury, and elucidates that consuming the rich plant sources of LU will alleviate the reproductive toxicity induced by chemicals.

  7. Evaluation of ameliorative effect of curcumin on imidacloprid-induced male reproductive toxicity in wistar rats.

    PubMed

    Lonare, Milindmitra; Kumar, Manoj; Raut, Sachin; More, Amar; Doltade, Sagar; Badgujar, Prarabdh; Telang, Avinash

    2016-10-01

    This study was undertaken to investigate the toxic effects of imidacloprid (IM) on male reproductive system and ameliorative effect of curcumin (CMN) in male Wistar rats. For this purpose, IM (45 and 90 mg/kg, body weight) and CMN (100 mg/kg, body weight) were administered orally to the rats either alone or in combinations for a period of 28 days. At the end of experiment, male reproductive toxicity parameters (total sperm count and sperm abnormalities), testosterone level, steroidal enzymatic activity [3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD], and oxidative stress indicators were estimated in testis and plasma. IM treatments resulted in significant decrease (p < 0.05) in total epididymal sperm count, sperm motility, live sperm count, and increase (p < 0.05) in sperm abnormalities. Activities of gamma-glutamyl transpeptidase, lactate dehydrogenase-x, and sorbitol dehydrogenase were significantly increased (p < 0.05), while, 3β-HSD and 17β-HSD enzymatic activity along with testosterone concentration in testis and plasma were decreased significantly (p < 0.05) in IM-treated rats. IM exposure resulted in significant increase (p < 0.05) in LPO and decrease (p < 0.05) in GSH level along with decreased activities of CAT, SOD, GPx, and GST. IM-treated rats showed histopathological alterations in testis and epididymis. However, the reproductive toxicity parameters, oxidative stress indicators, and histopathological changes were minimized and functional restorations were noticed by co-administration of CMN in IM-treated rats. The results of this study suggest that IM-induced male reproductive toxic effects could be ameliorated by CMN supplementation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1250-1263, 2016.

  8. Impact of PCB-118 and transformer oil toxicity on anaerobic digestion of sludge: anaerobic toxicity assay results.

    PubMed

    Kaya, Devrim; Imamoglu, Ipek; Dilek Sanin, F

    2013-08-01

    In this study, possible toxicity of increasing doses of PCB-118 and transformer oil (TO) on anaerobic sludge digestion was investigated. For this purpose, five different sets of reactors were prepared in which four different PCB-118 concentration (1, 10, 20, and 30mgL(-1)) and three different TO concentration (0.38, 0.76, and 1.52gL(-1)) were applied. Throughout the study, biogas production and composition, pH, TS, VS, and COD as well as PCB concentration were monitored. Toxicity was investigated by anaerobic toxicity assay (ATA) evaluating the reduction in methane production. A notable inhibition was observed mostly in 30mgL(-1) PCB reactors. A negative influence of PCB-118 and TO was observed on COD and solids removal. A maximum of 26.5% PCB-118 removal was attained.

  9. The Invasion and Reproductive Toxicity of QDs-Transferrin Bioconjugates on Preantral Follicle in vitro

    PubMed Central

    Xu, Gaixia; Lin, Suxia; Law, Wing-Cheung; Roy, Indrajit; Lin, Xiaotan; Mei, Shujiang; Ma, Hanwu; Chen, Siping; Niu, Hanben; Wang, Xiaomei

    2012-01-01

    The toxicity of QD has been extensively studied over the past decade. However, the potential toxicity of QDs impedes its use for clinical research. In this work, we established a preantral follicle in vitro culture system to investigate the effects of QD-Transferrin (QDs-Tf) bioconjugates on follicle development and oocyte maturation. The preantral follicles were cultured and exposed to CdTe/ZnTe QDs-Tf bioconjugates with various concentrations and the reproductive toxicity was assessed at different time points post-treatment. The invasion of QDs-Tf for oocytes was verified by laser scanning confocal microscope. Steroid production was evaluated by immunoassay. C-band Giemsa staining was performed to observe the chromosome abnormality of oocytes. The results showed that the QDs-Tf bioconjugates could permeate into granulosa cells and theca cells, but not into oocyte. There are no obvious changes of oocyte diameter, the mucification of cumulus-oocyte-complexes and the occurrence of aneulpoidy as compared with the control group. However, delay in the antrum formation and decrease in the ratio of oocytes with first polar body were observed in QDs-Tf-treated groups. The matured oocytes with first polar body decreased significantly by ~16% (from 79.6±10 % to 63±2.9 %) when the concentration of QDs-Tf bioconjugates exceeded 2.89 nmol·L-1 (P < 0.05). Our results implied that the CdTe/ZnTe QDs-Tf bioconjugates were reproductive toxic for follicle development, and thus also revealed that this in vitro culture system of preantral follicle is a highly sensitive tool for study on the reproductive toxicity of nanoparticles. PMID:22916073

  10. Modeling Reproductive Toxicity for Chemical Prioritization into an Integrated Testing Strategy

    EPA Science Inventory

    The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals in over 500 assays of different molecular targets, cellular responses and cell-states. Of th...

  11. Validation, acceptance, and extension of a predictive model of reproductive toxicity using ToxCast data

    EPA Science Inventory

    The EPA ToxCast research program uses a high-throughput screening (HTS) approach for predicting the toxicity of large numbers of chemicals. Phase-I tested 309 well-characterized chemicals (mostly pesticides) in over 500 assays of different molecular targets, cellular responses an...

  12. Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening

    EPA Science Inventory

    The EPA ToxCast research program uses high throughput screening for bioactivity profiling and predicting the toxicity of large numbers of chemicals. ToxCast Phase‐I tested 309 well‐characterized chemicals in over 500 assays for a wide range of molecular targets and cellular respo...

  13. Interlaboratory validation of the rapid toxicity monitoring assay, DaphniaQuant{trademark}: State of development

    SciTech Connect

    Fort, D.J.; Atherton, R.A.; Stover, E.L.; Blankemeyer, J.T.; Burks, S.L.

    1994-12-31

    Recent regulatory emphasis on aquatic toxicity testing necessitates the development and validation of rapid, cost-effective, alternative bioassays to complement the standard assays used today. Because of this need, DaphniaQuant{trademark}, an assay designed to detect the health of Daphnia sp. at the cellular level was developed. The DaphniaQuant{trademark} assay uses the uptake of a fluorescent dye and corresponding fluorescence measurement as an early indicator of toxicity. Following 30 minutes of exposure to pure chemical compounds or complex environmental mixtures, fluorescence readings are collected, stored in a customized database system in a standard IBM compatible computer, and easily output for graphical display or statistical analysis. Preliminary results with reference toxicants collected during the development of the DaphniaQuant{trademark} system were encouraging and warranted further validation of the assay with conventional acute and subchronic bioassays. Interlaboratory validation studies using both reference toxicants and complex mixtures were performed in three separate laboratories. The current state of DaphniaQuant{trademark} development will be presented including, results from the interlaboratory validation studies, studies with different test species, and novel applications of the DaphniaQuant{trademark} test system in ecological hazard/risk assessment.

  14. CHEMICAL PRIORITIZATION FOR DEVELOPMENTAL TOXICITY USING LITERATURE MINING-BASED WEIGHTING OF TOXCAST ASSAYS

    EPA Science Inventory

    Defining a predictive model of developmental toxicity from in vitro and high-throughput screening (HTS) assays can be limited by the availability of developmental defects data. ToxRefDB (www.epa.gov/ncct/todrefdb) was built from animal studies on data-rich environmental chemicals...

  15. Statistical methods and software for validation studies on new in vitro toxicity assays.

    PubMed

    Schaarschmidt, Frank; Hothorn, Ludwig A

    2014-11-01

    When a new in vitro assay method is introduced, it should be validated against the best available knowledge or a reference standard assay. For assays resulting in a simple binary outcome, the data can be displayed as a 2×2 table. Based on the estimated sensitivity and specificity, and the assumed prevalence of true positives in the population of interest, the positive and negative predictive values of the new assay can be calculated. We briefly discuss the experimental design of validation experiments and previously published methods for computing confidence intervals for predictive values. The application of the methods is illustrated for two toxicological examples, by using tools available in the free software, namely, R: confidence intervals for predictive values are computed for a validation study of an in vitro test battery, and sample size calculation is illustrated for an acute toxicity assay. The R code necessary to reproduce the results is given.

  16. Developmental and reproductive toxicity evaluation of toluene vapor in the rat II. Developmental toxicity.

    PubMed

    Roberts, L G; Nicolich, M J; Schreiner, C A

    2007-06-01

    The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6-15 inclusive, 6h/day, at concentrations of 0, 250, 750, 1500 and 3000ppm (0, 938, 2812, 5625 and 11250mg/m(3)). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000ppm, in which maternal and fetal toxicity were observed at 2000ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions. Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000ppm, ataxia and hyper-responsivity at 1500ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000ppm and mean fetal weight was reduced at 1500ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250ppm but not at 750ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750ppm. Low incidences (toxicity NOAEL was 750ppm with a defined maternal and developmental toxicity LOAEL of 1500ppm. PMID:17360154

  17. Reproductive toxicity of commercial PCB mixtures: LOAELs and NOAELs from animal studies.

    PubMed Central

    Golub, M S; Donald, J M; Reyes, J A

    1991-01-01

    This paper reviews the developmental/reproductive toxicity of commercial polychlorinated biphenyl (PCB) mixtures in animals and reports on the "no-observable-adverse-effect levels" (NOAELs) and "lowest-observable-adverse-effect levels" (LOAELs) from these studies. Identification of the lowest effective doses for reproductive toxicity of PCB mixtures is difficult because a variety of reproductive and developmental effects have been reported in several species using different commercial mixtures. Factors to be considered include sensitivity of the end point, sensitivity of species, study quality, biological plausibility, and relevance to humans. End points affected at the lowest doses (sensitive end points) included postnatal growth, development, and function. Among species for whom sensitive end points have been evaluated, a LOAEL of 0.25 mg/kg/day was identified for rodents on the basis of developmental delays in growth and behavioral function, and a LOAEL of 0.008 mg/kg/day was identified for nonhuman primates based on postnatal skin hyperpigmentation. NOAELs were not identifiable for these sensitive end points because effects were reported at the lowest doses tested. PMID:1954934

  18. Reproductive toxicity assessment of benzo[a]pyrene in the marine polychaete Perinereis nuntia

    NASA Astrophysics Data System (ADS)

    Wu, Qingyang; Wang, Shuqi; Chen, Xiaopeng; Li, Ping

    2016-07-01

    Benzo[a]pyrene (B[a]P) is an increasingly present marine environmental pollutant, yet our understanding of the long-term consequences of reproductive toxicity in marine benthic polychaetes remains limited. To test the reproductive toxicity of B[a]P on polychaetes, Perinereis nuntia was exposed to B[a]P-contaminated artificial seawater and sexual maturation, the sex ratio, number of eggs spawned, fertilization and hatching rated, as well as vitellogenin (VTG) mRNA expression levels were analyzed. A low concentration of B[a]P (2.5 μg/L) had no Effects on the rate of sexual maturation, spawning, or fertilization but significantly increased the sex ratio (female: male) from 1.6±0.15:1 to 2.3±0.18:1, inhibited hatching rate by 27%, and significantly increased VTG mRNA expression level by 3.7-fold following a 60-day exposure, compared with those in the solvent controls. A higher concentration of B[a]P (25 μg/L) caused more serious Effects; sexual maturation, fertilization success, and hatching decreased by 31%, 17% and 46%, respectively, and the sex ratio (female: male) and VTG mRNA gene expression level increased by 54% and 7.1-fold, respectively. These results demonstrate that sublethal concentrations of B[a]P negatively aff ect reproductive performance of the sandworm P. nuntia.

  19. Potato (Solanum tuberosum) greenhouse tuber production as an assay for asexual reproduction effects from herbicides.

    PubMed

    Olszyk, David; Pfleeger, Thomas; Lee, E Henry; Plocher, Milton

    2010-01-01

    The present study determined whether young potato plants can be used as an assay to indicate potential effects of pesticides on asexual reproduction. Solanum tuberosum (Russet Burbank) plants were grown from seed pieces in a mineral soil in pots under greenhouse conditions. Plants were treated with herbicides (cloransulam, dicamba, glyphosate, imazapyr, primsulfuron, sulfometuron, or tribenuron) at simulated drift levels [assay for below-ground asexual reproductive responses to herbicides, especially acetolactate synthase inhibitors.

  20. Environmental toxicants cause sperm DNA fragmentation as detected by the Sperm Chromatin Structure Assay (SCSA[reg])

    SciTech Connect

    Evenson, Donald P. . E-mail: scsa@brookings.net; Wixon, Regina

    2005-09-01

    Studies over the past two decades have clearly shown that reproductive toxicants cause sperm DNA fragmentation. This DNA fragmentation can usually be detected prior to observing alterations of metaphase chromosomes in embryos. Thus, Sperm Chromatin Structure Assay (SCSA)-detected DNA damage is viewed as the molecular precursor to later gross chromosome damage observed under the light microscope. SCSA measurements of animal or human sperm consist of first obtaining a fresh or flash frozen neat semen sample in LN2 or dry ice. Samples are then sent to a SCSA diagnostic laboratory where the samples are thawed, diluted to {approx}1-2 x 106 sperm/ml, treated for 30 s with a pH 1.2 detergent buffer and then stained with acridine orange (AO). The low pH partially denatures DNA at the sites of DNA strand breaks and the AO-ssDNA fluoresces red while the AO-dsDNA fluoresces green. Flow cytometry measurements of 5000 sperm/sample provide statistically robust data on the ratio of red to green sperm, the extent of the DNA fragmentation and the standard deviations of measures. Numerous experiments on rodents treated with reproductive toxicants clearly showed that SCSA measures are highly dose responsive and have a very low CV. Different agents that act on germ cells at various stages of development usually showed sperm DNA fragmentation when that germ cell fraction arrived in the epididymis or ejaculate. Some of these treated samples were capable of successful in vitro fertilization but with frequent embryo failure. A 2-year longitudinal study of men living a valley town with a reported abnormal level of infertility and spontaneous miscarriages and also a seasonal atmospheric smog pollution, showed, for the first time, that SCSA measurements of human sperm DNA fragmentation were detectable and correlated with dosage of air pollution while the classical semen measures were not correlated. Also, young men spraying pesticides without protective gear are at an increased risk for

  1. Land treatment of PAH-contaminated soil: Performance measured by chemical and toxicity assays

    SciTech Connect

    Sayles, G.D.; Acheson, C.M.; Kupferle, M.J.; Shan, Y.; Zhou, Q.; Meier, J.R.; Chang, L.; Brenner, R.C.

    1999-12-01

    The performance of a soil remediation process can be determined by measuring the reduction in target soil contaminant concentrations and by assessing the treatment's ability to lower soil toxicity. Land treatment of polycyclic aromatic hydrocarbon (PAH)-contaminated soil from a former wood-treating site was simulated at pilot scale in temperature-controlled sol pans. Nineteen two- through six-ring PAHs were monitored with time (initial total PAHs = 2,800 mg/kg). Twenty-five weeks of treatment yielded a final total PAH level of 1,160 mg/kg. Statistically significant decreases in concentrations were seen in total, two-, three-, and four-ring PAHs. Carcinogenic and five- and six-ring PAHs showed no significant change in concentration. Land treatment resulted in significant toxicity reduction based on root elongation, Allium chromosomal aberration, and solid-phase Microtox bioassays. Acute toxicity, as measured by the earthworm survival assay, was significantly reduced and completely removed. The Ames spiral plate mutagenicity assay revealed that the untreated soil was slightly mutagenic and that treatment may have reduced mutagenicity. The variety of results generated from the chemical and toxicity assays emphasize the need for conducting a battery of such tests to fully understand soil remediation processes.

  2. Reproductive toxicity and thyroid effects in Sprague Dawley rats exposed to low doses of ethylenethiourea.

    PubMed

    Maranghi, Francesca; De Angelis, Simona; Tassinari, Roberta; Chiarotti, Flavia; Lorenzetti, Stefano; Moracci, Gabriele; Marcoccia, Daniele; Gilardi, Enzo; Di Virgilio, Antonio; Eusepi, Agostino; Mantovani, Alberto; Olivieri, Antonella

    2013-09-01

    Ethylenethiourea (ETU) is the common metabolite of the widely used ethylenebisdithiocarbamate fungicides. It is identified as Endocrine Disruptor given its ability to interfere with thyroid hormone biosynthesis by inhibiting thyroid peroxidase activity. As far as we know, no studies have been performed to assess potential effects of ETU exposure at low dose levels, i.e. below the established LOAEL and NOAEL, during critical phases of development. Therefore, the aim of the present study was to verify the short- and long-term effects on thyroid function, reproduction and development of oral exposure to ETU levels comparable to and lower than LOAEL/NOAEL in rats. Sixty dams were treated daily by gavage during pregnancy and lactation with 0, 0.1, 0.3, 1.0 mg/kg bw per day of ETU. F1 generation was similarly treated from weaning to sexual maturity. Thyroid biomarkers were analyzed in dams and in offspring. Reproductive biomarkers were analyzed in F1 rats. For the first time this study has demonstrated reproductive toxicity and hypothyroidism at a lower than LOAEL dose exposure in pregnant dams and F1 generation. Our data suggest that even low doses of ETU can interfere with thyroid homeostasis and reproductive hormone profile if exposure starts in critical stages of development. PMID:23774258

  3. Earthworm coelomocyte phagocytosis: An in vitro assay for terrestrial toxicity identification evaluation

    SciTech Connect

    Burch, S.W.; Goven, A.J.; Fitzpatrick, L.C.; Venables, B.J.; Callahan, C.A.

    1995-12-31

    An in vitro assay has been developed for rapid (48 h) evaluation of cytotoxic effects of exposure (24 h) of earthworm coelomocytes. The assay, inhibition of phagocytosis (24 h) of stained yeast cells and cell viability, links a traditional soil bioassay organism (Lumbricus terrestris) with a laboratory protocol for use in evaluating physical/chemical fractions resulting from terrestrial TIE manipulations. The assay was developed using copper sulfate as a reference toxicant. Copper exposures as low as 2--4 pg/ml. resulted in 20--60% inhibition of phagocytosis without significant decrease in cell viability. Exposures above 10 pg/ml resulted in reduced cell viability and inhibition of phagocytosis. The assay was successfully applied to terrestrial TIE fractions derived from extractions of soil from a PCP contaminated wood treatment site.

  4. Evaluation of N-methylpyrrolidone and its oxidative products toxicity utilizing the Microtox assay

    SciTech Connect

    Campbell, H.L.; Striebig, B.A.

    1999-06-01

    N-Methylpyrrolidone (NMP) is a cyclic nitrogen-containing organic chemical used to replace more volatile and toxic organic solvents in paint coating and cleaning applications. The Marine Corps Multi-Commodity Maintenance Center was concerned that the high NMP and organic levels in process water would upset treatment processes at the Industrial Process Water Plant (IWP). The NMP contaminated process water was oxidized by a semicontinuous advanced oxidation reactor to reduce the organic concentration. The oxidative byproducts of NMP were identified by GC/MS and tested for their toxicity. A toxicity test, utilizing the Microtox toxicity assay, revealed that methylsuccinimide was the most toxic identifiable product of NMP oxidation. The toxicity of the process water was reduced as methylsuccinimide and was further oxidized to succinimide and other amine products. The results indicate that NMP contaminated process water should be oxidized past the N-methylsuccinimide compound prior to standard industrial process water treatment procedures, so as to reduce toxicity concerns associated with NMP contaminated process water.

  5. Lead toxicity thresholds in 17 Chinese soils based on substrate-induced nitrification assay.

    PubMed

    Li, Ji; Huang, Yizong; Hu, Ying; Jin, Shulan; Bao, Qiongli; Wang, Fei; Xiang, Meng; Xie, Huiting

    2016-06-01

    The influence of soil properties on toxicity threshold values for Pb toward soil microbial processes is poorly recognized. The impact of leaching on the Pb threshold has not been assessed systematically. Lead toxicity was screened in 17 Chinese soils using a substrate-induced nitrification (SIN) assay under both leached and unleached conditions. The effective concentration of added Pb causing 50% inhibition (EC50) ranged from 185 to >2515mg/kg soil for leached soil and 130 to >2490mg/kg soil for unleached soil. These results represented >13- and >19-fold variations among leached and unleached soils, respectively. Leaching significantly reduced Pb toxicity for 70% of both alkaline and acidic soils tested, with an average leaching factor of 3.0. Soil pH and CEC were the two most useful predictors of Pb toxicity in soils, explaining over 90% of variance in the unleached EC50 value. The relationships established in the present study predicted Pb toxicity within a factor of two of measured values. These relationships between Pb toxicity and soil properties could be used to establish site-specific guidance on Pb toxicity thresholds. PMID:27266309

  6. The role of chorion on toxicity of silver nanoparticles in the embryonic zebrafish assay

    PubMed Central

    Kim, Ki-Tae; Tanguay, Robert L.

    2014-01-01

    Objectives This study was designed to investigate how the size- and surface coating-dependent toxicity of silver nanoparticles (AgNPs) is influenced by the presence and absence of the chorion in an embryonic zebrafish assay. Methods Normal and dechorinated embryos were exposed to four different AgNPs, 20 or 110 nm in size, with polypyrrolidone (PVP) or citrate surface coatings in a standard zebrafish embryo medium (EM). This was then compared to a 62.5 μM calcium chloride (CaCl2) solution where agglomeration was controlled. Results Embryonic toxicity in the absence of the chorion was greater than in its presence. The smaller 20 nm AgNPs were more toxic than the larger 110 nm AgNPs, regardless of the chorion and test media. However, surface coating affected toxicity, since PVPcoated AgNPs were more toxic than citrate-coated AgNPs; this was strongly affected by the presence of the chorion in both EM and CaCl2. Conclusions Our results demonstrate the permeability function of the chorion on the size- and surface coating-dependent toxicity of AgNPs. Thereafter, careful experiment should be conducted to assess nanoparticle toxicity in zebrafish embryos. PMID:25518841

  7. Risk assessment of an abandoned pyrite mine in Spain based on direct toxicity assays.

    PubMed

    García-Gómez, Concepción; Sánchez-Pardo, Beatriz; Esteban, Elvira; Peñalosa, Jesús Manuel; Fernández, María Dolores

    2014-02-01

    This research reports the risk assessment of an abandoned pyrite mine using direct toxicity assays of soil and groundwater samples taken at the site. The toxicity of As and heavy metals from mining soils to soil and aquatic organisms was studied using the Multispecies Soil System (MS-3) in soil columns. Ecotoxicological assessment was performed with soil samples diluted with a control soil at concentrations of 12.5, 25, 50 and 100% test soil/soil (w/w). In this way, changes in the mobility and bioavailability of soil contaminants due to changes in geochemical soil properties via soil dilution were studied. The toxicity of water samples was tested on algae and Daphnia magna. The assessment of the mining area indicated that the current presence of As and heavy metals at the site may cause injuries to soil and aquatic organisms in the entire research area. Moreover, this investigation demonstrated that changes in geochemical conditions can increase the availability of arsenic and, consequently, the environmental risk of these soils. A good correlation was not found between toxicity parameters and the concentrations of soil contaminants based on total and extracted element concentrations. This finding reinforces the usefulness of direct toxicity assays for evaluating environmental risk.

  8. Reproductive toxicity of ethylene glycol monoethyl ether tested by continuous breeding of CD-1 mice

    SciTech Connect

    Lamb, J.C. IV; Gulati, D.K.; Russell, V.S.; Hommel, L.; Sabharwal, P.S.

    1984-08-01

    The reproductive toxicity of ethylene glycol monoethyl ether (EGEE) was evaluated in the Fertility Assessment by Continuous Breeding protocol. Both male and female CD-1 mice were given 0, 0.5, 1.0 or 2% EGEE in the drinking water and were housed as breeding pairs continuously for 14 weeks. Significant adverse effects on fertility were seen at 1 and 2% but not at 0.5%. After the continuous breeding phase of this test was completed, treated males were housed with control females and treated females with control males and fertility and reproduction were compared to the corresponding pairs of control male and control female mice. Both males and females from the 1 and 2% groups were affected. Testicular atrophy decreased sperm motility and increased abnormal sperm were noted in the treated males, but no specific anomalies were detected in the females. 7 references, 1 figure, 7 tables.

  9. Male reproductive toxicity of lead in animals and humans. ASCLEPIOS Study Group

    PubMed Central

    Apostoli, P.; Kiss, P.; Porru, S.; Bonde, J. P.; Vanhoorne, M.

    1998-01-01

    OBJECTIVE: To critically review the literature on male reproductive toxicity of lead in animals and humans. METHODS: A systematic literature search identified a total of 32 experimental studies in animals and 22 epidemiological studies, one case report on humans and five review articles or documents. The studies were evaluated by paying attention mainly to sample size, study design, exposure, and dose characterisation, analytical method standardisation, and quality assurance. RESULTS: Several studies on rats and other rodents indicated that blood lead concentrations > 30-40 micrograms/dl were associated with impairment of spermatogenesis and reduced concentrations of androgens. However, other animal studies, mainly about histopathological, spermatozoal, and hormonal end points, indicated that certain species and strains were quite resistant to the reproductive toxicity of lead and that different testicular lead concentrations could account for these differences. The human studies focused mainly on semen quality, endocrine function, and birth rates in occupationally exposed subjects, and showed that exposure to concentrations of inorganic lead > 40 micrograms/dl in blood impaired male reproductive function by reducing sperm count, volume, and density, or changing sperm motility and morphology. No relevant effects were detected on endocrine profile. CONCLUSION: Several factors make it difficult to extrapolate the animal data to the human situation. The difficulties are mainly due to differences between species in reproductive end points and to the level of exposure. Concentrations of blood lead > 40 micrograms/dl seemed to be associated with a decrease in sperm count, volume, motility, and morphological alterations and a possible modest effect on endocrine profile. Dose-response relation, in particular at a threshold level, is poorly understood, and site, mode, or mechanism of action are unknown. Also, the effects were not always the same or associated in the same on

  10. Comparative analysis of antioxidants against cadmium induced reproductive toxicity in adult male rats.

    PubMed

    Jahan, Sarwat; Khan, Mehreen; Ahmed, Shakeel; Ullah, Hizb

    2014-02-01

    The present study was conducted to compare and evaluate the potential benefits of three different antioxidants in reversing cadmium (Cd)-induced reproductive toxicity in adult male rats. Rats (n = 5) weighing 180 +/- 20 gm were divided into five groups (control, Cd, Cd + sulforaphane, Cd + vitamin E, and Cd + plant extract). Treated groups received CdCl2 (0.2 mg/kg), sulforaphane (25 µg/rat), vitamin E (75 mg/kg), and plant extract (100 mg/kg) for 15 days. Blood samples and testicular tissues were obtained for estimation of testosterone, Zn, and Cd concentration and daily sperm production/efficiency of sperm production. Cadmium exposure caused a significant decrease in final body weight (p < 0.0001). The plasma concentrations of Cd were significantly increased and Zn concentration decreased (p < 0.0001) in the Cd group as compared to the control group. The testicular concentrations of Cd were significantly increased and Zn concentration decreased (p < 0.0001) in the Cd group as compared to the control group. Cadmium exposure caused a significant decrease (p < 0.0001) in plasma testosterone concentrations and daily sperm production as compared to the control group. More significant effects were observed with Cd+sulforaphane, Cd + vitamin E, and Cd + plant extract treated groups in slashing Cd-induced toxicity. Present findings suggest that Ficus religiosa and sulforaphane are more powerful antioxidants as compared to vitamin E in reversing the oxidative stress and can have a protective role against Cd induced reproductive toxicity in adult male rats. Part of the mechanism involved in this protective role seems to be associated with the antioxidant properties of these agents in reducing reproductive damage. PMID:24156729

  11. Toxicant-disease-environment interactions associated with suppression of immune system, growth, and reproduction. [PCB

    SciTech Connect

    Porter, W.P.; Hinsdill, R.; Fairbrother, A.; Olson, L.J.; Jaeger, J.; Yuill, T.; Bisgaard, S.; Hunter, W.G.; Nolan, K.

    1984-06-01

    The effects of marginal malnourishment, infections, and environmental chemicals on growth and reproductive success in Swiss-Webster white mice and wild deer mice were studied with fractional factorial designs. Interaction effects were discovered. For example, malnourished mice were more sensitive to virus exposure and environmental chemicals (a plant growth regulator or polychlorinated biphenyls). Since several commercial plant growth regulators also appear to suppress the immune system, these results cast doubt on the adequacy of current toxicity testing procedures in which factors are studied individually and not in combination.

  12. Toxicity of South American snake venoms measured by an in vitro cell culture assay.

    PubMed

    Oliveira, J C R; de Oca, H M; Duarte, M M; Diniz, C R; Fortes-Dias, C L

    2002-03-01

    Cytotoxicity of venoms from eight medically important South American Crotalidae snakes (Bothrops and Lachesis genera) was determined, based on a procedure originally described for the screening of cytotoxic agents in general. The assay, the conditions of which were adapted to snake venoms, determines the survival of viable cells in monolayer culture upon exposure to the toxic agent. Snake venom toxicity was expressed as the venom dose that killed 50% of the cells (CT(50)) under the assay conditions. Bothrops neuwieddi mattogrossensis (CT(50)=4.74+/-0.35 microg/ml) and Bothrops leucurus (CT(50)=4.95+/-0.51 microg/ml) were the most cytotoxic whereas Bothrops atrox (CT(50)=34.64+/-2.38 microg/ml) and Bothrops sp. (CT(50)=33.89+/-3.89 microg/ml) were the least cytotoxic venoms, respectively. The relationship between CT(50) and other biological activities of these snake venoms was evaluated. PMID:11711131

  13. Health assessment of gasoline and fuel oxygenate vapors: reproductive toxicity assessment.

    PubMed

    Gray, Thomas M; Steup, David; Roberts, Linda G; O'Callaghan, James P; Hoffman, Gary; Schreiner, Ceinwen A; Clark, Charles R

    2014-11-01

    Vapor condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000mg/m(3), 6h/day, 7days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study. Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME offspring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000mg/m(3) for all vapor condensates except for lower offspring NOAELs of 10,000mg/m(3) for G/TBA and 2000mg/m(3) for G/TAME. PMID:24813181

  14. Health assessment of gasoline and fuel oxygenate vapors: reproductive toxicity assessment.

    PubMed

    Gray, Thomas M; Steup, David; Roberts, Linda G; O'Callaghan, James P; Hoffman, Gary; Schreiner, Ceinwen A; Clark, Charles R

    2014-11-01

    Vapor condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000mg/m(3), 6h/day, 7days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study. Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME offspring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000mg/m(3) for all vapor condensates except for lower offspring NOAELs of 10,000mg/m(3) for G/TBA and 2000mg/m(3) for G/TAME.

  15. The submitochondrial particle assay as a screening test for acute aquatic toxicity of surfactant molecules

    SciTech Connect

    Bookland, E.A.; Bettermann, A.D.

    1995-12-31

    Two complementary protocols of the submitochondrial particle assay (SMP) were evaluated as screening tools for predicting the acute aquatic toxicity of various classes and chain lengths of surfactant molecules. SMP contain the functionally intact mitochondrial enzyme systems responsible for electron transport and oxidative phosphorylation. Both the Electron Transfer Assay (ETR) and the Reverse Electron Transfer Assay (RET) have been shown in prior work to generally be sensitive to agents capable of membrane and protein interactions, both suspected mechanisms of action for surfactants. The toxicity of ten compounds; four anionic surfactants, C{sub 12} alkyl sulfate (C{sub 12}AS), C{sub 12} and C{sub 15} alkyl ethoxy sulfate (C{sub 12}E{sub 4}S, C{sub 15}E{sub 4}S), linear alkyl benzene sulfonate (C{sub 12.3}LAS); one nonionic surfactant, alkyl ethoxylate (C{sub 12}E{sub 3}); three cationic surfactants, C{sub 8}, C{sub 12}, and C{sub 16} alkyl trimethyl ammonium chloride (C{sub 8}TMAC, C{sub 12}TMAC, C{sub 16}TMAC); an alcohol (C{sub 12}OH); and an amine, alkyl dimethylamine (C{sub 12}DMA); was determined. In all cases, both the ETR and the RET gave results showing equal or greater sensitivity than previously reported acute fish and invertebrate LC{sub 50}`s. In addition, increasing toxicity with increasing alkyl chain length was observed. As a rapid screening tool, the SMP bioassay avoids exposure concerns such as degradation of test material, a common concern for acute in vivo toxicity testing with rapidly degradable materials. Results indicate that the SMP bioassay can be useful as a predictive screening tool for the aquatic toxicity of surfactants.

  16. Effects of atrazine on fathead minnow in a short-term reproduction assay.

    PubMed

    Bringolf, Robert B; Belden, Jason B; Summerfelt, Robert C

    2004-04-01

    Atrazine is the most extensively used herbicide in the United States. Part-per-million concentrations of atrazine have been reported in agricultural runoff. It is detectable in surface waters and precipitation throughout the year, and it has been found in groundwater sources of drinking water. Recent studies indicate that atrazine may be a potent endocrine-disrupting compound in frogs exposed to part-per-billion (microg/L) concentrations. For these reasons, the effects of atrazine (5 and 50 microg/L) on several endpoints related to reproductive fitness were examined in fathead minnows (Pimephales promelas) in a 21-d static exposure. Estradiol (0.5 microg/L) was included as a positive-control treatment. Endpoints examined in adult fish during and after the exposures included survival, egg production, number of spawns, eggs/spawn, relative gonad weight, gonad histology, number of nuptial tubercles, and plasma vitellogenin concentration. Eggs produced during the exposures were hatched and reared in control water. The percentages of embryos fertilized and hatched as well as larval survival were evaluated. Decreasing trends were observed in relative testis weight, testis maturity, and percentage embryo fertilization. These trends suggest that further investigation is warranted, but the differences in these and other endpoints were not statistically significant in the atrazine-exposed fish. Nearly all endpoints concerning fish exposed to estradiol were significantly different from atrazine-exposed fish and control fish. These results suggest that atrazine did not have strong estrogenic effects in adult fathead minnows and did not cause overt reproductive toxicity at environmentally relevant concentrations.

  17. Developmental and reproductive toxicity of inorganic arsenic: animal studies and human concerns.

    PubMed

    Golub, M S; Macintosh, M S; Baumrind, N

    1998-01-01

    Information on the reproductive and developmental toxicity of inorganic arsenic is available primarily from studies in animals using arsenite and arsenate salts and arsenic trioxide. Inorganic arsenic has been extensively studied as a teratogen in animals. Data from animal studies demonstrate that arsenic can produce developmental toxicity, including malformation, death, and growth retardation, in four species (hamsters, mice, rats, rabbits). A characteristic pattern of malformations is produced, and the developmental toxicity effects are dependent on dose, route, and the day of gestation when exposure occurs. Studies with gavage and diet administration indicate that death and growth retardation are produced by oral arsenic exposure. Arsenic is readily transferred to the fetus and produces developmental toxicity in embryo culture. Animal studies have not identified an effect of arsenic on fertility in males or females. When females were dosed chronically for periods that included pregnancy, the primary effect of arsenic on reproduction was a dose-dependent increase in conceptus mortality and in postnatal growth retardation. Human data are limited to a few studies of populations exposed to arsenic from drinking water or from working at or living near smelters. Associations with spontaneous abortion and stillbirth have been reported in more than one of these studies, but interpretation of these studies is complicated because study populations were exposed to multiple chemicals. Thus, animal studies suggest that environmental arsenic exposures are primarily a risk to the developing fetus. In order to understand the implications for humans, attention must be given to comparative pharmacokinetics and metabolism, likely exposure scenarios, possible mechanisms of action, and the potential role of arsenic as an essential nutrient.

  18. Apium graveolens modulates sodium valproate-induced reproductive toxicity in rats.

    PubMed

    Hamza, Alaaeldin A; Amin, Amr

    2007-04-01

    Sodium valproate (VPA), a common treatment of epilepsy and other diseases, is known to have severe toxic effects on testis both in experimental animals and in humans. The present study was designed to investigate the protective effect of Apium graveolens (AG) against the VPA-induced testis injury. Testicular toxicity was induced by the administration of VPA (500 mg/kg/day) once daily for 7 consecutive days. Protective group received daily doses (200 mg/kg/day) of AG crude extract for 23 days prior to VPA administration. VPA-induced reproductive toxicity was assessed based on the weight of testes, sperm analysis, and serum concentrations of sexual hormones. The relative weights of testes and epididymes and the sperm numbers viability were all decreased following the valproate administration. Testosterone levels dropped while follicle stimulating hormone (FSH) level increased following the drug administration. Severe histopathological changes in testis were observed such as degeneration of seminiferous tubules and depletion of germ cells. These biochemical and histological changes were also associated with alterations of oxidative stress markers. Levels of malondialdehyde have increased, while superoxide dismutase activity has decreased. Pretreatment with A. graveolens extract has effectively alleviated most of the VPA-induced effects suggesting a protective role of A. graveolens extract against experimental VPA-induced toxicity. Apigenin content was estimated and was shown as a major fraction of the A. graveolens extract.

  19. Scientific and regulatory policy committee (SRPC) paper: assessment of circulating hormones in nonclinical toxicity studies III. female reproductive hormones.

    PubMed

    Andersson, Håkan; Rehm, Sabine; Stanislaus, Dinesh; Wood, Charles E

    2013-08-01

    Hormonally mediated effects on the female reproductive system may manifest as pathologic changes of endocrine-responsive organs and altered reproductive function. Identification of these effects requires proper assessment, which may include investigative studies to profile female reproductive hormones. Here, we briefly describe normal hormonal patterns across the estrous or menstrual cycle and provide general guidance on measuring female reproductive hormones and characterizing hormonal disturbances in nonclinical toxicity studies. Although species used in standard toxicity studies share basic features of reproductive endocrinology, there are important species differences that affect both study design and interpretation of results. Diagnosing female reproductive hormone disturbances can be complicated by many factors, including estrous/menstrual cyclicity, diurnal variation, and age- and stress-related factors. Thus, female reproductive hormonal measurements should not generally be included in first-tier toxicity studies of standard design with groups of unsynchronized intact female animals. Rather, appropriately designed and statistically powered investigative studies are recommended in order to properly identify ovarian and/or pituitary hormone changes and bridge these effects to mechanistic evaluations and safety assessments. This article is intended to provide general considerations and approaches for these types of targeted studies.

  20. Neutral red retention time assay in determination of toxicity of nanoparticles.

    PubMed

    Hu, Wentao; Culloty, Sarah; Darmody, Grainne; Lynch, Sharon; Davenport, John; Ramirez-Garcia, Sonia; Dawson, Kenneth; Lynch, Iseult; Doyle, Hugh; Sheehan, David

    2015-10-01

    The neutral red retention time (NRRT) assay is useful for detecting decreased lysosomal membrane stability in haemocytes sampled from bivalves, a phenomenon often associated with exposure to environmental pollutants including nanomaterials. Bivalves are popular sentinel species in ecotoxicology and use of NRRT in study of species in the genus Mytilus is widespread in environmental monitoring. The NRRT assay has been used as an in vivo test for toxicity of carbon nanoparticles (Moore MN, Readman JAJ, Readman JW, Lowe DM, Frickers PE, Beesley A. 2009. Lysosomal cytotoxicity of carbon nanoparticles in cells of the molluscan immune system: An in vivo study. Nanotoxicology. 3 (1), 40-45). We here report application of this assay adapted to a microtitre plate format to a panel of metal and metal oxide nanoparticles (2 ppm). This showed that copper, chromium and cobalt nanoparticles are toxic by this criterion while gold and titanium nanoparticles are not. As the former three nanoparticles are often reported to be cytotoxic while the latter two are thought to be non-cytotoxic, these data support use of NRRT as a general in vitro assay in nanotoxicology.

  1. Neutral red retention time assay in determination of toxicity of nanoparticles.

    PubMed

    Hu, Wentao; Culloty, Sarah; Darmody, Grainne; Lynch, Sharon; Davenport, John; Ramirez-Garcia, Sonia; Dawson, Kenneth; Lynch, Iseult; Doyle, Hugh; Sheehan, David

    2015-10-01

    The neutral red retention time (NRRT) assay is useful for detecting decreased lysosomal membrane stability in haemocytes sampled from bivalves, a phenomenon often associated with exposure to environmental pollutants including nanomaterials. Bivalves are popular sentinel species in ecotoxicology and use of NRRT in study of species in the genus Mytilus is widespread in environmental monitoring. The NRRT assay has been used as an in vivo test for toxicity of carbon nanoparticles (Moore MN, Readman JAJ, Readman JW, Lowe DM, Frickers PE, Beesley A. 2009. Lysosomal cytotoxicity of carbon nanoparticles in cells of the molluscan immune system: An in vivo study. Nanotoxicology. 3 (1), 40-45). We here report application of this assay adapted to a microtitre plate format to a panel of metal and metal oxide nanoparticles (2 ppm). This showed that copper, chromium and cobalt nanoparticles are toxic by this criterion while gold and titanium nanoparticles are not. As the former three nanoparticles are often reported to be cytotoxic while the latter two are thought to be non-cytotoxic, these data support use of NRRT as a general in vitro assay in nanotoxicology. PMID:26065811

  2. In vitro red blood cell assay for oxidant toxicity of petroleum oil

    SciTech Connect

    Couillard, C.M.; Leighton, F.A. )

    1993-05-01

    Petroleum oil has caused hemolytic anemia in birds and mammals. In birds, an oxidant damage on circulating red cells has been identified as the primary toxic effect of ingested petroleum oils. An in vitro red blood cell assay was developed to discriminate among the oxidant activities of different petroleum oils. The assay used rabbit red blood cells with a rat liver enzyme system and formation of methemoglobin was measured as an indicator of oxidant damage to the red cells. The assay was applied to five different petroleum oils and to naphthalene, a petroleum hydrocarbon known to cause hemolytic anemia. Different petroleum oils differed in their capacity to induce methemoglobin formation. Methemoglobin levels varied from 2.9% with Arabian light crude oil to 6.2% with South Louisiana crude oil. Naphthalene induced formation of up to 37% methemoglobin. Naphthalene and the five petroleum oils generated methemoglobin only in the presence of liver enzymes.

  3. In vitro assays of chemotaxis as a window into mechanisms of toxicant-induced immunomodulation.

    PubMed

    Pietrosimone, Kathryn M; Bhandari, Sadikshya; Lemieux, Michael G; Knecht, David A; Lynes, Michael A

    2013-01-01

    Dysregulated cell movement can lead to developmental abnormalities, neoplasia, and immune system disorders, and there are a variety of contexts in which xenobiotics (and biologic) effects on this movement are of interest. Many toxins and toxicants have been shown to disrupt controlled cell movement. Identification of compounds that affect cell movement is crucial to drug discovery. Drug components may have unexpected consequences with respect to cell motility, which would exclude these compounds in drug development. Finally, the development of drugs that target chemotactic pathways may be useful in the treatment of tumors, which often reprogram chemotactic pathways to become metastatic. The effects of these agents on cell movement can be measured using several different in vitro chemotactic assays. This review details the procedures of three in vitro measurements of chemotaxis: the Boyden chamber, the under-agarose assay, and the automated, real-time, ECIS/Taxis assay, and discusses the inferences that can be drawn from the results of such studies.

  4. Effect of restraint stress on lead-induced male reproductive toxicity in rats.

    PubMed

    Priya, P Hari; Reddy, P Sreenivasula

    2012-08-01

    This study was undertaken to investigate whether chronic immobilization stress interferes with lead-induced reproductive toxicity in rats. Early pubertal male Wistar rats were subjected to either restraint stress (5 hr/day) or maintained on lead (0.15%) containing water or both for 60 days. Restraint stress or lead treatment significantly decreased the weight of the testes and epididymis. The daily sperm production, epididymal sperm count, sperm motility, and sperm viability were also decreased after exposure to lead or subjected to restraint stress. The levels of serum testosterone and also activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased with a significant increase in the serum follicle stimulating and luteinizing hormone levels in rats exposed to lead or restraint stress indicating decreased steroidogenesis. A significant increase in lipid peroxidation levels and decrease in catalase and superoxide dismutase activity levels were observed in the testes of rats subjected to restraint stress or exposed to lead indicating increased oxidative stress. Extensive histopathological malformations were observed in the testis of the treated rats. From the findings, the study suggests that restraint stress or exposure to lead affects male reproduction in rats by inducing oxidative stress followed by decreasing steroidogenesis and spermatogenesis. A significant decrease in spermatogenesis and steroidogenesis was also observed in rats subjected to both restraint stress and lead treatment as compared to lead alone treated rats indicating immobilization stress augments lead-induced testicular and epididymal toxicity in rats. PMID:22753343

  5. Regulatory acceptance and use of the Extended One Generation Reproductive Toxicity Study within Europe.

    PubMed

    Schiffelers, Marie-Jeanne W A; Blaauboer, Bas J; Bakker, Wieger E; Hendriksen, Coenraad F M; Krul, Cyrille

    2015-02-01

    The two-generation study (OECD TG 416) is the standard requirement within REACH to test reproductive toxicity effects of chemicals with production volumes >100 tonnes. This test is criticized in terms of scientific relevance and animal welfare. The Extended One Generation Reproductive Toxicity Study (EOGRTS), incorporated into the OECD test guidelines in 2011 (OECD TG 443) has the potential to replace TG 416, while using only one generation of rats and being more informative. However, its regulatory acceptance proved challenging. This article reconstructs the process of regulatory acceptance and use of the EOGRTS and describes drivers and barriers influencing the process. The findings derive from literature research and expert interviews. A distinction is made between three sub-stages; The stage of Formal Incorporation of the EOGRTS into OECD test guidelines was stimulated by retrospective analyses on the value of the second generation (F2), strong EOGRTS advocates, animal welfare concern and changing US and EU chemicals legislation; the stage of Actual Regulatory Acceptance within REACH was challenged by legal factors and ongoing scientific disputes, while the stage of Use by Industry is influenced by uncertainty of registrants about regulatory acceptance, high costs, the risk of false positives and the manageability of the EOGRTS.

  6. Effect of restraint stress on lead-induced male reproductive toxicity in rats.

    PubMed

    Priya, P Hari; Reddy, P Sreenivasula

    2012-08-01

    This study was undertaken to investigate whether chronic immobilization stress interferes with lead-induced reproductive toxicity in rats. Early pubertal male Wistar rats were subjected to either restraint stress (5 hr/day) or maintained on lead (0.15%) containing water or both for 60 days. Restraint stress or lead treatment significantly decreased the weight of the testes and epididymis. The daily sperm production, epididymal sperm count, sperm motility, and sperm viability were also decreased after exposure to lead or subjected to restraint stress. The levels of serum testosterone and also activity levels of testicular hydroxysteroid dehydrogenases were significantly decreased with a significant increase in the serum follicle stimulating and luteinizing hormone levels in rats exposed to lead or restraint stress indicating decreased steroidogenesis. A significant increase in lipid peroxidation levels and decrease in catalase and superoxide dismutase activity levels were observed in the testes of rats subjected to restraint stress or exposed to lead indicating increased oxidative stress. Extensive histopathological malformations were observed in the testis of the treated rats. From the findings, the study suggests that restraint stress or exposure to lead affects male reproduction in rats by inducing oxidative stress followed by decreasing steroidogenesis and spermatogenesis. A significant decrease in spermatogenesis and steroidogenesis was also observed in rats subjected to both restraint stress and lead treatment as compared to lead alone treated rats indicating immobilization stress augments lead-induced testicular and epididymal toxicity in rats.

  7. Zinc inhibits the reproductive toxicity of Zearalenone in immortalized murine ovarian granular KK-1 cells

    PubMed Central

    Li, Yijia; He, Xiaoyun; Yang, Xuan; Huang, Kunlun; Luo, Yunbo; Zhu, Liye; Li, Yuzhe; Xu, Wentao

    2015-01-01

    Zearalenone (ZEA) mainly injures the reproductive system of mammals. In the present study, we aimed to explore the mechanism by which zinc inhibits ZEA-induced reproductive damage in KK-1 cells for the first time. The results shown that both zinc sulfate and zinc gluconate addition increased the intracellular zinc concentration and influenced the expression of zinc transporters (Slc30a1 and Slc39a1) in a time-dependent manner. Co-incubation of zinc with ZEA significantly reduced the ZEA-induced reactive oxygen species and malondialdehyde elevation by promoting the transcription of Mtf1 and Mt2. Meanwhile, two different zincs inhibited the ZEA-induced loss of mitochondrial membrane potential and elevation of late-stage apoptosis via activating the mitochondrial apoptotic pathway by recovering the mRNA and protein expression of pro-apoptotic genes (Bax, Casp3, Casp9). Zinc also recovered cells from S-phase cell cycle arrest. In addition, both of them promoted the ZEA-induced estrogen production but regulated the expression of steroidogenic enzymes (Star, Cyp11a1, Hsd3b1, Cyp17a1) in different way. All these results indicated that zinc could inhibit the reproductive toxicity of ZEA. PMID:26395757

  8. Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study.

    PubMed Central

    Pease, W; Vandenberg, J; Hooper, K

    1991-01-01

    This paper compares four alternative approaches for deriving regulatory levels for reproductive toxicants by applying them to the available data on the human spermatotoxicant 1,2-dibromo-3-chloropropane (DBCP). The alternatives examined include the Proposition 65 approach (application of a mandatory 1000-fold uncertainty factor to a no-observed-adverse-effect level [NOAEL]), the Environmental Protection Agency (EPA) approach (application of flexible uncertainty factors to a NOAEL), the Benchmark Dose approach (application of flexible uncertainty factors to a dose associated with a known level of change in a reproductive parameter), and the Quantitative Risk Estimation approach (using low-dose linear extrapolation and a model of the relationship between sperm count and infertility). Applied to DBCP, these approaches do not produce substantially different estimates of allowable exposure levels. However, the approaches do have different data requirements and provide different amounts of information on reproductive hazards to risk managers and the public. Neither the Proposition 65 nor the EPA approach provides information about the extent of health risk remaining at a regulatory level. In contrast, the Benchmark Dose approach can provide estimates of the magnitude of sperm count reduction at a regulatory level, and the Quantitative Risk Estimation approach can provide estimates of exposure-induced infertility. PMID:2040244

  9. NTP-CERHR expert panel report on the reproductive anddevelopmental toxicity of hydroxyurea

    SciTech Connect

    Liebelt, E.L.; Balk, S.J.; Faber, W.; Fisher, J.W.; Hughes, C.L.; Lanzkron, S.M.; Lewis, K.M.; Marchetti, F.; Mehendale, H.M.; Rogers,J.M.; Shad, A.T.; Skalko, R.G.; Stanek, E.J.

    2007-01-01

    The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed. Hydroxyurea was selected for evaluation by a CERHR expert panel because of (1) its increasing use in the treatment of sickle cell disease in children and adults, (2) knowledge that it inhibits DNA synthesis and is cytotoxic, and (3) published evidence of its reproductive and developmental toxicity in rodents. Hydroxyurea is FDA-approved for reducing the frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia who experience recurrent moderate-to-severe crises. Hydroxyurea is used in the treatment of cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease aside from blood transfusion used in children. Hydroxyurea may be used in the treatment of children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea may be associated with cytotoxic and myelosuppressive effects, and hydroxyurea is mutagenic.

  10. Using Online Tool (iPrior) for Modeling ToxCast™ Assays Towards Prioritization of Animal Toxicity Testing.

    PubMed

    Abdelaziz, Ahmed; Sushko, Yurii; Novotarskyi, Sergii; Körner, Robert; Brandmaier, Stefan; Tetko, Igor V

    2015-01-01

    The use of long-term animal studies for human and environmental toxicity estimation is more discouraged than ever before. Alternative models for toxicity prediction, including QSAR studies, are gaining more ground. A recent approach is to combine in vitro chemical profiling and in silico chemical descriptors with the knowledge about toxicity pathways to derive a unique signature for toxicity endpoints. In this study we investigate the ToxCast™ Phase I data regarding their ability to predict long-term animal toxicity. We investigated thousands of models constructed in an effort to predict 61 toxicity endpoints using multiple descriptor packages and hundreds of in vitro assays. We investigated the use of in vitro assays and biochemical pathways on model performance. We identified 10 toxicity endpoints where biologically derived descriptors from in vitro assays or pathway perturbations improved the model prediction ability. In vivo toxicity endpoints proved generally challenging to model. Few models were possible to readily model with a balanced accuracy (BA) above 0.7. We also constructed in silico models to predict the outcome of 144 in vitro assays. This showed better statistical metrics with 79 out of 144 assays having median balanced accuracy above 0.7. This suggests that the in vitro datasets have a better modelability than in vivo animal toxicities for the given datasets. Moreover, we published an online platform (http://iprior.ochem.eu) that automates large-scale model building and analysis.

  11. The significance of growth in Chironomus tentans sediment toxicity tests: Relationship to reproduction and demographic endpoints

    SciTech Connect

    Sibley, P.K.; Benoit, D.A.; Ankley, G.T.

    1995-12-31

    This study assessed the biological relevance of growth, as used in sediment toxicity bioassessment, through evaluation of the relationship between growth and reproduction in the midge C. tentans. Newly-hatched larvae were fed one of six food levels (3.5, 4.0, 4.5, 5.0, 5.5, 6.0 mg Tetrafin fish food) on a daily basis for one complete generation. Larvae were exposed in 300 ml beakers containing 100 ml of 75/{micro}m sand housed within an intermittent water renewal system. Food supply had no effect on larval (65--82%), pupal (93--95%), or adult (90--98%) survivorship. Larval growth and adult weight decreased significantly (p{<=}0.05) with decreasing food supply (r{sup 2} = 0.92, 0.91 respectively). The data suggest that a threshold larval dry weight of approximately 0.6 mg must be obtained for emergence to occur. This value also corresponded to the approximate minimum adult weight observed in this study. Emergence rate and total emergence were delayed at lower feeding levels; however, total emergence was not less than 60% for any treatment. Egg mass production, oviposition rate, and mean number of eggs produced per female declined significantly with reduced food supply. Larval growth and adult weight were significantly correlated with age-specific fecundity (r{sup 2} = 0.96). Application of the reproductive data in a demographic model showed that the expected number of offspring recruited to subsequent generations declined significantly with a decrease in food supply. The results of this study demonstrate a direct relationship between growth and reproduction in C. tentans and clearly emphasize the biological and ecological relevance of the growth endpoint in sediment toxicity bioassessment.

  12. Optimization and Performance Assessment of the Chorion-Off [Dechorinated] Zebrafish Developmental Toxicity Assay.

    PubMed

    Panzica-Kelly, Julieta M; Zhang, Cindy X; Augustine-Rauch, Karen A

    2015-07-01

    The Dechorinated Zebrafish Embryo Developmental toxicity assay was originally developed from a training set of 31 compounds and reported to be 87% concordant with in vivo teratogenicity data (Brannen, K. C., Panzica-Kelly, J. M., Danberry, T. L., and Augustine-Rauch, K. A. (2010). Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. Birth Defects Res. 89, 66-77.). The assay includes scoring larva treated in a concentration range for malformations of specific morphological structures/organ systems. The model includes identifying a no-adverse-effect-level (NOAEL) and the concentration resulting in 25% lethality (LC25) at 5 days postfertilization. An LC25/NOAEL ratio ≥10 classifies a compound positive for teratogenic potential. A consortium effort evaluated a modified version of this assay which involved enzymatic chorion treatment instead of manual dissection and used experimental replicates for final classification. The modified assay achieved an 85% overall predictivity (Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X., Panzica-Kelly, J., Cao, J., Coburn, A., Enright, B. P., et al. (2012). Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I. Reprod. Toxicol. 33, 155-164.). The objective of this study was to perform a thorough performance evaluation of the dechorinated assay by repeating the original training set and testing additional compounds in experimental replicates. When the initial training set was repeated with inclusion of experimental replicates, the overall predictivity was 83%. Model performance was tested with an additional 34 compounds and achieved overall predictivity of 74%. When the training and test sets were combined (63 compounds) the assay's final sensitivity was 83% and the specificity was 71%. Total predictivity was 78% with relatively balanced predictivity for nonteratogens (77%) and teratogens (78%). The

  13. Paper-disc method: An efficient assay for evaluating metal toxicity to soil algae.

    PubMed

    Nam, Sun-Hwa; An, Youn-Joo

    2016-09-01

    The probabilistic ecological risk assessment using terrestrial toxicity data has been mainly based on microfauna or mesofauna. Soil algae, which are food source for microfauna and mesofauna, may be alternatively used for assessing soil toxicity. However, there are no internationally recommended guidelines for soil algal bioassays, and the collection of algae from the test soils has some limitations. In this study, we suggested the paper-disc method as an easy-to-use alternative. This method has been widely used for testing the antibacterial toxicity of various chemicals in agar media by measuring the diameter of the inhibition zone around the disc. We adapted the paper-disc method for screening the toxicity of copper (Cu) and nickel (Ni) to the soil alga Chlorococcum infusionum using various evaluation endpoints, such as growth zone, chlorophyll fluorescence, and photosynthetic activity. Chlorophyll fluorescence and photosynthetic activity decreased with the increasing concentrations of Cu(+2) or Ni(+2) contaminated soils. Algal growth zone was analyzed visually and showed similar results to those of chlorophyll fluorescence. The direct ethanol extraction method and indirect culture medium extraction method were similarly effective; however, the former was easier to perform, while the latter might facilitate the analysis of additional endpoints in future studies. Overall, the results suggested that the paper-disc method was not only a user-friendly assay for screening soil toxicity, but also effective due to its association with indirect soil quality indicators. PMID:27219045

  14. Sensitivity of isolated eggs of pond snails: a new method for toxicity assays and risk assessment.

    PubMed

    Liu, Tengteng; Koene, Joris M; Dong, Xiaoxiao; Fu, Rongshu

    2013-05-01

    The concentration of heavy metals in the environment is normally low. We here address whether using the development of isolated pond snail Radix auricularia eggs would provide a more sensitive endpoint and whether the gelatinous matrix of the egg mass surrounding the eggs indeed protects the snail embryos. In the present study, artificial removal of the gelatinous matrix of egg masses greatly increased the sensitivity of developing eggs to a heavy metal (cadmium). The sensitivity of isolated eggs to cadmium was determined using several convenient endpoints, including mortality, hatching rate, and heart rate, with an acute toxicity test and a subchronic test. In the acute toxicity test, a 96-h LC(50) value of 58.26 μg/L cadmium was determined. In the subchronic toxicity test, sublethal effects in terms of a significant reduction in hatching rate could be found in the 25-μg/L treatment, and a significant decrease of heart rate was observed in both treatments (5 and 25 μg/L). The high sensitivity of isolated eggs indicates that such tests can be efficient for toxicity assays and risk assessment, although one needs to keep in mind that the ecologically relevant measure of toxicity will be how eggs are affected when they are still inside the egg mass.

  15. Perspectives on Validation of High-Throughput Assays Supporting 21st Century Toxicity Testing1

    PubMed Central

    Judson, Richard; Kavlock, Robert; Martin, Matt; Reif, David; Houck, Keith; Knudsen, Thomas; Richard, Ann; Tice, Raymond R.; Whelan, Maurice; Xia, Menghang; Huang, Ruili; Austin, Christopher; Daston, George; Hartung, Thomas; Fowle, John R.; Wooge, William; Tong, Weida; Dix, David

    2014-01-01

    Summary In vitro, high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals, but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. Here we discuss streamlining the validation process, specifically for prioritization applications in which HTS assays are used to identify a high-concern subset of a collection of chemicals. The high-concern chemicals could then be tested sooner rather than later in standard guideline bioassays. The streamlined validation process would continue to ensure the reliability and relevance of assays for this application. We discuss the following practical guidelines: (1) follow current validation practice to the extent possible and practical; (2) make increased use of reference compounds to better demonstrate assay reliability and relevance; (3) deemphasize the need for cross-laboratory testing, and; (4) implement a web-based, transparent and expedited peer review process. PMID:23338806

  16. Sediment toxicity screening with cost-effective microbiotests and conventional assays: A comparative study

    SciTech Connect

    Vanciheluwe, M.L.; Janssen, C.R.; Persoone, G.

    1995-12-31

    A large monitoring study of freshwater sediments, using the TRIAD approach, was conducted in Flanders (Belgium). This paper reports on the results of the toxicity assessment of 80 sediment samples evaluated with a battery of microbiotests and conventional assays. Sediment pore waters, extracted by squeezing, were tested with the Microtox{reg_sign} (Vibrio fischerii) and Thamnotoxkit{trademark} F (Thamnocephalus platyurus) microbiotests and the conventional (acute) assays with algae (Selenastrum capricornutum) and daphnids (Daphnia magna). A newly developed 5 day ELS test with the catfish Clarias gariepinus was also applied to the pore waters. Solid-phase testing was performed with the Microtox Sp{reg_sign} assay and the 10 day tests with Chironomus riparius and Hyalella azteca. Uni- and multivariate statistical techniques were applied to the data matrix to select a minimal test battery from the water phase and solid phase assays and from all tests combined. The influence of sediment associated confounding factors on the validity of the test results obtained with the various assays will be discussed. Finally a comparison of the predictive power of the selected battery of signal tests and that of the complete battery will be made and the potential use of the minimal battery for the initial hazard assessment of contaminated sediments will be reviewed.

  17. Application of a fish DNA damage assay as a biological toxicity screening tool for metal plating wastewater

    SciTech Connect

    Choi, K.; Zong, M.; Meier, P.G.

    2000-01-01

    The utility of a fish DNA damage assay as a rapid monitoring tool was investigated. Metal plating wastewater was chosen as a sample because it contains various genotoxic metal species. Fish DNA damage assay results were compared to data generated from the conventional whole effluent toxicity (WET) test procedure. The Microtox{reg_sign} assay (Azur Environmental, Carlsbad, CA, USA) using Vibrio fischeri was also employed. Eleven samples from two metal plating companies were collected for this evaluation. For the fish DNA damage assay, 7-d-old fathead minnow larvae, Pimephales promelas, were utilized. They were exposed to a series of dilutions at 20 C for 2 h. Whole effluent toxicity tests conducted in this study included two acute toxicity tests with Daphnia magna and fathead minnows and two chronic toxicity tests with Ceriodaphnia dubia and fathead minnows. The fish DNA damage assay showed good correlations with both the acute and chronic WET test results, especially with those obtained with fathead minnows. The kappa values, an index of agreement, between the fish DNA damage assay and WET tests were shown to be acceptable. These findings imply that this novel fish DNA damage assay has use as an expedient toxicity screening procedure since it produces comparable results to those of the acute and chronic fathead minnow toxicity tests.

  18. Evaluation of usefulness of Microbial Assay for Risk Assessment (MARA) in the cyanobacterial toxicity estimation.

    PubMed

    Sieroslawska, Anna

    2014-07-01

    The aim of the study was to elucidate the usefulness of the Microbial Assay for Risk Assessment (MARA) to evaluate toxicity in samples containing cyanobacterial products. Cyanobacterial extracts with different cyanotoxin contents and pure cyanotoxins-microcystin-LR, cylindrospermopsin and anatoxin-a-were tested. On the basis of the microbial reaction, MARA indicated only slight or no toxicity in the studied extracts. Similarly, no or low toxicity of pure toxins was detected at the concentrations used (up to 10 μg/ml). Weak relationships between the reactions of individual organisms exposed to cyanotoxin-containing extracts and to the same pure toxins were observed. On the other hand, inhibition of some organisms, such as Pichia anomalia, whose growth was not impacted by pure cyanotoxins, indicated the presence of other biologically active compounds in the studied extracts. In conclusion, MARA assay is not enough sensitive to be used as a good tool for cyanotoxin screening. It may, however, be applied in searching for antimicrobial/antifungal cyanobacteria-derived compounds. PMID:24682641

  19. Rapid assay for detection of toxic shock syndrome toxin 1 from human sera.

    PubMed Central

    Miwa, K; Fukuyama, M; Kunitomo, T; Igarashi, H

    1994-01-01

    A noncompetitive enzyme-linked immunosorbent assay that enables the quantitation of toxic shock syndrome toxin 1 (TSST-1) to as little as 30 pg/ml and the detection of TSST-1 to 10 pg/ml in phosphate-buffered saline including 33% human serum or plasma was developed. It takes only 3 h to complete this assay after plate preparation. In this study, 64 human serum samples obtained from 30 patients with toxic shock syndrome or toxic shock syndrome-like symptoms were subjected to testing for the detection of TSST-1. With a cutoff level for TSST-1 of less than 100 pg/ml, 28 samples obtained from 12 patients were positive for TSST-1. The mean and maximum concentrations for these TSST-1-positive samples were 440 and 5,450 pg/ml, respectively. Of these 12 patients, 8 were Staphylococcus aureus culture positive, 3 were negative upon bacterial culturing, and 1 had no cultures done. PMID:8150970

  20. The use of human adipose-derived stem cells based cytotoxicity assay for acute toxicity test.

    PubMed

    Abud, Ana Paula Ressetti; Zych, Jaiesa; Reus, Thamile Luciane; Kuligovski, Crisciele; de Moraes, Elizabeth; Dallagiovanna, Bruno; de Aguiar, Alessandra Melo

    2015-12-01

    Human adipose-derived stem cells (ADSC) were evaluated as cell culture model for cytotoxicity assay and toxicity prediction by using the neutral red uptake assay (NRU). In this study, we compared ADSC and the murine cell line BALB/c 3T3 clone A31 to predict the toxicity of 12 reference substances as recommended by the Interagency Coordinating Committee on the Validation of Alternative Methods. We predicted the LD50 for RC-rat-only weight and RC-rat-only millimole regressions for both cell culture models. For RC rat-only weight regression, both cells had the same accordance (50%), while for RC rat-only millimole regression, the accordance was 50% for ADSC and 42% for 3T3s. Thus, ADSC have similar capability for GHS class prediction as the 3T3 cell line for the evaluated reference substances. Therefore, ADSCs showed the potential to be considered a novel model for use in evaluating cytotoxicity in drug development and industry as well as for regulatory purposes to reduce or replace the use of laboratory animals with acceptable sensitivity for toxicity prediction in humans. These cells can be used to complete the results from other models, mainly because of its human origin. Moreover, it is less expensive in comparison with other existing models.

  1. Interference sources in ATP bioluminescence assay of silica nanoparticle toxicity to activated sludge.

    PubMed

    Sibag, Mark; Kim, Seung Hwan; Kim, Choah; Kim, Hee Jun; Cho, Jinwoo

    2015-06-01

    ATP measurement provides an overview of the general state of microbial activity, and thus it has proven useful for the evaluation of nanoparticle toxicity in activated sludge. ATP bioluminescence assay, however, is susceptible to interference by the components of activated sludge other than biomass. This paper presents the interference identified specific to the use of this assay after activated sludge respiration inhibition test of silica nanoparticles (OECD 209). We observed a high degree of interference (90%) in the presence of 100 mg/L silica nanoparticles and a low level of ATP being measured (0.01 μM); and 30% interference by the synthetic medium regardless of silica nanoparticle concentration and ATP level in the samples. ATP measurement in activated sludge with different MLSS concentrations revealed interference of high biomass content. In conclusion, silica nanoparticles, synthetic medium and activated sludge samples themselves interfere with ATP bioluminescence; this will need to be considered in the evaluation of silica nanoparticle toxicity to activated sludge when this type of assay is used. PMID:25892589

  2. Interference sources in ATP bioluminescence assay of silica nanoparticle toxicity to activated sludge.

    PubMed

    Sibag, Mark; Kim, Seung Hwan; Kim, Choah; Kim, Hee Jun; Cho, Jinwoo

    2015-06-01

    ATP measurement provides an overview of the general state of microbial activity, and thus it has proven useful for the evaluation of nanoparticle toxicity in activated sludge. ATP bioluminescence assay, however, is susceptible to interference by the components of activated sludge other than biomass. This paper presents the interference identified specific to the use of this assay after activated sludge respiration inhibition test of silica nanoparticles (OECD 209). We observed a high degree of interference (90%) in the presence of 100 mg/L silica nanoparticles and a low level of ATP being measured (0.01 μM); and 30% interference by the synthetic medium regardless of silica nanoparticle concentration and ATP level in the samples. ATP measurement in activated sludge with different MLSS concentrations revealed interference of high biomass content. In conclusion, silica nanoparticles, synthetic medium and activated sludge samples themselves interfere with ATP bioluminescence; this will need to be considered in the evaluation of silica nanoparticle toxicity to activated sludge when this type of assay is used.

  3. Association of oxidative stress with the formation of reproductive toxicity from mercury exposure on hermaphrodite nematode Caenorhabditis elegans.

    PubMed

    Wu, Qiuli; He, Kewen; Liu, Peidang; Li, Yinxia; Wang, Dayong

    2011-09-01

    Here we selected HgCl(2) to investigate the mechanism of Hg toxicity on reproduction in hermaphrodite nematodes. Accompanied with decrease of brood size, Hg exposure caused severe deficits in egg number in uterus, egg laying and reproductive structures, including gonad arms and vulva, and formation of protruding phenotype for vulva. Meanwhile, Hg exposure induced severe stress response and oxidative damage in gonad and vulva. Pre-treatment with vitamin E, a potent antioxidant, at the L2-larval stage prevented the oxidative damage and formation of reproductive deficits in Hg exposed nematodes; however, pre-treatment with paraquat, a regent generating superoxide anions, induced more severe reproductive deficits in Hg exposed nematodes. Moreover, Hg exposure increased expression of clk-2 and isp-1 genes, whose mutations decrease ROS production, and decreased expression of mev-1 and gas-1 genes, whose mutations increase ROS production. Thus, oxidative stress may be essential for the induction of reproductive deficits in Hg exposed hermaphrodite nematodes.

  4. PROFILE OF TOXIC RESPONSE TO SEDIMENTS USING WHOLE-ANIMAL AND IN VITRO SUBMITOCHONDRIAL PARTICLE (SMP) ASSAYS

    EPA Science Inventory

    A rapid bioassy for monitoring acute toxicity of wastewater, ground water, and soil and sediment extracts using submitochondrial particles (SMP) has been developed. The assay utilizes the mitochondrial electron transfer enzyme complex present in all eukaryotic cells. Prior develo...

  5. Differential effects of arsenite and arsenate to Drosophila melanogaster in a combined adult/developmental toxicity assay

    SciTech Connect

    Goldstein, S.H.; Babich, H.

    1989-02-01

    Current concern of the environmental consequences of chemical wastes in soils has led to the development of microbial, plant, and, to a lesser extent, animal bioassays for terrestrial ecosystems. This paper evaluated a Drosophila assay that yields data both on acute toxicity to adults and on developmental toxicity to offspring and which is applicable for screening extracts from soils contaminated with chemical wastes. Acute toxicity assays with Drosophila have been used to evaluate the relative potencies of chemicals. The acute toxicity to adults and the developmental exposure bioassays were designed to be performed as separate tests. This paper combined these two tests into a single bioassay, using arsenic compounds as the test agents. Arsenite and arsenate were selected to evaluate the sensitivity of this combined assay in distinguishing between the toxicities of closely related chemicals.

  6. Toxicity evaluation of ZnO nanostructures on L929 fibroblast cell line using MTS assay

    NASA Astrophysics Data System (ADS)

    Bakhori, Siti Khadijah Mohd; Mahmud, Shahrom; Ann, Ling Chuo; Mohamed, Azman Seeni; Saifuddin, Siti Nazmin; Masudi, Sam'an Malik; Mohamad, Dasmawati

    2015-04-01

    ZnO has wide applications in medical and dentistry apart from being used as optoelectronic devices such as solar cells, photodetectors, sensors and light emitting diodes (LEDs). Therefore, the toxicity evaluation is important to know the toxicity level on normal cell line. The toxicity of two grades ZnO nanostructures, ZnO-4 and ZnO-8 have been carried out using cytotoxicity test of MTS assay on L929 rat fibroblast cell line. Prior to that, ZnO-4 and ZnO-8 were characterized for its morphology, structure and optical properties using FESEM, X-ray diffraction, and Photoluminescence respectively. The two groups revealed difference in morphology and exhibit slightly shifted of near band edge emission of Photoluminescence other than having a similar calculated crystallite size of nanostructures. The viability of cells after 72h were obtained and the statistical significance value was calculated using SPSS v20. The p value is more than 0.05 between untreated and treated cell with ZnO. This insignificant value of p>0.05 can be summarized as a non-toxic level of ZnO-4 and ZnO-8 on the L929 cell line.

  7. Toxicity evaluation of ZnO nanostructures on L929 fibroblast cell line using MTS assay

    SciTech Connect

    Bakhori, Siti Khadijah Mohd; Mahmud, Shahrom; Ann, Ling Chuo; Mohamed, Azman Seeni; Saifuddin, Siti Nazmin; Masudi, Sam’an Malik; Mohamad, Dasmawati

    2015-04-24

    ZnO has wide applications in medical and dentistry apart from being used as optoelectronic devices such as solar cells, photodetectors, sensors and light emitting diodes (LEDs). Therefore, the toxicity evaluation is important to know the toxicity level on normal cell line. The toxicity of two grades ZnO nanostructures, ZnO-4 and ZnO-8 have been carried out using cytotoxicity test of MTS assay on L929 rat fibroblast cell line. Prior to that, ZnO-4 and ZnO-8 were characterized for its morphology, structure and optical properties using FESEM, X-ray diffraction, and Photoluminescence respectively. The two groups revealed difference in morphology and exhibit slightly shifted of near band edge emission of Photoluminescence other than having a similar calculated crystallite size of nanostructures. The viability of cells after 72h were obtained and the statistical significance value was calculated using SPSS v20. The p value is more than 0.05 between untreated and treated cell with ZnO. This insignificant value of p>0.05 can be summarized as a non-toxic level of ZnO-4 and ZnO-8 on the L929 cell line.

  8. Adapting the medaka embryo assay to a high-throughput approach for developmental toxicity testing.

    PubMed

    Oxendine, Sharon L; Cowden, John; Hinton, David E; Padilla, Stephanie

    2006-09-01

    Chemical exposure during embryonic development may cause persistent effects, yet developmental toxicity data exist for very few chemicals. Current testing procedures are time consuming and costly, underlining the need for rapid and low cost screening strategies. While in vitro methods are useful for screening, these methods do not replicate all the intricacies of embryonic development and should ideally be complemented by an in vivo screening strategy. In this study, we modify a medaka fish embryo assay to meet the requirements of high-throughput, developmental toxicant testing in vivo. The Japanese medaka (Oryzias latipes) offers several advantages over traditional mammalian model systems, including economic husbandry, high fecundity, and rapid ex utero development. In most studies where fish eggs are exposed to a chemical, the exposure takes place in a common vessel, with many embryos being exposed to the same solution. This type of design is not amenable to high-throughput methodology, does not allow the investigator to follow the same embryo throughout gestation, and may confound statistical analysis of the results. Therefore, we developed a 96-well microtiter plate method to facilitate exposure of individual medaka embryos in single wells and compared this approach to the common vessel method using the industrial solvent dimethyl sulfoxide (DMSO) as the test compound. At lower DMSO concentrations (0% or 1%), the 96-well microtiter plate assay replicated results obtained using the common vessel exposure method. There was, however, increased lethality and decreased hatching rate in the bottle-reared embryos treated with the higher DMSO concentrations (5% or 10%). Because the embryos reared in the 96-well microtiter plates never showed increased adverse effects (as compared to the bottle-reared embryos) at any DMSO concentration, we conclude that the 96-well microtiter plate assay provides a rapid and efficient alternative for developmental toxicity screens that

  9. Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats.

    PubMed

    Akagi, Jun-Ichi; Toyoda, Takeshi; Cho, Young-Man; Mizuta, Yasuko; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2015-05-01

    Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague-Dawley (SD) rats. DEN-treated gpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treated gpt delta rats also showed increased frequencies of gpt and Spi(-) mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals.

  10. Prediction of Chemical Carcinogenicity in Rodents from in vitro Genetic Toxicity Assays

    NASA Astrophysics Data System (ADS)

    Tennant, Raymond W.; Margolin, Barry H.; Shelby, Michael D.; Zeiger, Errol; Haseman, Joseph K.; Spalding, Judson; Caspary, William; Resnick, Michael; Stasiewicz, Stanley; Anderson, Beth; Minor, Robert

    1987-05-01

    Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays. To help put this project into its proper context, we emphasize certain features of the study: 1) Standard protocols were used to mimic the major use of STTs worldwide--screening for mutagens and carcinogens; no attempt was made to optimize protocols for specific chemicals. 2) The 73 NTP chemicals and their 60% incidence of carcinogenicity are probably not representative of the universe of chemicals but rather reflect the recent chemical selection process for the NTP carcinogenicity assay. 3) The small, diverse group of chemicals precludes a meaningful evaluation of the predictive utility of chemical structure information. 4) The NTP is currently testing these same 73 chemicals in two in vivo STTs for chromosomal effects. 5) Complete data for an additional group of 30 to 40 NTP chemicals will be gathered on

  11. Zinc sulphate and vitamin E alleviate reproductive toxicity caused by aluminium sulphate in male albino rats.

    PubMed

    Rawi, Sayed M; Seif Al Nassr, Fatma M

    2015-03-01

    This study was designed to investigate the reproductive toxicity of aluminium sulphate and the therapeutic effects of administration of zinc sulphate and vitamin E individually or in combination against the toxic effect caused by aluminium (Al) in male albino rats. The animals were divided into five groups: group 1 received distilled water and served as control; group 2 received only aluminium sulphate (50 mg/kg body weight (b.w.)); group 3 received aluminium sulphate (50 mg/kg b.w.) plus zinc sulphate (50 mg/kg b.w.); group 4 received aluminium sulphate (50 mg/kg b.w.) and vitamin E (15 mg/kg b.w.); group 5 received aluminium sulphate plus a combination of zinc sulphate and vitamin E in similar doses as above. Doses were administered orally once daily for 45 consecutive days. The results revealed that aluminium sulphate induced significant decrease in body weight gain and testis weight and significant increase in Al level in both serum and testes of male rats. Biochemical analysis showed significant decrease in serum total protein and phospholipids levels, while serum total lipid was significantly elevated post Al treatment. In addition, significant decrease in total protein, phospholipids and cholesterol levels in the testes of Al-treated rats was recorded. The data also showed significant decrease in the levels of serum testosterone, leutinizing hormone and follicle stimulating hormone and significant increase in the level of serum prolactin in Al-intoxicated rats. Moreover, histological examination showed that aluminium sulphate caused apparent alterations in the testicular structure of the treated animals. Treatment with zinc sulphate and vitamin E individually or in combination ameliorated the harmful effects of Al, which was proved histopathologically by the noticeable improvement in the testicular tissues. We can conclude that the tested dose of aluminium sulphate induced toxic effect on the reproductive system of male albino rats and the treatment with

  12. Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment.

    PubMed

    Gaukler, Shannon M; Ruff, James S; Galland, Tessa; Underwood, Tristan K; Kandaris, Kirstie A; Liu, Nicole M; Morrison, Linda C; Veranth, John M; Potts, Wayne K

    2016-06-01

    A major problem in pharmaceutical development is that adverse effects remain undetected during preclinical and clinical trials, but are later revealed after market release when prescribed to many patients. We have developed a fitness assay known as the organismal performance assay (OPA), which evaluates individual performance by utilizing outbred wild mice (Mus musculus) that are assigned to an exposed or control group, which compete against each other for resources within semi-natural enclosures. Performance measurements included reproductive success, survival, and male competitive ability. Our aim was to utilize cerivastatin (Baycol(®), Bayer), a pharmaceutical with known adverse effects, as a positive control to assess OPAs as a potential tool for evaluating the safety of compounds during preclinical trials. Mice were exposed to cerivastatin (~4.5 mg/kg/day) into early adulthood. Exposure ceased and animals were released into semi-natural enclosures. Within enclosures, cerivastatin-exposed females had 25% fewer offspring and cerivastatin-exposed males had 10% less body mass, occupied 63% fewer territories, sired 41% fewer offspring, and experienced a threefold increase in mortality when compared to controls. OPAs detected several cerivastatin-induced adverse effects indicating that fitness assays, commonly used in ecology and evolutionary biology, could be useful as an additional tool in safety testing during pharmaceutical development.

  13. Dose-response fallacy in human reproductive studies of toxic exposures

    SciTech Connect

    Selevan, S.G.; Lemasters, G.K.

    1987-05-01

    The manner in which exposure is defined can affect the findings of reproductive studies of toxic exposures. The individual end points potentially examined, such as fetal loss, subfertility, and congenital malformations observed at birth, are on a continuum by severity of effect: The most extreme effect of the three being infertility because no pregnancy is possible, and the least extreme, congenital malformations recognized at birth. End points observed at birth are survivors of a long and complex process. The process yielding one of these adverse end points may result from a number of factors, including level of exposure. For example, a very high exposure could result in early fetal loss, whereas a lower one might result in a congenital malformation observed at birth. If the probability of a less severe end point falls due to increasing probability of more severe end points with increasing exposure, then a nontraditional dose-response relationship may be observed in the study of one type of outcome.

  14. Dose-response fallacy in human reproductive studies of toxic exposures

    SciTech Connect

    Selevan, S.G.; Lemasters, G.K.

    1987-01-01

    The manner in which exposure is defined can affect the findings of reproductive studies of toxic exposures. The individual end points potentially examined, such as fetal loss, subfertility, and congenital malformations observed at birth, are on a continuum by severity of effect: the most extreme effects of the three being infertility because no pregnancy is possible, and the least extreme, congenital malformations recognized at birth. End points observed at birth are survivors of a long and complex process. The process yielding one of these adverse end points may result from a number of factors, including level of exposure could result in early fetal loss, whereas a lower one might result in a congenital malformation observed at birth. If the probability of a less-severe end point falls due to increasing probability of more-severe end points with increasing exposure, then a nontraditional dose-response relationship may be observed in the study of one type of outcome.

  15. Fluorescence-based assay as a new screening tool for toxic chemicals

    PubMed Central

    Moczko, Ewa; Mirkes, Evgeny M.; Cáceres, César; Gorban, Alexander N.; Piletsky, Sergey

    2016-01-01

    Our study involves development of fluorescent cell-based diagnostic assay as a new approach in high-throughput screening method. This highly sensitive optical assay operates similarly to e-noses and e-tongues which combine semi-specific sensors and multivariate data analysis for monitoring biochemical processes. The optical assay consists of a mixture of environmental-sensitive fluorescent dyes and human skin cells that generate fluorescence spectra patterns distinctive for particular physico-chemical and physiological conditions. Using chemometric techniques the optical signal is processed providing qualitative information about analytical characteristics of the samples. This integrated approach has been successfully applied (with sensitivity of 93% and specificity of 97%) in assessing whether particular chemical agents are irritating or not for human skin. It has several advantages compared with traditional biochemical or biological assays and can impact the new way of high-throughput screening and understanding cell activity. It also can provide reliable and reproducible method for assessing a risk of exposing people to different harmful substances, identification active compounds in toxicity screening and safety assessment of drugs, cosmetic or their specific ingredients. PMID:27653274

  16. Fluorescence-based assay as a new screening tool for toxic chemicals

    NASA Astrophysics Data System (ADS)

    Moczko, Ewa; Mirkes, Evgeny M.; Cáceres, César; Gorban, Alexander N.; Piletsky, Sergey

    2016-09-01

    Our study involves development of fluorescent cell-based diagnostic assay as a new approach in high-throughput screening method. This highly sensitive optical assay operates similarly to e-noses and e-tongues which combine semi-specific sensors and multivariate data analysis for monitoring biochemical processes. The optical assay consists of a mixture of environmental-sensitive fluorescent dyes and human skin cells that generate fluorescence spectra patterns distinctive for particular physico-chemical and physiological conditions. Using chemometric techniques the optical signal is processed providing qualitative information about analytical characteristics of the samples. This integrated approach has been successfully applied (with sensitivity of 93% and specificity of 97%) in assessing whether particular chemical agents are irritating or not for human skin. It has several advantages compared with traditional biochemical or biological assays and can impact the new way of high-throughput screening and understanding cell activity. It also can provide reliable and reproducible method for assessing a risk of exposing people to different harmful substances, identification active compounds in toxicity screening and safety assessment of drugs, cosmetic or their specific ingredients.

  17. Characterization of Diversity in Toxicity Mechanism Using In Vitro Cytotoxicity Assays in Quantitative High Throughput Screening

    PubMed Central

    Huang, Ruili; Southall, Noel; Cho, Ming-Hsuang; Xia, Menghang; Inglese, James; Austin, Christopher P.

    2009-01-01

    Assessing the potential health risks of environmental chemical compounds is an expensive undertaking which has motivated the development of new alternatives to traditional in vivo toxicological testing. One approach is to stage the evaluation, beginning with less expensive and higher throughput in vitro testing before progressing to more definitive trials. In vitro testing can be used to generate a hypothesis about a compound's mechanism of action, which can then be used to design an appropriate in vivo experiment. Here we begin to address the question of how to design such a battery of in vitro cell-based assays by combining data from two different types of assays, cell viability and caspase activation, with the aim of elucidating mechanism of action. Because caspase activation is a transient event during apoptosis, it is not possible to design a single end-point assay protocol that would identify all instances of compound-induced caspase activation. Nevertheless, useful information about compound mechanism of action can be obtained from these assays in combination with cell viability data. Unsupervised clustering in combination with Dunn's cluster validity index is a robust method for identifying mechanisms of action without requiring any a priori knowledge about mechanisms of toxicity. The performance of this clustering method is evaluated by comparing the clustering results against literature annotations of compound mechanisms. PMID:18281954

  18. Phytic Acid Exposure Alters AflatoxinB1-induced Reproductive and Oxidative Toxicity in Albino Rats (Rattus norvegicus).

    PubMed

    Abu El-Saad, Abdelaziz S; Mahmoud, Hamada M

    2009-09-01

    The increased use of feed in Egypt's aquaculture and animal industries raises concerns about the possible presence of mycotoxins in feedstuffs. The use of alternative medicine, such as botanicals and nutritional supplements, has become popular with inflammatory cases. The present study aimed to testify the role played by phytic acid (IP6) in enhancing the reproductive and oxidative toxicity induced in aflatoxinB1 (AFB1) treated white male albino rats (Rattus norvegicus) throughout treatment and withdrawal periods. One hundred and twenty white male albino rats were grouped into four groups. Group 1, was injected with 300 mug kg(-1) body wt of AFB1 once every 3 days for 15 days and left uninjected for another 15 days to study the withdrawal effect. Group 2, was injected with 300 mug kg(-1) body wt of AFB1 once every 3 days for 15 days and treated simultaneously with IP6 daily for another 15 days. Group 3, was treated daily with IP6 (40 mg kg(-1) body wt) for 15 days and with no treatment for other 15 days. Group 4, injected with equivalent volume of sterile phosphate buffer saline solution as a control group. Sera were taken at the experimental intervals and assayed for testosterone hormone, follicular-stimulating hormone (FSH) and luteinizing hormone (LH) to determine the toxicological impact of AFB1 and the possibility of amelioration by phytic acid on the reproductive performance of the studied animal. The effects of AFB1 treatment on the absolute and relative weight of testis as well as its histopathologic effect on the testis and the possibility of amelioration by IP6 treatment were evaluated. The activities of enzymatic and non-enzymatic anti-oxidants, in addition to lipid peroxidation were measured in the testis' homogenate of AFB1-treated rats. A decrease in sex hormone levels, an increase in testicular lipid peroxidation product levels and a significant decrease in testicular glutathione content, catalase and total peroxidase and superoxide dismutase

  19. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.

    PubMed

    Di Renzo, Gian Carlo; Conry, Jeanne A; Blake, Jennifer; DeFrancesco, Mark S; DeNicola, Nathaniel; Martin, James N; McCue, Kelly A; Richmond, David; Shah, Abid; Sutton, Patrice; Woodruff, Tracey J; van der Poel, Sheryl Ziemin; Giudice, Linda C

    2015-12-01

    Exposure to toxic environmental chemicals during pregnancy and breastfeeding is ubiquitous and is a threat to healthy human reproduction. There are tens of thousands of chemicals in global commerce, and even small exposures to toxic chemicals during pregnancy can trigger adverse health consequences. Exposure to toxic environmental chemicals and related health outcomes are inequitably distributed within and between countries; universally, the consequences of exposure are disproportionately borne by people with low incomes. Discrimination, other social factors, economic factors, and occupation impact risk of exposure and harm. Documented links between prenatal exposure to environmental chemicals and adverse health outcomes span the life course and include impacts on fertility and pregnancy, neurodevelopment, and cancer. The global health and economic burden related to toxic environmental chemicals is in excess of millions of deaths and billions of dollars every year. On the basis of accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals, the International Federation of Gynecology and Obstetrics (FIGO) joins other leading reproductive health professional societies in calling for timely action to prevent harm. FIGO recommends that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice. PMID:26433469

  20. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals.

    PubMed

    Di Renzo, Gian Carlo; Conry, Jeanne A; Blake, Jennifer; DeFrancesco, Mark S; DeNicola, Nathaniel; Martin, James N; McCue, Kelly A; Richmond, David; Shah, Abid; Sutton, Patrice; Woodruff, Tracey J; van der Poel, Sheryl Ziemin; Giudice, Linda C

    2015-12-01

    Exposure to toxic environmental chemicals during pregnancy and breastfeeding is ubiquitous and is a threat to healthy human reproduction. There are tens of thousands of chemicals in global commerce, and even small exposures to toxic chemicals during pregnancy can trigger adverse health consequences. Exposure to toxic environmental chemicals and related health outcomes are inequitably distributed within and between countries; universally, the consequences of exposure are disproportionately borne by people with low incomes. Discrimination, other social factors, economic factors, and occupation impact risk of exposure and harm. Documented links between prenatal exposure to environmental chemicals and adverse health outcomes span the life course and include impacts on fertility and pregnancy, neurodevelopment, and cancer. The global health and economic burden related to toxic environmental chemicals is in excess of millions of deaths and billions of dollars every year. On the basis of accumulating robust evidence of exposures and adverse health impacts related to toxic environmental chemicals, the International Federation of Gynecology and Obstetrics (FIGO) joins other leading reproductive health professional societies in calling for timely action to prevent harm. FIGO recommends that reproductive and other health professionals advocate for policies to prevent exposure to toxic environmental chemicals, work to ensure a healthy food system for all, make environmental health part of health care, and champion environmental justice.

  1. Reproductive toxicity of chronic lead exposure in male and female mice.

    PubMed

    Pinon-Lataillade, G; Thoreux-Manlay, A; Coffigny, H; Masse, R; Soufir, J C

    1995-11-01

    The reproductive toxicity of lead was investigated in NMRI mice exposed to 0.5% lead acetate in drinking water from day 1 of intra-uterine life until 60 days after birth. Compared with control mice, the weights of lead-exposed fetuses and subsequently of the lead-exposed weaned pups, male and female, diminished by 11 and 13% respectively. The lead-exposed male and female offspring of lead-exposed dams were mated with unexposed females and males, to examine the effect of lead exposure on reproductive function. Male fertility was not affected but reduced female fertility was observed: litters were smaller and a smaller number of implantation sites was found in lead-exposed females. In lead-exposed males, the weights of the body, testes and epididymes diminished by about 13%, and seminal vesicle and ventral prostate weights, by about 29%. Testicular histology and the number and morphology of epididymal spermatozoa were normal. The levels of plasma FSH, LH and testosterone, and of testicular testosterone, were not modified. These results suggest that the hypothalamic-pituitary-testicular axis is not adversely affected by the above lead exposure, and that therefore the decreased seminal vesicle and ventral prostate weights might not be the consequence of reduced testosterone levels. The hypothesis that lead has a direct effect on these organs as well as a secondary effect resulting from possibly reduced food consumption by lead-exposed mice cannot be excluded. Consequently, in male NMRI mice, exposure to lead might affect reproductive function by acting directly and/or indirectly on accessory sex organs.

  2. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide.

    PubMed

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; Dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-03-01

    β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide.

  3. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide

    PubMed Central

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-01-01

    β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63–116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20–52.54% and −0.95–62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide. PMID:24688298

  4. Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide.

    PubMed

    Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; Dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2014-03-01

    β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide. PMID:24688298

  5. Cypermethrin induced reproductive toxicity in male Wistar rats: protective role of Tribulus terrestris.

    PubMed

    Sharma, Poonam; Huq, Amir Ul; Singh, Rambir

    2013-09-01

    The present study was designed to investigate role of ethanolic extract of Tribulus terrestris (EETT) against alpha-cypermethrin induced reproductive toxicity in male Wistar rats. 24 male Wistar rats weighing about 250-300g were divided in four groups. Group-I was control. alpha-cypermethrin (3.38 mg kg-1b.wt.) was given to group-IlI for 28 days. In Group-Ill, alpha-cypermethrin and EETT (100 mg kg -1b.wt.) were administered in combination for 28 days. Rats in group-IV were given EETT for 28 days. At the end of the experiment, rats were sacrificed, testes and epididymis were removed and sperm characteristics, sex hormones and various biochemical parameters were studied. Decrease in weight of testes and epididymis, testicular sperm head count, sperm motility, live sperm count, serum testosterone (T), follicle stimulating hormone (FSH), leutinizing hormone (LH), catalase (CAT), superoxide dismutase (SOD), glutathione S transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), total protein content and increase in sperm abnormalities and lipid peroxidation (LPO) level was observed in rats exposed to cypermethrin. In combination group-Ill, EETT treatment ameliorated alpha-cypermethrin induced damage. EETT treatment in group-IV increased testes and epididymis weight, sperm head counts, sperm motility, live sperm counts, testosterone, FSH, LH, GSH, CAT, SOD, GST, GR, GPx and total protein content. The study suggested that Tribulus terrestris plant possess reproductive system enhancement and antioxidant activity.

  6. Reproductive and developmental toxicity of the Ginkgo biloba special extract EGb 761® in mice.

    PubMed

    Koch, Egon; Nöldner, Michael; Leuschner, Jost

    2013-12-15

    Extracts from leaves of Ginkgo biloba are among the most widely used and best investigated phytopharmaceuticals worldwide. Almost all clinical trials and the majority of preclinical studies have been performed with a specifically defined extract (EGb 761(®)) standardized to contain confined concentrations of active ingredients and limited quantities of potentially harmful substances. Besides pharmaceutical grade extracts poorly characterized Ginkgo preparations are now increasingly appearing on the market as nutraceuticals. While the safety of EGb 761(®) has been evaluated in an extensive set of toxicology studies, adverse effects of Ginkgo extracts of non-pharmaceutical quality on reproductive functions in mice have been reported in several publications in recent years. As this species has not previously been used in reproductive toxicity studies with EGb 761(®), the present investigation was conducted to examine the influence of EGb 761(®) (100, 350 and 1225mg/kg/day) on embryo-fetal development in mice during the critical period of organogenesis. During external and internal inspection of the fetuses as well as examination of skeletal and soft tissues no embryotoxic properties were noted. In particular, the incidence of malformations, variations or retardations was not increased and the general condition of dams was not influenced. Thus, the no-observed-effect level (NOEL) was above 1225mg/kg/day for the dams and the fetuses.

  7. Polyethylene glycol-g-polyvinyl alcohol grafted copolymer: reproductive toxicity study in Wistar rats.

    PubMed

    Heuschmid, Franziska F; Schneider, Steffen; Schuster, Paul; Lauer, Birthe; van Ravenzwaay, Bennard

    2013-07-01

    Polyethylene glycol-g-polyvinyl alcohol (PEG-PVA) grafted copolymer was administered by gavage to groups of 25 male and 25 female young Wistar rats at doses of 0 (vehicle control), 100, 300, or 1000 mg/kg bw/day for one generation (F0). The study followed the treated F0 generation through mating, gestation, lactation, and weaning of the F1 generation. F1 animals were mated and followed to gestation day (GD) 15-17 at which time F2 implants were evaluated. There were no indications from the various clinical and gross pathological examinations that the oral administration of PEG-PVA grafted copolymer to the F0-parental rats produced any signs of general, reproductive, or developmental toxicity in the F0 or F1 animals or F2 implants. Based on the lack of any dose-related or biologically relevant effects on fertility, reproduction, development, and overall health of rats gavaged with PEG-PVA grafted copolymer and their progeny, the no-observed-adverse effect level (NOAEL) was determined to be the highest dose tested of 1000 mg/kg bw/day.

  8. Evaluation of the reproductive toxicity of fungicide propiconazole in male rats.

    PubMed

    Costa, Nathália Orlandini; Vieira, Milene Leivas; Sgarioni, Vanessa; Pereira, Marina Rangel F; Montagnini, Bruno Garcia; Mesquita, Suzana de Fátima Paccola; Gerardin, Daniela Cristina Ceccatto

    2015-09-01

    The propiconazole (Prop) is a fungicide extensively used in agriculture. There are evidences that this compound may cause endocrine disrupting effects. In vitro studies have demonstrated that Prop inhibits the activity of CYP 19 (aromatase), responsible for converting androgens into estrogens and also is an androgen and estrogen receptor antagonist. Therefore, this study evaluated the reproductive toxicity of Prop treatment in male rats. The Wistar rats were divided in three groups and were treated daily, by gavage, with corn oil (control group), propiconazole 4 mg/kg (Prop 4) and 20 mg/kg (Prop 20), from post-natal day 50 to 120. The following were observed: the body weight gain, sexual behavior, testosterone and estradiol plasmatic levels, organs weight, sperm count and morphology and testicular histomorphology. There was an increase in abnormal tail morphology sperm, seminal vesicle and vas deferens weight, and a decrease in estradiol levels in Prop 4 group. Sexual behavior was affected only in the Prop 20 group. These results suggest that Prop treatment induced alterations in some reproductive parameters, what could be related with an endocrine disruption.

  9. Evaluation of 1066 ToxCast Chemicals in a human stem cell assay for developmental toxicity (SOT)

    EPA Science Inventory

    To increase the diversity of assays used to assess potential developmental toxicity, the ToxCast chemical library was screened in the Stemina devTOX quickPREDICT assay using human embryonic stem (hES) cells. A model for predicting teratogenicity was based on a training set of 23 ...

  10. Reproductive Toxicity of Endosulfan: Implication From Germ Cell Apoptosis Modulated by Mitochondrial Dysfunction and Genotoxic Response Genes in Caenorhabditis elegans

    PubMed Central

    Du, Hua; Wang, Meimei; Wang, Lei; Dai, Hui; Wang, Min; Hong, Wei; Nie, Xinxin; Wu, Lijun; Xu, An

    2015-01-01

    Endosulfan as a new member of persistent organic pollutants has been shown to induce reproductive dysfunction in various animal models. However, the action mechanism of endosulfan-produced reproductive toxicity remains largely unknown. This study was focused on investigating the reproductive toxicity induced by α-endosulfan and clarifying the role of mitochondria and genotoxic response genes in germ cell apoptosis of Caenorhabditis elegans. Our data showed that endosulfan induced a dose-dependent decrease of life span, fecundity, and hatchability, whereas the germ cell apoptosis was dose-dependently increased. The mitochondria membrane potential was disrupted by endosulfan, leading to a significant increase of germ cell apoptosis in mev-1(kn-1) mutant. However, the apoptotic effects of endosulfan were blocked in mutants of cep-1(w40), egl-1(n487), and hus-1(op241), indicating conserved genotoxic response genes played an essential role in endosulfan-induced germ cell apoptosis. Furthermore, exposure to endosulfan induced the accumulation of HUS-1::GFP foci and the germ cell cycle arrest. These findings provided clear evidence that endosulfan caused significant adverse effects on the reproduction system of C. elegans and increased germ cell apoptosis, which was regulated by mitochondrial dysfunction and DNA damage response genes. This study may help to understand the signal transduction pathways involved in endosulfan-induced reproductive toxicity. PMID:25666835

  11. Reproductive Toxicity of Endosulfan: Implication From Germ Cell Apoptosis Modulated by Mitochondrial Dysfunction and Genotoxic Response Genes in Caenorhabditis elegans.

    PubMed

    Du, Hua; Wang, Meimei; Wang, Lei; Dai, Hui; Wang, Min; Hong, Wei; Nie, Xinxin; Wu, Lijun; Xu, An

    2015-05-01

    Endosulfan as a new member of persistent organic pollutants has been shown to induce reproductive dysfunction in various animal models. However, the action mechanism of endosulfan-produced reproductive toxicity remains largely unknown. This study was focused on investigating the reproductive toxicity induced by α-endosulfan and clarifying the role of mitochondria and genotoxic response genes in germ cell apoptosis of Caenorhabditis elegans. Our data showed that endosulfan induced a dose-dependent decrease of life span, fecundity, and hatchability, whereas the germ cell apoptosis was dose-dependently increased. The mitochondria membrane potential was disrupted by endosulfan, leading to a significant increase of germ cell apoptosis in mev-1(kn-1) mutant. However, the apoptotic effects of endosulfan were blocked in mutants of cep-1(w40), egl-1(n487), and hus-1(op241), indicating conserved genotoxic response genes played an essential role in endosulfan-induced germ cell apoptosis. Furthermore, exposure to endosulfan induced the accumulation of HUS-1::GFP foci and the germ cell cycle arrest. These findings provided clear evidence that endosulfan caused significant adverse effects on the reproduction system of C. elegans and increased germ cell apoptosis, which was regulated by mitochondrial dysfunction and DNA damage response genes. This study may help to understand the signal transduction pathways involved in endosulfan-induced reproductive toxicity.

  12. Cumulative toxicity of an environmentally relevant mixture of nine regulated disinfection by-products in a multigenerational rat reproductive bioassay

    EPA Science Inventory

    CUMULATIVE TOXICITY OF AN ENVIRONMENTALLY RELEVANT MIXTURE OF NINE REGULATED DISINFECTION BY-PRODUCTS IN A MULTIGENERATIONAL RAT REPRODUCTIVE BIOASSAY J E Simmons, GR. Klinefelter, JM Goldman, AB DeAngelo, DS Best, A McDonald, LF Strader, AS Murr, JD Suarez, MH George, ES Hunte...

  13. Reproductive toxicity of a mixture of regulated drinking-water disinfection by-products in a multigenerational rat bioassay

    EPA Science Inventory

    BACKGROUND:Trihalomethanes (THMs) and haloaretic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown.OBJECTIVE: We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs ...

  14. Reproductive toxicity and growth effects in rats exposed to lead at different periods during development.

    PubMed

    Ronis, M J; Badger, T M; Shema, S J; Roberson, P K; Shaikh, F

    1996-02-01

    The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/v) lead acetate was administered in the drinking water ad libitum. Three series of experiments were conducted in which lead exposure was initiated beginning in utero, prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed from in utero (in the in utero group). Little effect was observed in adult female rats. However, in female animals exposed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed. More severe reproductive disruption was accompanied by suppression of circulating estradiol in the in utero group. Effects on circulating sex steroids were accompanied by variable effects on circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LH beta mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in the in utero group. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was not significantly different from controls in any of the experiments, despite continued exposure to high lead levels in the drinking water. In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2 alpha and 16 alpha, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimorphic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due

  15. Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice.

    PubMed

    Heindel, J J; Gulati, D K; Russell, V S; Reel, J R; Lawton, A D; Lamb, J C

    1990-11-01

    A continuous breeding reproduction study design was utilized to examine the reproductive toxicity of ethylene glycol monobutyl ether (EGBE) and ethylene glycol monophenyl ether (EGPE). Swiss CD-1 mice were administered EGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3, and 2.1 g/kg body wt/day) and EGPE was administered via the feed (0, 0.25, 1.25, and 2.5%, i.e., 0, 0.4, 2.0, and 4 g/kg body wt/day). Both male and female mice were dosed for 7 days prior to and during a 98-day cohabitation period. EGBE was toxic at the high (2%) and mid dose (1%) to adult F0 female mice: 13 out of 22 females at the high dose and 6 out of 20 at the mid dose died during the cohabitation period. Both the high- and mid-dose animals produced fewer litters/pair, fewer pups/litter, with decreased pup weight. These effects occurred in the presence of decreased body weight, decreased water consumption, and increased kidney weight. A crossover mating trial indicated that the reproductive effects could be attributed primarily to an effect on the female. This was substantiated at necropsy where testes and epididymis weights were normal as were sperm number and motility. Fertility of the offspring of the 0.5% group was normal in the presence of increased liver weights. With respect to EGPE, there was no change in the ability to produce five litters during the continuous breeding period. There was, however, a significant but small (10-15%) decrease in the number of pups/litter and in pup weight in the high-dose group. A crossover mating trial suggested a female component of the reproductive toxicity of EGPE. While fertility was only minimally compromised, severe neonatal toxicity was observed. By Day 21 there were only 8 out of 40 litters in the mid- and high-dose groups which had at least one male and female/litter. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight. In summary the reproductive

  16. Comparing rapid-screening and standard toxicity assays to assess known chemical contamination at a hazardous waste site

    SciTech Connect

    Martino, L.; Swigert, J.; Roberts, C.

    1995-12-31

    The thrust to streamline the Superfund site investigation/remediation program makes it critical for site investigators to utilize rapid screening methodologies to facilitate decision-making. However, screening methodologies providing information upon which decision-making is based must not only be rapid but also scientifically valid. This presentation compares and contrasts two rapid screening toxicity assessments, the Daphnia magna IQ Toxicity Test {trademark} and Microtox{trademark}, to a battery of standard aquatic toxicity tests using Lemna, Rana, Pimephales, Selenastruni and Ceriodaphnia. Chemical analysis of test water samples provided evidence of potential toxicological risk associated with the test samples. The study site was J-Field, Aberdeen Proving Ground, Maryland, a federal facility listed on the National Priority List that used to test and/or dispose of high explosives and chemical warfare agents in open pits or fields. Surface water samples from 20 sites were collected and used in the toxicity assessments. Water samples also were analyzed for explosives, chemical surety degradation compounds, Target Analyte List (inorganics), Target Compound List (organics) and selected pesticides and PCBs. The Microtox{trademark} assay did not reveal any toxicity present in the samples analyzed. Correlation analyses showed only slight correlation between the Daphnia magna IQ{trademark} assay and the standard 48-hour toxicity test. No correlation existed between the Microtox{trademark} assay and the aquatic toxicity tests. Results are discussed in light of the expected risk of the chemicals known to be present and the outcome of the toxicity tests.

  17. Perturbations in polar lipids, starvation survival and reproduction following exposure to unsaturated fatty acids or environmental toxicants in Daphnia magna.

    PubMed

    Sengupta, Namrata; Gerard, Patrick D; Baldwin, William S

    2016-02-01

    Acclimating to toxicant stress is energy expensive. In laboratory toxicology tests dietary conditions are ideal, but not in natural environments where nutrient resources vary in quality and quantity. We compared the effects of additional lipid resources, docosahexaenoic acid (n-3; DHA) or linoleic acid (n-6; LA), or the effects of the toxicants, atrazine or triclosan on post-treatment starvation survival, reproduction, and lipid profiles. Chemical exposure prior to starvation had chemical-specific effects as DHA showed moderately beneficial effects on starvation survival and all of the other chemicals showed adverse effects on either survival or reproduction. Surprisingly, pre-exposure to triclosan inhibits adult maturation and in turn completely blocks reproduction during the starvation phase. The two HR96 activators tested, atrazine and LA adversely reduce post-reproduction survival 70% during starvation and in turn show poor fecundity. DHA and LA show distinctly different lipid profiles as DHA primarily increases the percentage of large (>37 carbon) phosphatidylcholine (PC) species and LA primarily increases the percentage of smaller (<37 carbon) PC species. The toxicants atrazine and triclosan moderately perturb a large number of different phospholipids including several phosphatidylethanolamine species. Some of these polar lipid species may be biomarkers for diets rich in specific fatty acids or toxicant classes. Overall our data demonstrates that toxicants can perturb lipid utilization and storage in daphnids in a chemical specific manner, and different chemicals can produce distinct polar lipid profiles. In summary, biological effects caused by fatty acids and toxicants are associated with changes in the production and use of lipids. PMID:26606184

  18. Perturbations in polar lipids, starvation survival and reproduction following exposure to unsaturated fatty acids or environmental toxicants in Daphnia magna.

    PubMed

    Sengupta, Namrata; Gerard, Patrick D; Baldwin, William S

    2016-02-01

    Acclimating to toxicant stress is energy expensive. In laboratory toxicology tests dietary conditions are ideal, but not in natural environments where nutrient resources vary in quality and quantity. We compared the effects of additional lipid resources, docosahexaenoic acid (n-3; DHA) or linoleic acid (n-6; LA), or the effects of the toxicants, atrazine or triclosan on post-treatment starvation survival, reproduction, and lipid profiles. Chemical exposure prior to starvation had chemical-specific effects as DHA showed moderately beneficial effects on starvation survival and all of the other chemicals showed adverse effects on either survival or reproduction. Surprisingly, pre-exposure to triclosan inhibits adult maturation and in turn completely blocks reproduction during the starvation phase. The two HR96 activators tested, atrazine and LA adversely reduce post-reproduction survival 70% during starvation and in turn show poor fecundity. DHA and LA show distinctly different lipid profiles as DHA primarily increases the percentage of large (>37 carbon) phosphatidylcholine (PC) species and LA primarily increases the percentage of smaller (<37 carbon) PC species. The toxicants atrazine and triclosan moderately perturb a large number of different phospholipids including several phosphatidylethanolamine species. Some of these polar lipid species may be biomarkers for diets rich in specific fatty acids or toxicant classes. Overall our data demonstrates that toxicants can perturb lipid utilization and storage in daphnids in a chemical specific manner, and different chemicals can produce distinct polar lipid profiles. In summary, biological effects caused by fatty acids and toxicants are associated with changes in the production and use of lipids.

  19. Comparative evaluation of genetic toxicity patterns of carcinogens and noncarcinogens: strategies for predictive use of short-term assays.

    PubMed Central

    Tennant, R W; Spalding, J W; Stasiewicz, S; Caspary, W D; Mason, J M; Resnick, M A

    1987-01-01

    The results of a recent comprehensive evaluation of the relationship between four measures of in vitro genetic toxicity and the capacity of the chemicals to induce neoplasia in rodents carry some important implications. The results showed that while the Salmonella mutagenesis assay detected only about half of the carcinogens as mutagens, the other three in vitro assays (mutagenesis in MOLY cells or induction of aberrations or SCEs in CHO cells) did not complement Salmonella since they failed to effectively discriminate between the carcinogens and noncarcinogens found negative in the Salmonella assay. The specificity of the Salmonella assay for this group of 73 chemicals was relatively high (only 4 of 29 noncarcinogens were positive). Therefore, we have begun to evaluate in vivo genetic toxicity assays for their ability to complement Salmonella in the identification of carcinogens. PMID:3319571

  20. Cigarette Filter-based Assays as Proxies for Toxicant Exposure and Smoking Behavior A Literature Review

    PubMed Central

    Pauly, John L.; O’Connor, Richard J.; Paszkiewicz, Geraldine M.; Cummings, K. Michael; Djordjevic, Mirjana V.; Shields, Peter G.

    2009-01-01

    Background Cigarettes are being marketed with filters that differ in composition and design. The filters have different toxicant trapping efficiency and smoking stains reflect variations in smoking behavior. Presented herein are the results of a structured literature review that was performed to identify cigarette filter-based assays that may serve as proxies for mouth-level exposure and assessing smoking methods. Methods A search of the published scientific literature and internal tobacco company documents from 1954 to 2009 was performed. Results The literature search identified diverse schemes for assessing cigarette filters, including visual inspection and digital imaging of smoked-stained spent filters, and quantitative determinations for total particulate matter (TPM), nicotine, and solanesol. The results also showed that: (a) there is sufficient data to link filter-based chemical measures to standardized smoking machine-measured yields of tar and nicotine; (b) TPM eluted from filters or in chemical digest of filters can be used to estimate the efficiency of the filter for trapping smoke solids; (c) visual and digital inspection of spent filters are useful as indicators of variations in smoking behaviors; and (d) there is a correlation between solanesol and nicotine measured in filters and exposure biomarkers in smokers. Conclusions The cigarette filter may prove useful in estimating smoking behaviors such as filter vent blocking and puffing intensity, and may have utility as proxy measures of mouth-level smoke exposure in clinical trials. Additional investigations are needed to compare the different proposed assay schemes and the assay results with measurements of human biomarker assays of smoke exposure. PMID:19959679

  1. Evaluation of In Vitro Assays For Assessing the Toxicity of Cigarette Smoke and Smokeless Tobacco

    PubMed Central

    Wan, J.; Johnson, M.; Schilz, J.; Djordjevic, M.V.; Rice, J.R.; Shields, P.G.

    2009-01-01

    Introduction In vitro toxicology studies of tobacco and tobacco smoke have been used to understand why tobacco use causes cancer and to assess the toxicological impact of tobacco product design changes. The need for toxicology studies has been heightened given that the FDA’s newly granted authority over tobacco products requires mandating performance standards for tobacco products and evaluate manufacturers’ health claims. The goal of this review is to critically evaluate in vitro toxicology methods related to cancer for assessing tobacco products and to identify related research gaps. Methods PubMed database searches were used to identify tobacco-related in vitro toxicology studies published since 1980. Articles published prior to 1980 with high relevance also were identified. The data was compiled to examine: 1) goals of the study; 2) methods for collecting test substances; 3) experimental designs; 4) toxicological endpoints, and; 5) relevance to cancer risk. Results A variety of in vitro assays are available to assess tobacco and tobacco smoke that address different modes of action, mostly using non-human cell models. Smokeless tobacco products perform poorly in these assays. While reliable as a screening tool for qualitative assessments, the available in vitro assays have been poorly validated for quantitative comparisons of different products. Assay batteries have not been developed, although they exist for non-tobacco assessments. Extrapolating data from in vitro studies to human risks remains hypothetical. Conclusions In vitro toxicology methods are useful for screening toxicity, but better methods are needed for today’s context of regulation and evaluation of health claims. PMID:19959677

  2. Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome

    SciTech Connect

    Zenick, H.; Hastings, L.; Goldsmith, M.; Niewenhuis, R.J.

    1982-03-01

    Acute injections of high doses of Cd induced marked testicular necrosis. However, the effects of low-dose, oral Cd exposure on a chronic basis are not well documented. The present investigation was designed to examine the effects of such exposure as reflected in parameters of spermatotoxicity and histology. Moreover, the impact on fetal outcome was measured by evaluating teratological and postnatal neurobehavior endpoints. Male Long-Evans hooded rats (100 d of age) were exposed to 0, 17.2, 34.4, or 68.8 ppm Cd for 70 d. During this period, the animals were maintained on a semipurified diet to control for the contribution of Zn and other trace elements. Near the end of exposure the males were mated to three female rats. One was sacrificed on d 21 of pregnancy for teratological assessment, including fetal weight, and determination of preimplantation and postimplantation loss. The other two dams were allowed to deliver, and their offspring were tested on tasks of exploratory behavior (d 21) and learning (d 90). Subsequently, the male parent was sacrified and a variety of measures recorded including weights of testes and caudae epididymides, sperm count and sperm morphology, and Cd content of liver and kidney. One of the testes was also evaluated histologically. No significant effects were observed on any of the parameters of reproductive toxicity or fetal outcome. These findings suggest that, at the doses employed in this study, Cd did not have signficant deleterious effects on the male reproductive system. Morever, the traditional view of Cd-related testicular insult, based on acute exposure, injection protocols, needs to be reevaluated in terms of environmental relevance.

  3. Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome.

    PubMed

    Zenick, H; Hastings, L; Goldsmith, M; Niewenhuis, R J

    1982-03-01

    Acute injections of high doses of Cd induce marked testicular necrosis. However, the effects of low-dose, oral Cd exposure on a chronic basis are not well documented. The present investigation was designed to examine the effects of such exposure as reflected in parameters of spermatotoxicity and histology. Moreover, the impact on fetal outcome was measured by evaluating teratological and postnatal neurobehavior endpoints. Male Long-Evans hooded rats (100 d of age) were exposed to 0, 17.2, 34.4, or 68.8 ppm Cd for 70 d. During this period, the animals were maintained on a semipurified diet to control for the contributions of Zn and other trace elements. Near the end of exposure the males were mated to three female rats. One was sacrificed on d 21 of pregnancy for teratological assessment, including fetal weight, and determination of preimplantation and postimplantation loss. The other two dams were allowed to deliver, and their offspring were tested on tasks of exploratory behavior (d 21) and learning (d 90). Subsequently, the male parent was sacrificed and a variety of measures recorded including weights of testes and caudae epididymides, sperm count and sperm morphology, and Cd content of liver and kidney. One of the testes was also evaluated histologically. No significant effects were observed on any of the parameters of reproductive toxicity or fetal outcome. These findings suggest that, at the doses employed in this study, Cd did not have significant deleterious effects on the male reproductive system. Morever, the traditional view of Cd-related testicular insult, based on acute exposure, injection protocols, needs to be reevaluated in terms of environmental relevance.

  4. Prediction of Chemical Carcinogenicity in Rodents from in vitro Genetic Toxicity Assays

    NASA Astrophysics Data System (ADS)

    Tennant, Raymond W.; Margolin, Barry H.; Shelby, Michael D.; Zeiger, Errol; Haseman, Joseph K.; Spalding, Judson; Caspary, William; Resnick, Michael; Stasiewicz, Stanley; Anderson, Beth; Minor, Robert

    1987-05-01

    Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays. To help put this project into its proper context, we emphasize certain features of the study: 1) Standard protocols were used to mimic the major use of STTs worldwide--screening for mutagens and carcinogens; no attempt was made to optimize protocols for specific chemicals. 2) The 73 NTP chemicals and their 60% incidence of carcinogenicity are probably not representative of the universe of chemicals but rather reflect the recent chemical selection process for the NTP carcinogenicity assay. 3) The small, diverse group of chemicals precludes a meaningful evaluation of the predictive utility of chemical structure information. 4) The NTP is currently testing these same 73 chemicals in two in vivo STTs for chromosomal effects. 5) Complete data for an additional group of 30 to 40 NTP chemicals will be gathered on

  5. Profile of toxic response to sediments using whole-animal and in vitro submitochondrial particle (SMP) assays

    SciTech Connect

    Bettermann, A.D.; Dorofi, J.C.; Lazorchak, J.M.

    1996-03-01

    A rapid bioassay for monitoring acute toxicity of wastewater, ground water, and soil and sediment extracts using submitochondrial particles (SMP) has been developed. The assay utilizes the mitochondrial electron transfer enzyme complex, present in all eukaryotic cells. Prior developmental work with pure chemicals chosen from the US Environmental Protection Agency`s (EPA) priority pollutant list documented order-of-magnitude predictability between the bioassay response and whole-organism tests (e.g., fathead minnow). Recent work has adapted the assay for analysis of uncharacterized environmental samples, including stormwater runoff, landfill leachate, and soil and sediment extracts. A feasibility study was performed to determine whether the SMP assay could detect toxicity in samples previously assessed for toxicity to amphipods. Acute toxicity tests using Hyalella azteca were performed on 30 sediment samples from Colorado`s Arkansas River, Eagle River, and Chalk Creek watersheds, all of which have been directly or indirectly affected by heavy metal mine tailings and drainage. In parallel, two SMP assay protocols designed to differentiate between modes of toxicity were performed on elutriate samples from 23 of the above sites. The results from analysis of the sediments differed widely in the nature and degree of test responses. Significant correlation was found between the responses of the SMP electron transfer protocol and the whole-organisms assay, and between the responses of the SMP electron transfer protocol and levels of zinc and sulfur, as determined by inductively coupled plasma spectroscopy.

  6. Reproductive toxicity parameters and biological monitoring in occupationally and environmentally boron-exposed persons in Bandirma, Turkey.

    PubMed

    Duydu, Yalçın; Başaran, Nurşen; Üstündağ, Aylin; Aydin, Sevtap; Ündeğer, Ülkü; Ataman, Osman Yavuz; Aydos, Kaan; Düker, Yalçın; Ickstadt, Katja; Waltrup, Britta Schulze; Golka, Klaus; Bolt, Hermann M

    2011-06-01

    Boric acid and sodium borates have been considered as being "toxic to reproduction and development", following results of animal studies with high doses. Experimentally, a NOAEL (no observed adverse effect level) of 17.5 mg B/kg-bw/day has been identified for the (male) reproductive effects of boron in a multigeneration study of rats, and a NOAEL for the developmental effects in rats was identified at 9.6 mg B/kg-bw/day. These values are being taken as the basis of current EU safety assessments. The present study was conducted to investigate the reproductive effects of boron exposure in workers employed in boric acid production plant in Bandirma, Turkey. In order to characterize the external and internal boron exposures, boron was determined in biological samples (blood, urine, semen), in workplace air, in food, and in water sources. Unfavorable effects of boron exposure on the reproductive toxicity indicators (concentration, motility, morphology of the sperm cells and blood levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone) were not observed. The mean calculated daily boron exposure (DBE) of the highly exposed group was 14.45 ± 6.57 (3.32-35.62) mg/day. These human exposures represent worst-case exposure conditions to boric acid/borates in Turkey. These exposure levels are considerably lower than exposures, which have previously led to reproductive effects in experimental animals. In conclusion, this means that dose levels of boron associated with developmental and reproductive toxic effects in animals are by far not reachable for humans under conditions of normal handling and use.

  7. Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of light catalytic cracked naphtha distillate in rats.

    PubMed

    Schreiner, C; Bui, Q; Breglia, R; Burnett, D; Koschier, F; Podhasky, P; Lapadula, E; White, R; Schroeder, R E

    1999-11-26

    A distillate of light catalytic cracked naphtha (CAS number 64741-55-5, LCCN-D), administered by inhalation, was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening Protocol. LCCN-D was administered as a vapor, 6 h/d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 7 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for 8 consecutive weeks. Dams and litters were sacrificed on postnatal d 4, and males were sacrificed within the following week. Parental systemic effects observed at the 7500 ppm exposure level were increased kidney weights and relative liver weights in males and increased spleen weights in high-dose females. Livers and spleens from rats in the high-dose group were normal in appearance at necropsy. IncreaSed kidney weights in high-dose males were indicative of male-rat-specific light hydrocarbon nephropathy. No test-related microscopic changes were observed in the reproductive organs or nasal turbinate tissues of either sex. Reproductive performance was unaffected by treatment with LCCN-D. Fertility index was > or =90% in all dose groups. There were no exposure-related differences in implantation sites and live pups per litter, and no gross abnormalities were observed. Pups born from treated dams showed comparable body weights and weight gains to controls. The viability index on postpartum d 4 was > or =97%; the high-dose group had more male than female pups at birth and at d 4 postpartum. Under the conditions of this study, the no-observable-adverse-effect level (NOAEL) for exposure to light catalytic cracked naphtha distillate for parental toxicity was 2500 ppm and the NOAEL for reproductive performance and developmental toxicity was 7500 ppm.

  8. Monitoring toxic Ostreopsis cf. ovata in recreational waters using a qPCR based assay.

    PubMed

    Casabianca, Silvia; Perini, Federico; Casabianca, Anna; Battocchi, Cecilia; Giussani, Valentina; Chiantore, Mariachiara; Penna, Antonella

    2014-11-15

    Ostreopsis sp. is a toxic marine benthic dinoflagellate that causes high biomass blooms, posing a threat to human health, marine biota and aquaculture activities, and negatively impacting coastal seawater quality. Species-specific identification and enumeration is fundamental because it can allow the implementation of all the necessary preventive measures to properly manage Ostreopsis spp. bloom events in recreational waters and aquaculture farms. The aim of this study was to apply a rapid and sensitive qPCR method to quantify Ostreopsis cf. ovata abundance in environmental samples collected from Mediterranean coastal sites and to develop site-specific environmental standard curves. Similar PCR efficiencies of plasmid and environmental standard curves allowed us to estimate the LSU rDNA copy number per cell. Moreover, we assessed the effectiveness of mitochondrial COI and cob genes as alternative molecular markers to ribosomal genes in qPCR assays for Ostreopsis spp. quantification.

  9. Monitoring toxic Ostreopsis cf. ovata in recreational waters using a qPCR based assay.

    PubMed

    Casabianca, Silvia; Perini, Federico; Casabianca, Anna; Battocchi, Cecilia; Giussani, Valentina; Chiantore, Mariachiara; Penna, Antonella

    2014-11-15

    Ostreopsis sp. is a toxic marine benthic dinoflagellate that causes high biomass blooms, posing a threat to human health, marine biota and aquaculture activities, and negatively impacting coastal seawater quality. Species-specific identification and enumeration is fundamental because it can allow the implementation of all the necessary preventive measures to properly manage Ostreopsis spp. bloom events in recreational waters and aquaculture farms. The aim of this study was to apply a rapid and sensitive qPCR method to quantify Ostreopsis cf. ovata abundance in environmental samples collected from Mediterranean coastal sites and to develop site-specific environmental standard curves. Similar PCR efficiencies of plasmid and environmental standard curves allowed us to estimate the LSU rDNA copy number per cell. Moreover, we assessed the effectiveness of mitochondrial COI and cob genes as alternative molecular markers to ribosomal genes in qPCR assays for Ostreopsis spp. quantification. PMID:25282181

  10. Endocrine-disrupting effects and reproductive toxicity of low dose MCLR on male frogs (Rana nigromaculata) in vivo.

    PubMed

    Jia, Xiuying; Cai, Chenchen; Wang, Jia; Gao, Nana; Zhang, Hangjun

    2014-10-01

    Toxic cyanobacterial blooms are potential global threats to aquatic ecosystems and human health. The World Health Organization has set a provisional guideline limit of 1 μg/L microcystin-LR (MCLR) in freshwater. However, MCLR concentrations in several water bodies have exceeded this level. Despite this recommended human safety standard, MCLR-induced endocrine-disrupting effects and reproductive toxicity on male frog (Rana nigromaculata) were demonstrated in this study. Results showed that sperm motility and sperm count were significantly and negatively correlated with exposure time and concentration. By contrast, abnormal sperm rate was positively correlated with both parameters. Ultrastructural observation results revealed abnormal sperm morphologies, vacuoles in spermatogenic cells, cell dispersion, incomplete cell structures, and deformed nucleoli. These results indicated that MCLR could induce toxic effects on the reproductive system of frogs, significantly decrease testosterone content, and rapidly increase estradiol content. Prolonged exposure and increased concentration enhanced the relative expression levels of P450 aromatase and steroidogenic factor 1; thus, endocrine function in frogs was disrupted. This study is the first to demonstrate in vivo MCLR toxicity in the reproductive system of male R. nigromaculata. This study provided a scientific basis of the global decline in amphibian populations.

  11. Subchronic and reproductive/developmental (screening level) toxicity of complexation products of iron trichloride and sodium tartrate (FemTA).

    PubMed

    Lynch, Barry; Emmen, Harry; van Otterdijk, Francois; Lau, Annette

    2013-09-01

    A complexation/reaction product, termed FemTA, of sodium tartrate [D(-)- and L(+)-tartaric acid and mesotartaric acid], sodium hydroxide, and iron trichloride may have use as an anticaking agent in salt preparations. FemTA is composed of about 4% sodium tartrate, approximately 10% mesotartaric acid, approximately 7% chloride, approximately 4% iron, approximately 7% sodium, approximately 0.3% sodium oxalate, and approximately 65% water. FemTA was tested in a 90-d oral toxicity study, which included a screening level reproductive/developmental toxicity phase, in Harlan Wistar rats. FemTA was administered by oral gavage at 500, 1000, and 2000 mg/kg body weight/d prior to and during mating, or about 20, 40, or 80 mg of iron/kg body weight/d, such that males received 90/91 d of treatment and females 104 to 109 d. Treatment was associated with inflammatory lesions of the lower GI tract at the mid- and high-dose levels, increased liver and kidney weights, increased serum bile acids and blood urea nitrogen, decreased chloride, and changes to hematological parameters consistent with inflammation. The effects were considered the result of iron overload. There were no effects on reproductive/developmental toxicity parameters. The no-observed-adverse-effect level (NOAEL), based on gastrointestinal tract effects was 500 mg/kg body weight/d. The NOAEL for reproductive/developmental toxicity was 2000 mg/kg body weight/d, the highest dose tested.

  12. Evaluation of toxic effects of CdTe quantum dots on the reproductive system in adult male mice.

    PubMed

    Li, Xiaohui; Yang, Xiangrong; Yuwen, Lihui; Yang, Wenjing; Weng, Lixing; Teng, Zhaogang; Wang, Lianhui

    2016-07-01

    Fluorescent quantum dots (QDs) are highly promising nanomaterials for various biological and biomedical applications because of their unique optical properties, such as robust photostability, strong photoluminescence, and size-tunable fluorescence. Several studies have reported the in vivo toxicity of QDs, but their effects on the male reproduction system have not been examined. In this study, we investigated the reproductive toxicity of cadmium telluride (CdTe) QDs at a high dose of 2.0 nmol per mouse and a low dose of 0.2 nmol per mouse. Body weight measurements demonstrated there was no overt toxicity for both dose at day 90 after exposure, but the high dose CdTe affected body weight up to 15 days after exposure. CdTe QDs accumulated in the testes and damaged the tissue structure for both doses on day 90. Meanwhile, either of two CdTe QDs treatments did not significantly affect the quantity of sperm, but the high dose CdTe significantly decreased the quality of sperm on day 60. The serum levels of three major sex hormones were also perturbed by CdTe QDs treatment. However, the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those mated with untreated male mice. These results suggest that CdTe QDs can cause testes toxicity in a dose-dependent manner. The low dose of CdTe QDs is relatively safe for the reproductive system of male mice. Our preliminary result enables better understanding of the reproductive toxicity induced by cadmium-containing QDs and provides insight into the safe use of these nanoparticles in biological and environmental systems.

  13. Assessment of biocompatibility of 3D printed photopolymers using zebrafish embryo toxicity assays.

    PubMed

    Macdonald, N P; Zhu, F; Hall, C J; Reboud, J; Crosier, P S; Patton, E E; Wlodkowic, D; Cooper, J M

    2016-01-21

    3D printing has emerged as a rapid and cost-efficient manufacturing technique to enable the fabrication of bespoke, complex prototypes. If the technology is to have a significant impact in biomedical applications, such as drug discovery and molecular diagnostics, the devices produced must be biologically compatible to enable their use with established reference assays and protocols. In this work we demonstrate that we can adapt the Fish Embryo Test (FET) as a new method to quantify the toxicity of 3D printed microfluidic devices. We assessed the biocompatibility of four commercially available 3D printing polymers (VisiJetCrystal EX200, Watershed 11122XC, Fototec SLA 7150 Clear and ABSplus P-430), through the observation of key developmental markers in the developing zebrafish embryos. Results show all of the photopolymers to be highly toxic to the embryos, resulting in fatality, although we do demonstrate that post-printing treatment of Fototec 7150 makes it suitable for zebrafish culture within the FET. PMID:26646354

  14. An RNA synthesis inhibition assay for detecting toxic substances using click chemistry.

    PubMed

    Kametani, Yukiko; Iwai, Shigenori; Kuraoka, Isao

    2014-04-01

    Biological risk assessment studies of chemical substances that induce DNA lesions have been primarily based on the action of DNA polymerases during replication. However, DNA lesions interfere not only with replication, but also with transcription. There is no simple method for the detection of the DNA lesion-induced inhibition of transcription. Here, we report an assay for estimating the toxicity of chemical substances by visualizing transcription in mammalian cells using nucleotide analog 5-ethynyluridine (EU) and its click chemistry reaction. Ultraviolet light and representative chemical substances (camptothecin, 4-nitroquinoline-1-oxide, mitomycin C, and cisplatin, but not etoposide) of DNA- damaging agents show toxicity, as indicated by RNA synthesis inhibition in response to DNA damage in HeLa cells. Using titanium dioxide, we observed RNA synthesis inhibition in response to the rutile form, but not the anatase form, indicating that rutile titanium dioxide is a toxic substance. Because this method is based on the transcriptional response to DNA lesions, we can use terminally differentiated neuron-like PC12 cells, the differentiation of which can be induced by nerve growth factors, for evaluating chemical substances. Ultraviolet light and some chemicals (camptothecin, 4-nitroquinoline-1-oxide, mitomycin C, and cisplatin, but not etoposide) inhibited RNA synthesis in non-differentiated PC12 cells. Conversely, camptothecin and cisplatin did not inhibit RNA synthesis in differentiated PC12 cells, but 4-nitroquinoline-1-oxide, mitomycin C, and etoposide did. And using titanium dioxide, we did not observed any RNA synthesis inhibition. These data suggest that this method might be used to estimate the potential risk of chemical substances in differentiated mammalian cells, which are the most common cell type found in the human body.

  15. Characteristics of the ToxRefDB In Vivo Datasets from Chronic, Reproductive and Developmental Assays

    EPA Science Inventory

    ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

  16. Reproductive toxicity of 2,4-toluenediamine in the rat. 2. Spermatogenic and hormonal effects

    SciTech Connect

    Thysen, B.; Bloch, E.; Varma, S.K.

    1985-01-01

    The present study was undertaken to evaluate the endocrinologic and spermatogenic effects of 2,4-toluenediamine (TDA) in the rat. Adult male rats were fed 0, 0.01, and 0.03% TDA ad libitum for 10 wk. At the end of wk 10 and at 11 wk post TDA treatment, the animals were killed, and cauda epididymal sperm counts and reproductive organ weights were determined. Blood samples were obtained for analyses of testosterone and gonadotropins. Treatment with 0.03% TDA for 10 wk reduced the weight of the seminal vesicles and epididymides and reduced serum testosterone levels. Cauda epididymal sperm counts were decreased in animals treated with 0.03% TDA for 10 wk and in TDA-treated animals placed on normal diet for 11 wk. Serum luteinizing hormone (LH) concentrations were increased and weights of epididymides and testes were reduced in 0.03%-TDA-treated animals placed on normal diet for 11 wk. The results indicate that TDA exerts a toxic effect on spermatogenesis and appears to affect androgen action production in the male rat. Since the males exhibited reduced cauda epididymal sperm counts 11 wk after 0.03% TDA treatment, it appears that TDA induced damage to the germinal components of the testes.

  17. Reproductive and Developmental Toxicity Screening Test of Ethyl Hydrogen Adipate in Rats

    PubMed Central

    Nam, Chunja; Hwang, Jae-Sik; Han, Kyoung-Goo; Jo, Eunhye; Yoo, Sun-kyoung; Eom, Ig-Chun; Kang, Jong-Koo

    2016-01-01

    This study aimed to evaluate the potential toxicity and safety of ethyl hydrogen adipate (EHA) by determining its effect on the reproductive function and development of Sprague-Dawley (SD) rats at dose levels of 0 (control), 200, 400, and 800 mg/kg/day. One male and five females of the 800 mg/kg/day died. Body weight loss was observed in the males of the 800 mg/kg/day and in females of the 400 and 800 mg/kg/day. In addition, mating indices decreased and pre-implantation loss rates increased in parental animals of the 400 and 800 mg/kg/day. The gestation index decreased in the male and female rats of the 800 mg/kg/day. Moreover, the body weight of the pups from the 800 mg/kg/day group decreased on post-parturition day 4. These results indicated that the no-observed-adverse-effect level of EHA for parental males and females was 400 mg/kg/day and 200 mg/kg/day, respectively, and that for pups was 400 mg/kg/day.

  18. Preclinical Reproductive and Developmental Toxicity Profile of a Glycine Transporter Type 1 (Glyt1) Inhibitor.

    PubMed

    Barrow, Paul; Parrott, Neil; Alberati, Daniela; Paehler, Axel; Koerner, Annette

    2016-06-01

    Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri-natal pup death when rat dams were treated during parturition at a dose resulting in five-times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two-fold higher than in the mother. As illustrated by knock-out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well-developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn. PMID:27221585

  19. Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

    PubMed

    Narotsky, Michael G; Klinefelter, Gary R; Goldman, Jerome M; Best, Deborah S; McDonald, Anthony; Strader, Lillian F; Suarez, Juan D; Murr, Ashley S; Thillainadarajah, Inthirany; Hunter, E Sidney; Richardson, Susan D; Speth, Thomas F; Miltner, Richard J; Pressman, Jonathan G; Teuschler, Linda K; Rice, Glenn E; Moser, Virginia C; Luebke, Robert W; Simmons, Jane Ellen

    2013-09-17

    Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. Using a multigenerational rat bioassay, we evaluated an environmentally relevant "whole" mixture of DBPs representative of chlorinated drinking water, including unidentified DBPs as well as realistic proportions of known DBPs at low-toxicity concentrations. Source water from a water utility was concentrated 136-fold, chlorinated, and provided as drinking water to Sprague-Dawley rats. Timed-pregnant females (P0 generation) were exposed during gestation and lactation. Weanlings (F1 generation) continued exposures and were bred to produce an F2 generation. Large sample sizes enhanced statistical power, particularly for pup weight and prenatal loss. No adverse effects were observed for pup weight, prenatal loss, pregnancy rate, gestation length, puberty onset in males, growth, estrous cycles, hormone levels, immunological end points, and most neurobehavioral end points. Significant, albeit slight, effects included delayed puberty for F1 females, reduced caput epidydimal sperm counts in F1 adult males, and increased incidences of thyroid follicular cell hypertrophy in adult females. These results highlight areas for future research, while the largely negative findings, particularly for pup weight and prenatal loss, are notable.

  20. Reproductive toxicity of the endocrine disrupters vinclozolin and bisphenol A in the terrestrial isopod Porcellio scaber (Latreille, 1804).

    PubMed

    Lemos, M F L; van Gestel, C A M; Soares, A M V M

    2010-02-01

    Endocrine Disruptor Compounds (EDCs) have been largely studied concerning their effects on vertebrates. Nevertheless, invertebrates as targets for these chemicals have been neglected and few studies are available. Specifically for edaphic invertebrates, data concerning the effects of EDCs is residual. Influences of EDCs on the reproduction systems of these organisms, with consequences at the population level, are expected but have not been confirmed. This work aimed to study the effects of bisphenol A (BPA) and vinclozolin (Vz) on the reproduction of the terrestrial isopod Porcellio scaber. Isopods were coupled and exposed to increasing concentrations of Vz and BPA and the females' reproductive cycle followed for 56d. Both compounds elicited reproductive toxicity. Vz and BPA decreased female reproductive allocation. Vz reduced pregnancy duration; increased the abortion percentage; decreased the number of pregnancies; and decreased the number of juveniles per female while BPA increased abortions at the lowest and highest test concentrations. The reproductive endpoints presented in here are indicative of the possible impact that this type of compounds might have on isopod population dynamics, which may eventually lead to population decline.

  1. Incorporating Results of Avian Toxicity Tests into a Model of Annual Reproductive Success

    EPA Science Inventory

    This manuscript presents a modeling approach for translating results from laboratory avian reproduction tests into an estimate of pesticide-caused change in the annual reproductive success of birds, also known as fecundity rate.

  2. A spheroid toxicity assay using magnetic 3D bioprinting and real-time mobile device-based imaging.

    PubMed

    Tseng, Hubert; Gage, Jacob A; Shen, Tsaiwei; Haisler, William L; Neeley, Shane K; Shiao, Sue; Chen, Jianbo; Desai, Pujan K; Liao, Angela; Hebel, Chris; Raphael, Robert M; Becker, Jeanne L; Souza, Glauco R

    2015-01-01

    An ongoing challenge in biomedical research is the search for simple, yet robust assays using 3D cell cultures for toxicity screening. This study addresses that challenge with a novel spheroid assay, wherein spheroids, formed by magnetic 3D bioprinting, contract immediately as cells rearrange and compact the spheroid in relation to viability and cytoskeletal organization. Thus, spheroid size can be used as a simple metric for toxicity. The goal of this study was to validate spheroid contraction as a cytotoxic endpoint using 3T3 fibroblasts in response to 5 toxic compounds (all-trans retinoic acid, dexamethasone, doxorubicin, 5'-fluorouracil, forskolin), sodium dodecyl sulfate (+control), and penicillin-G (-control). Real-time imaging was performed with a mobile device to increase throughput and efficiency. All compounds but penicillin-G significantly slowed contraction in a dose-dependent manner (Z' = 0.88). Cells in 3D were more resistant to toxicity than cells in 2D, whose toxicity was measured by the MTT assay. Fluorescent staining and gene expression profiling of spheroids confirmed these findings. The results of this study validate spheroid contraction within this assay as an easy, biologically relevant endpoint for high-throughput compound screening in representative 3D environments. PMID:26365200

  3. A spheroid toxicity assay using magnetic 3D bioprinting and real-time mobile device-based imaging

    PubMed Central

    Tseng, Hubert; Gage, Jacob A.; Shen, Tsaiwei; Haisler, William L.; Neeley, Shane K.; Shiao, Sue; Chen, Jianbo; Desai, Pujan K.; Liao, Angela; Hebel, Chris; Raphael, Robert M.; Becker, Jeanne L.; Souza, Glauco R.

    2015-01-01

    An ongoing challenge in biomedical research is the search for simple, yet robust assays using 3D cell cultures for toxicity screening. This study addresses that challenge with a novel spheroid assay, wherein spheroids, formed by magnetic 3D bioprinting, contract immediately as cells rearrange and compact the spheroid in relation to viability and cytoskeletal organization. Thus, spheroid size can be used as a simple metric for toxicity. The goal of this study was to validate spheroid contraction as a cytotoxic endpoint using 3T3 fibroblasts in response to 5 toxic compounds (all-trans retinoic acid, dexamethasone, doxorubicin, 5′-fluorouracil, forskolin), sodium dodecyl sulfate (+control), and penicillin-G (−control). Real-time imaging was performed with a mobile device to increase throughput and efficiency. All compounds but penicillin-G significantly slowed contraction in a dose-dependent manner (Z’ = 0.88). Cells in 3D were more resistant to toxicity than cells in 2D, whose toxicity was measured by the MTT assay. Fluorescent staining and gene expression profiling of spheroids confirmed these findings. The results of this study validate spheroid contraction within this assay as an easy, biologically relevant endpoint for high-throughput compound screening in representative 3D environments. PMID:26365200

  4. Use of a rat ex-vivo testis culture method to assess toxicity of select known male reproductive toxicants.

    PubMed

    Goldstein, Keith M; Seyler, David E; Durand, Philippe; Perrard, Marie-Hélène; Baker, Thomas K

    2016-04-01

    Due to the complex physiology of the testes, in vitro models have been largely unsuccessful at modeling testicular toxicity in vivo. We conducted a pilot study to evaluate the utility of the Durand ex vivo rat seminiferous tubule culture model [1-3] that supports spermatogenesis through meiosis II, including the formation of round spermatids. We used this system to evaluate the toxicity of four known testicular toxicants: 1,3-dinitrobenzene (DNB), 2-methoxyacetic acid (MAA), bisphenol A (BPA), and lindane over 21 days of culture. This organotypic culture system demonstrated the ability to successfully model in vivo testicular toxicity (Sertoli cell toxicity and disruption of meiosis) for all four compounds. These findings support the application of this system to study molecules and evaluate mechanisms of testicular toxicity. PMID:26802500

  5. Transdermal microemulsion drug delivery system for impairing male reproductive toxicity and enhancing efficacy of Tripterygium Wilfordii Hook f.

    PubMed

    Wang, Xiao; Xue, Mei; Gu, Jijin; Fang, Xiaoling; Sha, Xianyi

    2012-06-01

    The present study is trying to produce a transdermal microemulsion drug delivery system (TMDDS) for Tripterygium Wilfordii Hook f. (TWHF) and attempting to solve male reproductive toxicity problem of TWHF. The formulation was optimized by the central composite design with response surface methodology and was decided as 12% oleic acid, 19.7% Labrasol S, 19.7% ethanol and 19.7% Pharmasolve, and 29% water. TMDDS for TWHF had stronger transdermal ability than free TWHF, and TWHF microemulsion significantly inhibited the adjuvant-induced arthritis and at the same time, had preferable anti-inflammatory effect with the long-time administration. Various pharmacodynamics parameters proved that TWHF microemulsion can reduce the male reproductive toxicity and hepatotoxicity of rats. All these suggested that TMDDS could be a suitable delivery system for TWHF.

  6. Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of light catalytic reformed naphtha distillate in rats.

    PubMed

    Schreiner, C; Bui, Q; Breglia, R; Burnett, D; Koschier, F; Podhasky, P; White, R; Hoffman, G; Schroeder, R

    2000-06-01

    A distillate of light catalytic reformed naphtha (CAS number 64741-63-5, LCRN-D) administered by inhalation was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening protocol. LCRN-D was administered as a vapor, 6 h/d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 6 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for approximately 7 consecutive weeks. Dams and litters were sacrificed on postnatal d 4 and males were sacrificed within the week after the last litter was necropsied. Parental systemic effects observed at the 7500 ppm exposure level included slightly lower body weights for males throughout the study. Increased kidney to body weight and increased liver to body weight ratio in male rats exposed to 7500 ppm LCRN-D may be related to slightly lower final mean body weights. Body and organ weight data for female rats in all exposure groups were comparable to controls. No test-material-related microscopic changes were observed in the reproductive organs or nasal turbinate tissue of either sex. Reproductive performance was unaffected by exposure to LCRN-D. The mating and fertility indices were 100% in all groups. There were no significant exposure-related differences in implantation sites or live pups per litter, and no gross abnormalities were observed in pups from treated dams. Pups born from LCRN-D-exposed dams showed comparable body weights and weight gain to control pups. The viability index on postpartum d 4 was > or =97%. Under conditions of this study, the no-observed-adverse-effect level (NOAEL) for exposure to light catalytic reformed naphtha distillate for parental effects was 2500 ppm and the NOAEL for reproductive and developmental toxicity was 7500 ppm.

  7. A SHORT TERM REPRODUCTIVE ASSAY WITH THE FATHEAD MINNOW (PIMEPHALES PROMELAS). 1. METHOD DESCRIPTION

    EPA Science Inventory

    Due to the time and expense associated with full life-cycle testing, most current toxicology tests with fish do not explicity consider reproductive output as an endpoint but, rather, focus on early life-stage survival and development. However, some classes of chemicals could adve...

  8. Pea (Pisum sativum) Seed Production as an Assay for Reproductive Effects Due to Herbicides.

    EPA Science Inventory

    Even though herbicide drift can affect plant reproduction, current plant testing protocols emphasize effects on vegetative growth. In this study, we determined whether a short–growing season plant can indicate potential effects of herbicides on seed production. Pea (Pisum sativum...

  9. Identification of Chemical Vascular Disruptors During Development Using An Integrative Predictive Toxicity Model and Zebrafish and in Vitro Functional Angiogenesis Assays.

    EPA Science Inventory

    Identification of chemical vascular disruptors during development using an integrative predictive toxicity model and zebrafish and in vitro functional angiogenesis assays Chemically-induced vascular toxicity during embryonic development can result in a wide range of adverse pre...

  10. Assessment of the potential reproductive and subchronic toxicity of EDS coal liquids in Sprague-Dawley rats.

    PubMed

    McKee, R H; Plutnick, R T; Traul, K A

    1987-11-01

    The EDS direct coal liquefaction process is one of several methods of producing liquid fuels from coal which have reached the pilot or demonstration stage of development. Relatively high levels of polycyclic aromatic hydrocarbons are present in distillate fractions boiling above approximately 370 degrees C, and unrefined coal-derived liquids which contain substantial amounts of material from this boiling range are relatively potent dermal carcinogens. Because coal-derived liquids containing high boiling (i.e., greater than 370 degrees C) material may pose a variety of toxic hazards, efforts have been made to evaluate the potential effects on biological endpoints other than cancer. The present studies assessed the potential for reproductive and subchronic toxicity following repeated oral administration of 2 coal-derived liquids, recycle solvent and fuel oil, which contained substantial amounts of high boiling material. Few biologically important differences were found in any of the experimental parameters. In the reproductive toxicity study, frequency of fertilization and implantation, mean number of live births, fraction of litter surviving through the lactation period and mean weight gain of the litters during the lactation period were not affected by treatment; in addition, there was no evidence of increased frequency of malformation. In the subchronic toxicity study, weight gain was reduced in animals from the high dose groups, but was not significantly different from controls. Liver weights were significantly elevated, but there was no microscopic evidence of pathologic changes. Erythrocyte counts, hemoglobin levels and hematocrits were significantly reduced suggesting a tendency towards anemia. These findings suggested that repeated exposure to EDS recycle solvent and fuel oil at levels of up to 0.5 g/kg per day had no detectable effect on reproductive capacity or performance and did not induce substantial systemic toxicity.

  11. AZT, rodent somatic and germ cell mutagenicity and reproductive toxicity tests

    SciTech Connect

    Shelby, M.D.; Russell, L.B.; Generoso, W.

    1995-11-01

    AZT (3`-axido-3`-deoxythymidine, Zidovudine) is the most widely used therapeutic agent in the treatment of Acquired Immune Deficiency Syndrome (AIDS). Use of AZT has not been limited to HIV-seropositive individuals or to those with symptoms of AIDS. It has also been used as a chemoprophylactic agent in people accidentally exposed to HIV-contaminated body fluids, and to HIV-seropositive pregnant women to prevent infection of the fetus. Because of these latter uses, it is particularly important to determine whether long-term health effects might be associated with AZT exposure. Tests have been conducted to determine the in vivo genetic toxicity of AZT in mice. Dominant-lethal and morphological-specific-locus tests were conducted in males using 2 daily initraperitoneal injections of 750 mg/kg. The dominant-lethal test was negative for all germ cell stages from differentiating spermatogonia to mature sperm. Likewise, no evidence of the induction of specific locus mutations was observed in either spermatogonial stem cells or poststem-cell stages. Further, tests for effects on male and female reproduction and in utero development indicate a lack of effects. These results, along with preliminary clinical reports that birth outcomes are normal in newborns exposed to AZT in utero, are encouraging with regard to the risks to offspring of parents exposed to AZT, either prior to or during pregnancy. However, positive results in mouse bone marrow micronucleus tests and one report on the induction of chromosomal aberrations in the lymphocytes of AIDS patients on AZT therapy indicate that further studies are needed on the potential of AZT to adversely affect the long-term health of exposed individuals.

  12. Assessment of Reproductive and Developmental Toxicity of Mixtures of Regulated Drinking Water Chlorination By-Products in a Multigenerational Rat Bioassay

    EPA Science Inventory

    Epidemiological and animal toxicity studies have raised concerns regarding possible adverse reproductive and developmental effects of disinfection by-products (DBPs) in drinking water. To address these concerns, we provided mixtures of the regulated trihalomethanes (THMs; chlorof...

  13. Unique Nanoparticle Optical Properties Confound Fluorescent Based Assays Widely Employed in Their In Vitro Toxicity Screening and Ranking

    EPA Science Inventory

    Nanoparticles (NPs) are novel materials having at least one dimension less than 100 nm and display unique physicochemical properties due to their nanoscale size. An emphasis has been placed on developing high throughput screening (HTS) assays to characterize and rank the toxiciti...

  14. Fecal cortisol metabolite levels in free-ranging North American red squirrels: Assay validation and the effects of reproductive condition.

    PubMed

    Dantzer, Ben; McAdam, Andrew G; Palme, Rupert; Fletcher, Quinn E; Boutin, Stan; Humphries, Murray M; Boonstra, Rudy

    2010-06-01

    Patterns in stress hormone (glucocorticoid: GC) levels and their relationship to reproductive condition in natural populations are rarely investigated. In this study, we (1) validate an enzyme-immunoassay to measure fecal cortisol metabolite (FCM) levels in North American red squirrels (Tamiasciurus hudsonicus), and (2) examine relationships between FCM levels and reproductive condition in a free-ranging red squirrel population. Injected radiolabeled cortisol was entirely metabolized and excreted in both the urine (mean+/-SE; 70.3+/-0.02%) and feces (29.7+/-0.02%), with a lag time to peak excretion in the feces of 10.9+/-2.3h. Our antibody reacted with several cortisol metabolites, and an adrenocorticotropic injection significantly increased FCM levels above baseline levels at 8h post-injection. Relative to baseline levels, manipulation by handling also tended to increase FCM levels at 8h post-manipulation, but this difference was not significant. FCM levels did not differ significantly between samples frozen immediately and 5h after collection. Reproductive condition significantly affected FCM levels in free-ranging females (pregnant>lactating>post-lactating>non-breeding) but not males (scrotal testes vs. abdominal testes). Among females with known parturition dates, FCM levels increased during gestation, peaked at parturition, and declined during lactation. The difference between pregnant and lactating females was therefore dependent upon when the fecal samples were obtained during these periods, suggesting caution in categorizing reproductive stages. This study demonstrates the utility of fecal hormone metabolite assays to document patterns of glucocorticoid levels in free-ranging animals. PMID:20346362

  15. Application of the rat liver lysosome assay to determining the reduction of toxic gliadin content during breadmaking.

    PubMed

    Cornell, Hugh J; Stelmasiak, Teodor; Small, Darryl M; Buddrick, Oliver

    2016-02-01

    Enriched caricain was able to detoxify a major proportion of the gliadin in wholemeal wheat dough by allowing it to react for 5h at 37 °C during the fermentation stage. A reduction of 82% in toxicity, as determined by the rat-liver lysosome assay, was achieved using 0.03% enzyme on weight of dough. Without enzyme, only 26% reduction occurred. The difference in reduction of toxicity achieved is statistically significant (p < 0.01). The results are very similar to those obtained in our previous work using an immuno assay and the same enzyme preparation. They confirm the value of caricain as a means of reducing the toxicity of gliadin and open the way for enzyme therapy as an adjunct to the gluten free diet. This approach should lead to better control over the elimination of dietary gluten intake in conditions such as coeliac disease and dermatitis herpetiformis.

  16. Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring

    EPA Science Inventory

    The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human healt...

  17. Aminopropyltriethoxysilane-mediated surface functionalization of hydroxyapatite nanoparticles: synthesis, characterization, and in vitro toxicity assay

    PubMed Central

    Wang, Shige; Wen, Shihui; Shen, Mingwu; Guo, Rui; Cao, Xueyan; Wang, Jianhua; Shi, Xiangyang

    2011-01-01

    Background We report on aminopropyltriethoxysilane (APTS)-mediated surface modification of nanohydroxyapatite with different surface functional groups for potential biomedical applications. In this study, nanohydroxyapatite covalently linked with APTS (n-HA-APTS) was reacted with acetic anhydride or succinic anhydride to produce neutralized (n-HA-APTS. Ac) or negatively charged (n-HA-APTS.SAH) nanohydroxyapatite, respectively. Nanohydroxyapatite formed with amine, acetyl, and carboxyl groups was extensively characterized using Fourier transform infrared spectroscopy, transmission electron microscopy, 1H nuclear magnetic resonance spectroscopy, X-ray diffraction, inductively coupled plasma-atomic emission spectroscopy, and zeta potential measurements. Results In vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay revealed that the slight toxicity of the amine-functionalized n-HA-APTS could be eliminated by post-functionalization of APTS amines to form acetyl and carboxyl groups. Blood compatibility assessment demonstrated that the negligible hemolytic activity of the pristine nanohydroxyapatite particles did not appreciably change after APTS-mediated surface functionalization. Conclusion APTS-mediated functionalization of nanohydroxyapatite with different surface groups may be useful for further functionalization of nanohydroxyapatite with biologically active materials, thereby providing possibilities for a broad range of biomedical applications. PMID:22267929

  18. Tier-1 assays for assessing the toxicity of insecticidal proteins produced by genetically engineered plants to non-target arthropods.

    PubMed

    Li, Yun-He; Romeis, Jörg; Wu, Kong-Ming; Peng, Yu-Fa

    2014-04-01

    In assessing an insect-resistant genetically engineered (IRGE) crop before its commercialization, researchers normally use so-called "Tier-1 assays" as the initial step to determine the effects of the crop on non-target organisms. In these tests, the insecticidal proteins (IPs) produced by the IRGEs are added to the diets of test organisms in the laboratory. Test organisms in such assays can be directly exposed to much higher concentrations of the test IPs than they would encounter in the field. The results of Tier-1 assays are thus more conservative than those generated in studies in which the organisms are exposed to the IPs by feeding on IRGE plant tissue or in the case of predators or parasites, by feeding on invertebrate prey or hosts that have fed on IRGE plant tissue. In this report, we consider three important factors that must be considered in Tier-1 assays: (i) methods for delivery of the IP to the test organisms; (ii) the need for and selection of compounds used as positive controls; and (iii) methods for monitoring the concentration, stability and bioactivity of the IP during the assay. We also analyze the existing data from Tier-1 assays regarding the toxicity of Bt Cry proteins to non-target arthropod species. The data indicate that the widely used Bt proteins have no direct toxicity to non-target organisms.

  19. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line

    SciTech Connect

    Monteiro-Riviere, N.A.; Inman, A.O.; Zhang, L.W.

    2009-01-15

    Single-walled carbon nanotubes (SWCNT), fullerenes (C{sub 60}), carbon black (CB), nC{sub 60}, and quantum dots (QD) have been studied in vitro to determine their toxicity in a number of cell types. Here, we report that classical dye-based assays such as MTT and neutral red (NR) that determine cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C{sub 60}, nC{sub 60}, and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 AQueous One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One{sup TM} (CTO), and flow cytometry. In addition, trypan blue (TB) was quantitated by light microscopy. Assay linearity (R{sup 2} value) was determined with HEK plated at concentrations from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilutions of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to physical interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small molecules, CNM interact with assay markers to cause variable results with classical toxicology assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when determining nanoparticle toxicity for risk assessment.

  20. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... information concerning the effects of a test substance on male and female reproductive performance such as... the reproductive system. The number of implantation sites should be recorded. Corpora lutea should be...) Definitions. The definitions in section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice...

  1. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... information concerning the effects of a test substance on male and female reproductive performance such as... the reproductive system. The number of implantation sites should be recorded. Corpora lutea should be...) Definitions. The definitions in section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice...

  2. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... information concerning the effects of a test substance on male and female reproductive performance such as... the reproductive system. The number of implantation sites should be recorded. Corpora lutea should be...) Definitions. The definitions in section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice...

  3. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... information concerning the effects of a test substance on male and female reproductive performance such as... the reproductive system. The number of implantation sites should be recorded. Corpora lutea should be...) Definitions. The definitions in section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice...

  4. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... information concerning the effects of a test substance on male and female reproductive performance such as... the reproductive system. The number of implantation sites should be recorded. Corpora lutea should be...) Definitions. The definitions in section 3 of TSCA and in 40 CFR Part 792—Good Laboratory Practice...

  5. NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of Bisphenol A

    EPA Science Inventory

    The National Toxicology Program (NTP)1 established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of the CERHR is to provide timely, unbiased, scientifically sound evaluations of the potential for adverse effects on reproduction...

  6. Subacute and Reproductive Oral Toxicity Assessment of the Hydroethanolic Extract of Jacaranda decurrens Roots in Adult Male Rats

    PubMed Central

    Santos, Joyce Alencar; Arruda, Aline; Cardoso, Claudia Andrea Lima; Vieira, Maria do Carmo; Piccinelli, Ana Cláudia; Figueiredo de Santana Aquino, Diana; Kassuya, Cândida Aparecida Leite; Arena, Arielle Cristina

    2013-01-01

    Jacaranda decurrens subsp. symmetrifoliolata Farias & Proença (Bignoniaceae) is a species traditionally used for the treatment of inflammatory and infectious diseases. Previous findings from our group reported scientifically that J. decurrens has anti-inflammatory efficacy. However, more toxicological studies are needed to support and ensure its safe use. The present study was carried out to evaluate the toxic effects of a prolonged treatment with hydroethanolic root extract of J. decurrens (EJD) on hematological, biochemical, and reproductive parameters in adult male rats. The animals received by oral gavage 0; 250; 500; or 1000 mg/kg body weight of EJD for 28 days. After the treatment, biochemical, hematological, histopathological, and reproductive parameters were analyzed. The EJD treatment did not cause adverse effects on body weight gain, feed and water consumption, hematological and biochemical profiles, or histopathological analysis of liver and kidney. Similarly, there were no statistically significant differences in reproductive parameters, such as sperm production, number of sperm in the epididymis, and sperm morphology. These results demonstrate the absence of subacute toxicity as a result of the oral treatment with EJD for 28 days in adult male rats. However, other studies should be performed to evaluate the total safety of this plant. PMID:24348699

  7. Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay

    PubMed Central

    Gaukler, Shannon M.; Ruff, James S.; Galland, Tessa; Kandaris, Kirstie A.; Underwood, Tristan K.; Liu, Nicole M.; Young, Elizabeth L.; Morrison, Linda C.; Yost, Garold S.; Potts, Wayne K.

    2014-01-01

    Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete amongst each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study were undetected in preclinical trials with dose 2.5-8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could useful towards safety testing during pharmaceutical development. PMID:25446017

  8. Bisphenol A causes reproductive toxicity, decreases dnmt1 transcription, and reduces global DNA methylation in breeding zebrafish (Danio rerio)

    PubMed Central

    Laing, L. V.; Viana, J.; Dempster, E. L.; Trznadel, M.; Trunkfield, L. A.; Uren Webster, T. M.; van Aerle, R.; Paull, G. C.; Wilson, R. J.; Mill, J.; Santos, E. M.

    2016-01-01

    ABSTRACT Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish (Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 (dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment. PMID:27120497

  9. Bisphenol A causes reproductive toxicity, decreases dnmt1 transcription, and reduces global DNA methylation in breeding zebrafish (Danio rerio).

    PubMed

    Laing, L V; Viana, J; Dempster, E L; Trznadel, M; Trunkfield, L A; Uren Webster, T M; van Aerle, R; Paull, G C; Wilson, R J; Mill, J; Santos, E M

    2016-07-01

    Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish (Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 (dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment. PMID:27120497

  10. Reduced mutant yield at high doses in the Salmonella/activation assay: the cause is not always toxicity.

    PubMed

    McGregor, D; Prentice, R D; McConville, M; Lee, Y J; Caspary, W J

    1984-01-01

    In the Salmonella/activation assay developed by Ames et al [1973, 1975] toxicity is not measured, though it is recognized by the loss of a cloudy appearance on the plate. One approach to the measurement of toxicity is described here and uses a microscope-linked automated colony counter to estimate the number of microcolonies formed by histidine auxotrophs that stop growing after the depletion of histidine. This technique was used to evaluate the effect of toxicity on the revertant count for 16 mutagens, most of which were chosen because, from previous experience, their dose-response curves manifested a maximum at an intermediate dose tested. One of the sixteen, 2-nitrofluorene, was not toxic up to the maximum dose tested. The relationship between mutation and toxicity for the remaining fifteen allowed them to be grouped into two categories: (1) compounds that induced decreases in survival at the same dose at which the number of mutants decreased, and (2) compounds that induced toxicity, but survival was reduced at dose levels higher than those required to reduce the number of mutants. Possible explanations for this reduction of mutant counts occurring with little apparent concomitant increase in toxicity are examined. These results may be significant for attempts to estimate mutagenic potency and, to a lesser extent, construct mathematical models of the Ames test. PMID:6381041

  11. Automated High-Content Assay for Compounds Selectively Toxic to Trypanosoma cruzi in a Myoblastic Cell Line

    PubMed Central

    Alonso-Padilla, Julio; Cotillo, Ignacio; Presa, Jesús L.; Cantizani, Juan; Peña, Imanol; Bardera, Ana I.; Martín, Jose J.; Rodriguez, Ana

    2015-01-01

    Background Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, represents a very important public health problem in Latin America where it is endemic. Although mostly asymptomatic at its initial stage, after the disease becomes chronic, about a third of the infected patients progress to a potentially fatal outcome due to severe damage of heart and gut tissues. There is an urgent need for new drugs against Chagas disease since there are only two drugs available, benznidazole and nifurtimox, and both show toxic side effects and variable efficacy against the chronic stage of the disease. Methodology/Principal Findings Genetically engineered parasitic strains are used for high throughput screening (HTS) of large chemical collections in the search for new anti-parasitic compounds. These assays, although successful, are limited to reporter transgenic parasites and do not cover the wide T. cruzi genetic background. With the aim to contribute to the early drug discovery process against Chagas disease we have developed an automated image-based 384-well plate HTS assay for T. cruzi amastigote replication in a rat myoblast host cell line. An image analysis script was designed to inform on three outputs: total number of host cells, ratio of T. cruzi amastigotes per cell and percentage of infected cells, which respectively provides one host cell toxicity and two T. cruzi toxicity readouts. The assay was statistically robust (Z´ values >0.6) and was validated against a series of known anti-trypanosomatid drugs. Conclusions/Significance We have established a highly reproducible, high content HTS assay for screening of chemical compounds against T. cruzi infection of myoblasts that is amenable for use with any T. cruzi strain capable of in vitro infection. Our visual assay informs on both anti-parasitic and host cell toxicity readouts in a single experiment, allowing the direct identification of compounds selectively targeted to the parasite. PMID:25615687

  12. Abatement of toxicity of effluents containing Cr(VI) by heterogeneous photocatalysis. Toxicity assessment by AMPHITOX assay.

    PubMed

    Hojman, Jonatan Y; Meichtry, J Martín; Litter, Marta I; Pérez Coll, Cristina S

    2015-12-01

    Toxicity of a Cr(VI) solution before and after treatment by TiO2 heterogeneous photocatalysis (HP) was performed with AMPHITOX bioassay. Changes in toxicity on Rhinella arenarum larvae for 10-d were monitored after exposure to an untreated Cr(VI) solution and to the same solution after HP treatment. The HP treatment of a 41.60 mg L(-1) Cr(VI) solution reduced to 37.5% the concentration of the metal ion. A 10-fold reduction in toxicity at acute exposure (72 h) and 150-fold reduction in toxicity after 240 h was found. Further, the LOEC value increased from 0.001% for the untreated solution to 0.153% after HP treatment. Moreover, the safe concentration in untreated solution corresponded to 0.0001% sample, and it was 0.01% after the treatment, i.e., 100 times higher. A saving of water of about 100,000 L per L of effluent would be possible through dilution to allow safer concentrations for discharge; the saving would reach the highest value (1,000,000 L per L) at 240 h. Sub-lethal effects were completely absent in larvae exposed to the treated solution. The AMPHITOX test allowed to detect chronic effects at low Cr concentrations, i.e. at environmentally relevant levels.

  13. Disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat.

    PubMed

    Goetz, Amber K; Ren, Hongzu; Schmid, Judith E; Blystone, Chad R; Thillainadarajah, Inthirany; Best, Deborah S; Nichols, Harriette P; Strader, Lillian F; Wolf, Douglas C; Narotsky, Michael G; Rockett, John C; Dix, David J

    2007-01-01

    Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and triadimefon, and at PND50 by propiconazole and triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and triadimefon treatment. Serum testosterone was increased at PND50 by triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.

  14. Reproductive toxicity of 1-bromopropane, a newly introduced alternative to ozone layer depleting solvents, in male rats.

    PubMed

    Ichihara, G; Yu, X; Kitoh, J; Asaeda, N; Kumazawa, T; Iwai, H; Shibata, E; Yamada, T; Wang, H; Xie, Z; Maeda, K; Tsukamura, H; Takeuchi, Y

    2000-04-01

    1-Bromopropane has been newly introduced as an alternative to ozone-depleting solvents. We aimed to clarify its dose-dependent reproductive toxicity in male rats. Thirty-six Wistar male rats were randomly divided into 4 groups of 9. The groups were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h per day for 12 weeks. Epididymal sperm indices were evaluated after a 12-week exposure. The testes, epididymides, seminal vesicle, prostate, and other organs were weighed and examined histopathologically. Spermatogenic cells, in stage VII seminiferous tubules, and retained spermatids, at the basal region of stages IX-XI seminiferous epithelium, were counted. Plasma testosterone levels were measured by radioimmunoassay. The testicular weight did not significantly change, but the weight of epididymides, seminal vesicle, and prostate dose-dependently decreased. The weight of seminal vesicle decreased significantly at the lowest concentration of 200-ppm and over. 1-Bromopropane induced a dose-dependent decrease in the epididymal sperm count and in motility, as well as an increase in tailless sperm and sperm with an immature head shape. The spermatogonia, preleptotene spermatocytes, pachytene spermatocytes, and round spermatids did not decrease significantly at stage VII. Retained, elongated spermatids near the basement membrane at the postspermiation stages IX-XI increased dose-dependently. Plasma testosterone levels significantly decreased at the 800-ppm dosage. 1-Bromopropane caused failure of spermiation. Its reproductive toxicity is different from that of 2-bromopropane, which specifically impairs spermatogonia. Thus, this solvent may have serious reproductive toxic effects in men, and should be used very cautiously in the workplace.

  15. NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF 1-BROMOPROPANE

    EPA Science Inventory

    The National Toxicology Program (NTP) and the National Institute of Environmetnal Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in order to provide timely, unbiased, scientifically sound evaluations of human and exper...

  16. NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF 2-BROMOPROPANE

    EPA Science Inventory

    The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in order to provide timely, unbiased, scientifically sound evaluations of human and exper...

  17. Comprehensive Assessment of a Chlorinated Drinking Water Concentrate in a Rat Multigenerational Reproductive Toxicity Study##

    EPA Science Inventory

    Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

  18. Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study

    EPA Science Inventory

    Some epidemiological studies report associations between drinking water disinfection by-products (DBPs) and adverse reproductive and developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. To address concerns raised by these studies, w...

  19. Application of endocrine disruptor screening program fish short-term reproduction assay: Reproduction and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus) exposed to Bermuda pond sediment.

    PubMed

    Fort, Douglas J; Mathis, Michael; Fort, Chelsea E; Fort, Hayley M; Bacon, Jamie P

    2015-06-01

    A modified tier 1 Endocrine Disruptor Screening Program (EDSP) 21-d fish short-term reproduction assay (FSTRA) was used to evaluate the effects of sediment exposure from freshwater and brackish ponds in Bermuda on reproductive fecundity and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus). Reproductively active male and female fish were exposed to control sediment and sediment from 2 freshwater ponds (fathead minnow) and 2 marine ponds (killifish) contaminated with polyaromatic hydrocarbons and metals via flow-through exposure for 21 d. Reproductive fecundity was monitored daily. At termination, the status of the reproductive endocrine system was assessed by the gonadosomatic index, gonadal histology, plasma steroids (estrogen [E2], testosterone [T], and 11-ketotestosterone [11-KT]), steroidogenic enzymes (aromatase and combined 3β/17β -hydroxysteroid dehydrogenase [3β/17β-HSD]), and plasma vitellogenin (VTG). Decreased reproductive fecundity, lower male body weight, and altered endocrinological measures of reproductive status were observed in both species. Higher plasma T levels in female minnows and 11-KT levels in both male and female minnows and female killifish exposed to freshwater and brackish sediments, respectively. Decreased female E2 and VTG levels and gonadal cytochrome P19 (aromatase) activity were also found in sediment exposed females from both species. No effect on female 3β/17β-HSD activity was found in either species. The FSTRA provided a robust model capable of modification to evaluate reproductive effects of sediment exposure in fish.

  20. Effect of metals and other inorganic ions on soil microbial activity: soil dehydrogenase assay as a simple toxicity test

    SciTech Connect

    Rogers, J.E.; Li, S.W.

    1985-06-01

    The purpose of this report is to illustrate the utility of the soil dehydrogenase assay as an effective primary test for assessing the potential toxicity of chemicals to soil microbial activity. In this manuscript the authors describe their use of the soil dehydrogenase assay in determining the effects of a number of potential toxic inorganic ions on soil microbial activity. The ions include Cu/sup 2 +/, Mg/sup 2 +/, Ni/sup 2 +/, Zn/sup 2 +/, NH/sub 4//sup +/, Cd/sup 2 +/, Cr/sup 32/, F/sup -/, AsO/sub 4//sup 3 -/, BO/sub 3//sup 3 -/, and SO/sub 4//sup 2 -/.

  1. Pulmonary toxicity of nanomaterials: a critical comparison of published in vitro assays and in vivo inhalation or instillation studies.

    PubMed

    Landsiedel, Robert; Sauer, Ursula G; Ma-Hock, Lan; Schnekenburger, Jürgen; Wiemann, Martin

    2014-11-01

    To date, guidance on how to incorporate in vitro assays into integrated approaches for testing and assessment of nanomaterials is unavailable. In addressing this shortage, this review compares data from in vitro studies to results from in vivo inhalation or intratracheal instillation studies. Globular nanomaterials (ion-shedding silver and zinc oxide, poorly soluble titanium dioxide and cerium dioxide, and partly soluble amorphous silicon dioxide) and nanomaterials with higher aspect ratios (multiwalled carbon nanotubes) were assessed focusing on the Organisation for Economic Co-Operation and Development (OECD) reference nanomaterials for these substances. If in vitro assays are performed with dosages that reflect effective in vivo dosages, the mechanisms of nanomaterial toxicity can be assessed. In early tiers of integrated approaches for testing and assessment, knowledge on mechanisms of toxicity serves to group nanomaterials thereby reducing the need for animal testing. PMID:25490426

  2. NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine.

    PubMed

    Abulí, Anna; Boada, Montserrat; Rodríguez-Santiago, Benjamín; Coroleu, Buenaventura; Veiga, Anna; Armengol, Lluís; Barri, Pedro N; Pérez-Jurado, Luis A; Estivill, Xavier

    2016-06-01

    Next-generation sequencing (NGS) has the capacity of carrier screening in gamete donation (GD) programs. We have developed and validated an NGS carrier-screening test (qCarrier test) that includes 200 genes associated with 368 disorders (277 autosomal recessive and 37 X-linked). Carrier screening is performed on oocyte donation candidates and the male partner of oocyte recipient. Carriers of X-linked conditions are excluded from the GD program, whereas donors are chosen who do not carry mutations for the same gene/disease as the recipients. The validation phase showed a high sensitivity (>99% sensitivity) detecting all single-nucleotide variants, 13 indels, and 25 copy-number variants included in the validation set. A total of 1,301 individuals were analysed with the qCarrier test, including 483 candidate oocyte donors and 635 receptor couples, 105 females receiving sperm donation, and 39 couples seeking pregnancy. We identified 56% of individuals who are carriers for at least one genetic condition and 1.7% of female donors who were excluded from the program due to a carrier state of X-linked conditions. Globally, 3% of a priori assigned donations had a high reproductive risk that could be minimized after testing. Genetic counselling at different stages is essential for helping to facilitate a successful and healthy pregnancy.

  3. NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine.

    PubMed

    Abulí, Anna; Boada, Montserrat; Rodríguez-Santiago, Benjamín; Coroleu, Buenaventura; Veiga, Anna; Armengol, Lluís; Barri, Pedro N; Pérez-Jurado, Luis A; Estivill, Xavier

    2016-06-01

    Next-generation sequencing (NGS) has the capacity of carrier screening in gamete donation (GD) programs. We have developed and validated an NGS carrier-screening test (qCarrier test) that includes 200 genes associated with 368 disorders (277 autosomal recessive and 37 X-linked). Carrier screening is performed on oocyte donation candidates and the male partner of oocyte recipient. Carriers of X-linked conditions are excluded from the GD program, whereas donors are chosen who do not carry mutations for the same gene/disease as the recipients. The validation phase showed a high sensitivity (>99% sensitivity) detecting all single-nucleotide variants, 13 indels, and 25 copy-number variants included in the validation set. A total of 1,301 individuals were analysed with the qCarrier test, including 483 candidate oocyte donors and 635 receptor couples, 105 females receiving sperm donation, and 39 couples seeking pregnancy. We identified 56% of individuals who are carriers for at least one genetic condition and 1.7% of female donors who were excluded from the program due to a carrier state of X-linked conditions. Globally, 3% of a priori assigned donations had a high reproductive risk that could be minimized after testing. Genetic counselling at different stages is essential for helping to facilitate a successful and healthy pregnancy. PMID:26990548

  4. Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443).

    PubMed

    Moore, Nigel P; Beekhuijzen, Manon; Boogaard, Peter J; Foreman, Jennifer E; North, Colin M; Palermo, Christine; Schneider, Steffen; Strauss, Volker; van Ravenzwaay, Bennard; Poole, Alan

    2016-10-01

    The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding. The purpose of this document is to offer guidance on science-based triggers for these extended evaluations.

  5. A sensitive and high throughput bacterial luminescence assay for assessing aquatic toxicity--the BLT-Screen.

    PubMed

    van de Merwe, Jason P; Leusch, Frederic D L

    2015-05-01

    Bioassays using naturally luminescent bacteria are commonly used to assess the toxicity of environmental contaminants, detected by a decrease in luminescence. Typically, this has involved the use of commercial test kits such as Microtox and ToxScreen. These commercial assays, however, have limitations for routine environmental monitoring, including the need for specialized equipment, a low throughput and high on-going costs. There is therefore a need to develop a bacteria bioassay that is sensitive, high-throughput and cost effective. This study presents the development and application of the BLT-Screen (Bacterial Luminescence Toxicity Screen), a 96-well plate bioassay using Photobacterium leiognathi. During development of the method, the concentration of the phosphate buffer in the experimental medium was adjusted to maximize the sensitivity of the assay, and protocols for analyzing both solid-phase extracts and raw water samples were established. A range of organic compounds and metals were analyzed in the assay, as well as extracts of various water samples, including drinking water, wastewater effluent and river water. The IC50 values of the organic compounds and metals tested in the BLT-Screen were comparable to previously published ToxScreen and Microtox data. In addition, the assay was sensitive enough to detect toxicity in all water types tested, and performed equally well for both solid-phase extracts and raw water samples. The BLT-Screen therefore presents a cost-effective, sensitive and high throughput method for testing the toxicity of environmental contaminants in a range of water types that has widespread applications for research, as well as for routine monitoring and operation of wastewater and drinking water plants.

  6. Differential toxicity of Disperse Red 1 and Disperse Red 13 in the Ames test, HepG2 cytotoxicity assay, and Daphnia acute toxicity test.

    PubMed

    Ferraz, E R A; Umbuzeiro, G A; de-Almeida, G; Caloto-Oliveira, A; Chequer, F M D; Zanoni, M V B; Dorta, D J; Oliveira, D P

    2011-10-01

    Azo dyes are of environmental concern due to their degradation products, widespread use, and low-removal rate during conventional treatment. Their toxic properties are related to the nature and position of the substituents with respect to the aromatic rings and amino nitrogen atom. The dyes Disperse Red 1 and Disperse Red 13 were tested for Salmonella mutagenicity, cell viability by annexin V, and propidium iodide in HepG2 and by aquatic toxicity assays using daphnids. Both dyes tested positive in the Salmonella assay, and the suggestion was made that these compounds induce mainly frame-shift mutations and that the enzymes nitroreductase and O-acetyltransferase play an important role in the observed effect. In addition, it was shown that the presence of the chlorine substituent in Disperse Red 13 decreased the mutagenicity about 14 times when compared with Disperse Red 1, which shows the same structure as Disperse Red 13, but without the chlorine substituent. The presence of this substituent did not cause cytotoxicity in HepG2 cells, but toxicity to the water flea Daphnia similis increased in the presence of the chlorine substituent. These data suggest that the insertion of a chlorine substituent could be an alternative in the design of dyes with low-mutagenic potency, although the ecotoxicity should be carefully evaluated.

  7. A Quantitative Toxicogenomics Assay Reveals the Evolution and Nature of Toxicity during the Transformation of Environmental Pollutants

    PubMed Central

    2015-01-01

    The incomplete mineralization of contaminants of emerging concern (CECs) during the advanced oxidation processes can generate transformation products that exhibit toxicity comparable to or greater than that of the original contaminant. In this study, we demonstrated the application of a novel, fast, and cost-effective quantitative toxicogenomics-based approach for the evaluation of the evolution and nature of toxicity along the electro-Fenton oxidative degradation of three representative CECs whose oxidative degradation pathways have been relatively well studied, bisphenol A, triclosan, and ibuprofen. The evolution of toxicity as a result of the transformation of parent chemicals and production of intermediates during the course of degradation are monitored, and the quantitative toxicogenomics assay results revealed the dynamic toxicity changes and mechanisms, as well as their association with identified intermediates during the electro-Fenton oxidation process of the selected CECs. Although for the three CECs, a majority (>75%) of the parent compounds disappeared at the 15 min reaction time, the nearly complete elimination of toxicity required a minimal 30 min reaction time, and they seem to correspond to the disappearance of identified aromatic intermediates. Bisphenol A led to a wide range of stress responses, and some identified transformation products containing phenolic or quinone group, such as 1,4-benzoquinone and hydroquinone, likely contributed to the transit toxicity exhibited as DNA stress (genotoxicity) and membrane stress during the degradation. Triclosan is known to cause severe oxidative stress, and although the oxidative damage potential decreased concomitantly with the disappearance of triclosan after a 15 min reaction, the sustained toxicity associated with both membrane and protein stress was likely attributed at least partially to the production of 2,4-dichlorophenol that is known to cause the production of abnormal proteins and affect the cell

  8. Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances

    PubMed Central

    Auger, Jacques; Eustache, Florence; Rouiller-Fabre, Virginie; Canivenc-Lavier, Marie Chantal; Livera, Gabriel

    2014-01-01

    In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS) exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA) of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach) for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction. PMID:24369134

  9. Toxicity testing of heavy-metal-polluted soils with algae Selenastrum capricornutum: a soil suspension assay.

    PubMed

    Aruoja, Villem; Kurvet, Imbi; Dubourguier, Henri-Charles; Kahru, Anne

    2004-08-01

    A small-scale Selenastrum capricornutum (Rhapidocelis subcapitata) growth inhibition assay was applied to the toxicity testing of suspensions of heavy-metal-polluted soils. The OECD 201 standard test procedure was followed, and algal biomass was measured by the fluorescence of extracted chlorophyll. The soils, which contained up to (per kilogram) 1390 mg of Zn, 20 mg of Cd, and 1050 mg of Pb were sampled around lead and zinc smelters in northern France. The water extractability of the metals in suspensions (1 part soil/99 parts water w/v) was not proportional to the pollution level, as extractability was lower for soil samples that were more polluted. Thus, the same amount of metals could be leached out of soils of different levels of pollution, showing that total concentrations of heavy metals in soil (currently used for risk assessment purposes) are poor predictors of the real environmental risk via the soil-water path. Despite high concentrations of water-extracted zinc (0.6-1.4 mg/L of Zn in the test), exceeding by approximately 10-fold the EC(50) value for S. capricornutum (0.1 mg Zn/L), 72-h algal growth in the soil extracts was comparable or better than growth in the standard control OECD mineral medium. The soil suspension stimulated the growth of algae up to eightfold greater than growth using the OECD control medium. Growth stimulation of algae was observed even when soil suspensions contained up to 12.5 mg Zn/L and could not be explained by supplementary nitrogen, phosphorous, and carbonate leached from the soil. However, if the growth of algae in suspensions of clean and polluted soils was compared, a dose-dependent inhibitory effect of metals on algal growth was demonstrated. Thus, as soil contains nutrients/supplements that mask the adverse effect of heavy metals, a clean soil that has properties similar to the polluted soils should be used instead of mineral salt solution as a control for analysis of the ecotoxicity of soils. PMID:15269912

  10. Simultaneous detection of eight swine reproductive and respiratory pathogens using a novel GeXP analyser-based multiplex PCR assay.

    PubMed

    Zhang, Minxiu; Xie, Zhixun; Xie, Liji; Deng, Xianwen; Xie, Zhiqin; Luo, Sisi; Liu, Jiabo; Pang, Yaoshan; Khan, Mazhar I

    2015-11-01

    A new high-throughput GenomeLab Gene Expression Profiler (GeXP) analyser-based multiplex PCR assay was developed for the detection of eight reproductive and respiratory pathogens in swine. The reproductive and respiratory pathogens include North American porcine reproductive and respiratory syndrome virus (PRRSV-NA), classical swine fever virus (CSFV), porcine circovirus 2 (PCV-2), swine influenza virus (SIV) (including H1 and H3 subtypes), porcine parvovirus (PPV), pseudorabies virus (PRV) and Japanese encephalitis virus (JEV). Nine pairs of specific chimeric primers were designed and used to initiate PCRs, and one pair of universal primers was used for subsequent PCR cycles. The specificity of the GeXP assay was examined using positive controls for each virus. The sensitivity was evaluated using serial ten-fold dilutions of in vitro-transcribed RNA from all of the RNA viruses and plasmids from DNA viruses. The GeXP assay was further evaluated using 114 clinical specimens and was compared with real-time PCR/single RT-PCR methods. The specificity of the GeXP assay for each pathogen was examined using single cDNA/DNA template. Specific amplification peaks of the reproductive and respiratory pathogens were observed on the GeXP analyser. The minimum copies per reaction detected for each virus by the GeXP assay were as follows: 1000 copies/μl for PRV; 100 copies/μl for CSFV, JEV, PCV-2 and PPV; and 10 copies/μl for SIV-H1, SIV-H3 and PRRSV-NA. Analysis of 114 clinical samples using the GeXP assay demonstrated that the GeXP assay had comparable detection to real-time PCR/single RT-PCR. This study demonstrated that the GeXP assay is a new method with high sensitivity and specificity for the identification of these swine reproductive and respiratory pathogens. The GeXP assay may be adopted for molecular epidemiological surveys of these reproductive and respiratory pathogens in swine populations. PMID:26259690

  11. Estimation of in vivo dose of dermally applied chemicals leading to estrogen/androgen receptor-mediated toxicity from in vitro data--Illustration with four reproductive toxicants.

    PubMed

    Dancik, Yuri; Troutman, John A; Jaworska, Joanna

    2015-08-01

    We present a quantitative in vitro-in vivo extrapolation framework enabling the estimation of the external dermal exposure dose from in vitro experimental data relevant to a toxicity pathway of interest. The framework adapts elements of the biological pathway altering dose (BPAD) method [Judson et al. Chem Res Toxicol 2011;24:451] to the case of dermal exposure. Dermal doses of four toxicants equivalent to concentrations characterizing their effect on estrogen receptor α or androgen receptor activity in chemical-activated luciferase expression (CALUX) assays are estimated. The analysis shows that dermal BPADs, calculated from one in vitro concentration, can differ by up to a factor of 55, due to the impact applied dose and dermal exposure scenarios can have on skin permeation kinetics. These features should therefore be taken into account in risk assessment of dermally applied chemicals.

  12. Toxicity Screening of the ToxCast Chemical Library Using a Zebrafish Developmental Assay

    EPA Science Inventory

    As part of the chemical screening and prioritization research program of the U.S. Environmental Protection Agency, the toxicity of the 320 ToxCast™ Phase I chemicals were assessed using a vertebrate screen of developmental toxicity. Zebrafish embryos/larvae (Danio rerio) were exp...

  13. A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrine-disrupting chemicals

    EPA Science Inventory

    The fish short term reproduction assay (FSTRA) is a key component of the USEPA endocrine disruptor screening program (EDSP). The FSTRA considers several mechanistic and apical responses in fathead minnows (Pimephales promelas) to determine whether an unknown chemical is likely t...

  14. A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrined-disrupting chemicals

    EPA Science Inventory

    The fish short term reproduction assay (FSTRA) is a key component of the USEPA endocrine disruptor screening program (EDSP). The FSTRA considers several mechanistic and apical responses in fathead minnows (Pimephales promelas) to determine whether an unknown chemical is likely to...

  15. A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrine-disrupting chemicals (poster)

    EPA Science Inventory

    The fish short term reproduction assay (FSTRA) is a key component of the USEPA endocrine disruptor screening program (EDSP). The FSTRA considers several mechanistic and apical responses in fathead minnows (Pimephales promelas) to determine whether an unknown chemical is likely to...

  16. Toxic effects upon exposure to polycyclic aromatic hydrocarbon (chrysene) in scallop Chlamys farreri during the reproduction period.

    PubMed

    Xiu, Meng; Pan, Luqing; Jin, Qian

    2016-06-01

    This study aims to investigate potential toxic effects of chrysene (CHR) on mature scallop Chlamys farreri during the reproduction period, using indicators of antioxidant defences and oxidative stress. Scallops were exposed to 0.2, 0.8 and 3.2μg/L waterborne CHR for 21 days, at day 10 scallops were induced to spawn. At days 1, 3, 6, 10, 11, 15 and 21, aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin-O-deethylase (EROD), glutathione-s-transferase (GST), glutathione (GSH), superoxide dismutase (SOD), lipid peroxidation (LPO), protein carbonyl (PC) and DNA strand breaks in digestive glands were examined by separately analysing male and female scallops. During the pre-spawn period, Levels of enzymatic activities and oxidative stress were all induced by the exposure to CHR for females and males. GST activity presented a good time- and dose-dependent relationship only in males, and GSH content showed a dose-dependent manner in both sexes. During the post-spawn period, different trends were observed, while PC contents maintained growth in time- and dose-dependent manner. Overall, males were more sensitive than females to CHR exposure in enzyme activities, and correspondingly, females suffered from more serious oxidative damages. Both GSH and PC contents seemed to be potential biomarkers for PAH exposure. These results will offer the information on toxicity of CHR in this species, and ensure the influence of gender and reproductive status on PAH detoxification metabolism.

  17. Effects of multigenerational exposure to elevated temperature on reproduction, oxidative stress, and Cu toxicity in Daphnia magna.

    PubMed

    Bae, Eunhye; Samanta, Palas; Yoo, Jisu; Jung, Jinho

    2016-10-01

    This study evaluated the effect of temperature (20 and 25°C) on reproduction, oxidative stress, and copper (Cu) toxicity in Daphnia magna across three generations (F0, F1, and F2). Exposing D. magna to elevated temperature significantly decreased the number of offspring per female per day, the time to first brood, and body length compared to exposure to the optimal temperature (p<0.05). In addition, elevated temperature induced a significantly higher production of reactive oxygen species and lipid peroxidation (p<0.05). These findings suggest that D. magna likely responded to thermal stress by investing more energy into defense mechanisms, rather than growth and reproduction. In addition, oxidative stress at the elevated temperature gradually increased with each generation, possibly owing to the reduced fitness of the offspring. Exposing D. magna to 25°C (EC50=34±3µgL(-1)) substantially increased the median effective concentration of Cu in all generations compared to exposure to 20°C (EC50=25±3µgL(-1)), indicating a decrease in acute toxicity at elevated temperature. However, elevated temperature significantly increased the oxidative stress induced by a sublethal concentration of Cu (10µgL(-1)). The interaction between elevated temperature and Cu exposure appears to be synergistic; however, this needs to be confirmed using multiple generations in a long-term experiment. PMID:27376351

  18. The significance of growth in Chironomus tentans sediment toxicity tests: Relationship to reproduction and demographic endpoints

    SciTech Connect

    Sibley, P.K.; Benoit, D.A.; Ankley, G.T.

    1997-02-01

    In the Chironomus tentans 10-d growth test, changes in larval growth relative to sediment contamination are often ascribed ecological relevance by assuming that such changes become manifest at the population level through effects on reproductive output. The objective of this study was to evaluate the relationship between growth and reproduction in C. tentans and to use these data in a demographic model to predict the growth and size of a theoretical population. Growth was manipulated by varying food supply. The test was initiated with 12 newly hatched larvae per replicate and carried through one complete generation. Larval growth and survival were determined at 20 d, and reproduction was monitored daily during emergence. Food supply did not significantly affect survivorship at any life stage; survival of larvae at 20 d, pupae, and adults exceeded 83%, while survival of larvae in the reproduction replicates exceeded 65%. Both larval and adult dry weight declined significantly with a reduction in food supply. Total emergence was reduced at the lowest feeding level only, whereas the rate of emergence declined at food supplies below 0.42 mg/individual per d. Based on the relationship between larval and adult dry weight, a minimum larval tissue mass of between 0.5 and 0.6 mg dry weight/individual appears to be necessary before emergence can take place. The number of eggs/female declined significantly with a decrease in food supply below 0.42 mg/individual per d. Above this level, the addition of more food had no effect on reproductive output. Fecundity (number of daughters/female) and expected number of progeny declined linearly with reduced food supply. Application of the data in a demographic model showed that the growth and predicted size of a population would decline significantly with a decline in larval growth and reproductive output.

  19. Toxic Environmental Chemicals: The Role of Reproductive Health Professionals In Preventing Harmful Exposures

    PubMed Central

    SUTTON, Patrice; WOODRUFF, Tracey J.; PERRON, Joanne; STOTLAND, Naomi; CONRY, Jeanne A.; MILLER, Mark D.; GIUDICE, Linda C.

    2015-01-01

    Every pregnant woman in the U.S. is exposed to many and varied environmental chemicals. Rapidly accumulating scientific evidence documents that widespread exposure to environmental chemicals at levels encountered in daily life can adversely impact reproductive and developmental health. Preconception and prenatal exposure to environmental chemicals are of particular import because they may have a profound and lasting impact on health across the life course. Thus, preventing developmental exposures to environmental chemicals would benefit greatly from the active participation of reproductive health professionals in clinical and policy arenas. PMID:22405527

  20. Particle size as a modifying factor in sediment toxicity tests: Effects on growth, reproduction, and behavior in Chironomus tentans

    SciTech Connect

    Sibley, P.K.; Benoit, D.A.; Ankley, G.T.

    1995-12-31

    The potential for sediment grain size to interfere with the assessment of sublethal endpoints in sediment toxicity tests was evaluated using the midge C. tentans. Substrates, ranging in mean grain size from < 10 (clay) to 600 {micro}m, were used to evaluate growth in 2 and 10-day old larvae (10-day growth tests) and reproduction using newly hatched larvae (monitored through one complete generation). In a separate study, substrate selection behavior was evaluated using pair-wise choice experiments. Survivorship (> 85%) was not affected by grain size in any of the tests. Larval growth (10-day tests) was highest in substrates with mean grain size between 30 and 150 {micro}m, with maximum growth occurring at 75 pm. This relationship was observed for both 2 and 10 d old larvae, but was statistically significant only for 10 d old larvae. Reproductive potential (fecundity) was correlated with larval growth, being highest in smaller grain sizes (< 150 {micro}m). In pair-wise selection tests, larvae demonstrated only a slight preference (approximately 60:40) for the smaller of two particle sizes when the two substrates were supplied with equal amounts of food. However, when food was supplied to only one of the two grain sizes, larvae were significantly more abundant on the substrate containing food, independent of particle size. When the amount of available food was reduced, the proportion of larvae occurring on fed substrates declined. It is concluded that food availability is much more important than particle size in substrate selection by C. tentans, Together, the results of this study indicate that particle size can modify growth and reproductive potential in larval C. tentans and should be included in the interpretation of sediment toxicity tests results.

  1. Reproductive toxicity evaluation of the dental resin monomer bisphenol a glycidyl methacrylate (CAS 1565-94-2) in mice.

    PubMed

    Moilanen, Lori H; Dahms, Janell K; Hoberman, Alan M

    2013-01-01

    The reproductive toxicity potential of the dental resin monomer bisphenol A glycidyl methacrylate (BisGMA; CASRN 1565-94-2) was investigated in male and female Crl: CD1(ICR) mice, 4 dosage groups, and 25 mice/sex/group. Formulations of BisGMA (0, 0.008, 0.08, or 0.8 mg/kg/d) in 0.8% ethanol in deionized water were intubated once daily beginning 28 days before cohabitation and continuing through mating (males) or through gestation day 17. The following parameters were evaluated: viability, clinical signs, body weights, estrous cyclicity, necropsy observations, organ weights, sperm concentration/motility/morphology, cesarean sectioning and litter observations, and histopathological evaluation of select tissues. No deaths or clinical signs related to BisGMA occurred. No significant changes in male and female body weights and body weight gains were recorded at any of the administered dosages of BisGMA. All mating and fertility parameters, and all litter and fetal data, were considered to be unaffected by dosages of BisGMA as high as 0.8 mg/kg/d. Gross or histopathologic tissue changes attributable to the test article were not observed. Reproductive and developmental no observed effect levels (NOAELs) for BisGMA were 0.8 mg/kg/d, the highest dose tested. Comparison of this NOAEL value to published probabilistic estimates of human BisGMA exposure from dental products suggests a margin of safety of at least 280- to nearly 2000-fold. Under the conditions of this study, BisGMA is not a reproductive toxicant.

  2. Mating activity and sperm penetration assay in prediction of the reproduction potential of domestic goose ganders in a harem system.

    PubMed

    Gumułka, Małgorzata; Rozenboim, Israel

    2015-10-01

    In a natural mating system, the sexual behavior of birds has an important role in fertility success. Non-competitive mating system provides special conditions to study gander-goose interactions. Behavioral and physiological data from a domestic geese breeding flock was used to determine interrelationships between mating activity (MA) parameters, sperm penetration assay (SPA), plasma testosterone (T) concentration, and fertility (F). Moreover, variation in the frequency of gander-goose interactions during the intensive breeding period and the diurnal rhythm (short day - 10L:14D) were evaluated. The 2-/3-year-old ganders (n=15) and 1-/3-year-old geese (1♂:4♀) were observed. On the basis of successful copulation (SCop), groups of ganders with low (33.3%), intermediate (40%), and high (26.7%) frequency were categorized. Frequency of SCop was greater in the morning than in the afternoon. For the entire breeding period, SPA results obtained for the low frequency group were less than for the intermediate group. Fertility success for ganders from both low and intermediate groups was similar. There was a lack of association between MA, plasma T concentration, and SPA results. However, SCop was positively correlated with fertility. It is recommended that SCop be considered as a prognostic parameter for monitoring of ganders' reproductive potential. It is recommended that the sexual behavior of ganders be evaluated before the 1200h of the day. The SCop with an average frequency of 0.4-0.8 times during the day light hours appears to be associated with fertility results that are satisfactory for geese husbandry. Additionally, the SPA may be considered for identification of ganders with poor reproductive potential to facilitate the decision of changes in harem social structure during the first half of the breeding season.

  3. Mating activity and sperm penetration assay in prediction of the reproduction potential of domestic goose ganders in a harem system.

    PubMed

    Gumułka, Małgorzata; Rozenboim, Israel

    2015-10-01

    In a natural mating system, the sexual behavior of birds has an important role in fertility success. Non-competitive mating system provides special conditions to study gander-goose interactions. Behavioral and physiological data from a domestic geese breeding flock was used to determine interrelationships between mating activity (MA) parameters, sperm penetration assay (SPA), plasma testosterone (T) concentration, and fertility (F). Moreover, variation in the frequency of gander-goose interactions during the intensive breeding period and the diurnal rhythm (short day - 10L:14D) were evaluated. The 2-/3-year-old ganders (n=15) and 1-/3-year-old geese (1♂:4♀) were observed. On the basis of successful copulation (SCop), groups of ganders with low (33.3%), intermediate (40%), and high (26.7%) frequency were categorized. Frequency of SCop was greater in the morning than in the afternoon. For the entire breeding period, SPA results obtained for the low frequency group were less than for the intermediate group. Fertility success for ganders from both low and intermediate groups was similar. There was a lack of association between MA, plasma T concentration, and SPA results. However, SCop was positively correlated with fertility. It is recommended that SCop be considered as a prognostic parameter for monitoring of ganders' reproductive potential. It is recommended that the sexual behavior of ganders be evaluated before the 1200h of the day. The SCop with an average frequency of 0.4-0.8 times during the day light hours appears to be associated with fertility results that are satisfactory for geese husbandry. Additionally, the SPA may be considered for identification of ganders with poor reproductive potential to facilitate the decision of changes in harem social structure during the first half of the breeding season. PMID:26381080

  4. Cumulative Effects of In Utero Administration of Mixtures of Reproductive Toxicants that Disrupt Common Target Tissues via Diverse Mechanisms of Toxicity

    PubMed Central

    Rider, Cynthia V.; Furr, Johnathan R.; Wilson, Vickie S.; Gray, L. Earl

    2010-01-01

    Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act required the US Environmental Protection Agency to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures of chemicals to elucidate mechanisms of joint action at the systemic level with the end goal of providing a framework for assessing the cumulative effects of reproductive toxicants. Previous mixture studies conducted with antiandrogenic chemicals are reviewed briefly and two new studies are described in detail. In all binary mixture studies, rats were dosed during pregnancy with chemicals, singly or in pairs at dosage levels equivalent to approximately one half of the ED50 for hypospadias or epididymal agenesis. The binary mixtures included: androgen receptor (AR) antagonists (vinclozolin plus procymidone), phthalate esters (DBP plus BBP and DEHP plus DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone), a mixed mechanism androgen signaling disruptor (linuron) plus BBP, and two chemicals which disrupt epididymal differentiation through entirely different toxicity pathways: DBP (AR pathway) plus 2,3,7,8 TCDD (AhR pathway). We also conducted multi-component mixture studies combining several “antiandrogens” together. In the first study, seven chemicals (four pesticides and three phthalates) that elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e. AR antagonist or inhibition of androgen synthesis) were combined. In the second study, three additional phthalates were added to make a ten chemical mixture. In both the binary mixture studies and the multi-component mixture studies, chemicals that targeted male reproductive tract development displayed cumulative effects that exceeded predictions based upon a response addition model and most often were in accordance with predictions based upon dose addition models

  5. A combined approach to investigate the toxicity of an industrial landfill's leachate: Chemical analyses, risk assessment and in vitro assays

    SciTech Connect

    Baderna, D.; Maggioni, S.; Boriani, E.; Gemma, S.; Molteni, M.; Lombardo, A.; Colombo, A.; Bordonali, S.; Rotella, G.; Lodi, M.; Benfenati, E.

    2011-05-15

    Solid wastes constitute an important and emerging problem. Landfills are still one of the most common ways to manage waste disposal. The risk assessment of pollutants from landfills is becoming a major environmental issue in Europe, due to the large number of sites and to the importance of groundwater protection. Furthermore, there is lack of knowledge for the environmental, ecotoxicological and toxicological characteristics of most contaminants contained into landfill leacheates. Understanding leachate composition and creating an integrated strategy for risk assessment are currently needed to correctly face the landfill issues and to make projections on the long-term impacts of a landfill, with particular attention to the estimation of possible adverse effects on human health and ecosystem. In the present study, we propose an integrated strategy to evaluate the toxicity of the leachate using chemical analyses, risk assessment guidelines and in vitro assays using the hepatoma HepG2 cells as a model. The approach was applied on a real case study: an industrial waste landfill in northern Italy for which data on the presence of leachate contaminants are available from the last 11 years. Results from our ecological risk models suggest important toxic effects on freshwater fish and small rodents, mainly due to ammonia and inorganic constituents. Our results from in vitro data show an inhibition of cell proliferation by leachate at low doses and cytotoxic effect at high doses after 48 h of exposure. - Research highlights: {yields} We study the toxicity of leachate from a non-hazardous industrial waste landfill. {yields} We perform chemical analyses, risk assessments and in vitro assays on HepG2 cells. {yields} Risk models suggest toxic effects due to ammonia and inorganic constituents. {yields} In vitro assays show that leachate inhibits cell proliferation at low doses. {yields} Leachate can induce cytotoxic effects on HepG2 cells at high doses.

  6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ASSOCIATED WITH DISINFECTION BY-PRODUCTS OF DRINKING WATER

    EPA Science Inventory

    Over the past decade many toxicologic studies have addressed the potential for disinfection byproducts of drinking water to elicit alterations on the reproductive system and fetal development.
    The types and designs of these studies vary considerably, but in general they can ...

  7. NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF AMPHETAMINE AND METHAMPHETAMINE.

    EPA Science Inventory

    A manuscript describes the results of an expert panel meeting of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). The purpose CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects ...

  8. Incorporating "omics" in the study of reproduction and development: Virtual Tissue Models in Developmental Toxicity Research

    EPA Science Inventory

    In recent years, ground breaking research in genomic applications in the area of reproductive and developmental toxicology have been successful in linking changes in the expression of specific genes and their higher-level biological processes to effects induced by drugs or chemic...

  9. NTP-CERHR EXPERT PANEL REPORT ON REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF METHYLPHENIDATE.

    EPA Science Inventory

    A manuscript describes the results of an expert panel meeting of the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR). The purpose CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on...

  10. NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of hydroxyurea

    EPA Science Inventory

    The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound e...

  11. NTP-CERHR EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF ACRYLAMIDE

    EPA Science Inventory

    The National Toxicology Program Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) convened an expert panel in May 2004 to evaluate acrylamide. The report of the expert panel, prepared in accordance with CERHR Guidelines, provides a detailed summary of all publi...

  12. ADAPTING THE MEDAKA EMBRYO ASSAY TO A HIGH-THROUGHPUT APPROACH FOR DEVELOPMENTAL TOXICITY TESTING.

    EPA Science Inventory

    Chemical exposure during embryonic development may cause persistent effects, yet developmental toxicity data exist for very few chemicals. Current testing procedures are time consuming and costly, underlining the need for rapid and low cost screening strategies. While in vitro ...

  13. Evaluation of acute toxicity and teratogenic effects of plant growth regulators by Daphnia magna embryo assay.

    PubMed

    Wang, Kai-Sung; Lu, Chi-Yuan; Chang, Shih-Hsien

    2011-06-15

    This study selected common plant growth regulators (Atonik, Cytokinin, Ethephon, Gibberellic acid and Paclobutrazol) to investigate their biological toxicity to the waters of the important biological indicator Daphnia magna. The methods used in this study included traditional neonate acute toxicity test, new Daphnia embryo toxicity test, and teratogenic embryo test. The study concluded that the acute toxicity of the five PGRs to Daphnia neonate had EC(50) value range of 1.9-130.5 mg l(-1), while acute toxicity of PGRs on Daphnia embryo had EC(50) value range of 0.2-125 mg l(-1); the Daphnia embryos' LOEC values (0.05-48 mg l(-1)) for the five PGRs were lower than embryo EC(50) values. The toxic ratios of 48 h EC(50) (neonate)/48 h LOEC (embryo) for 5 PGRs were 19-512 times. The study found that teratogenic effects of Paclobutrazol and Cytokinin induced in embryo were higher than those of most other PGRs. Microscopic observation of the teratogenic effects showed that all 5 PGRs induced malformations of the second antenna, rostrum, Malpighian tube, sensory bristles, and tail spine as well as function loss and death.

  14. Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation.

    PubMed

    Shinde, Vaibhav; Klima, Stefanie; Sureshkumar, Perumal Srinivasan; Meganathan, Kesavan; Jagtap, Smita; Rempel, Eugen; Rahnenführer, Jörg; Hengstler, Jan Georg; Waldmann, Tanja; Hescheler, Jürgen; Leist, Marcel; Sachinidis, Agapios

    2015-06-17

    Efficient protocols to differentiate human pluripotent stem cells to various tissues in combination with -omics technologies opened up new horizons for in vitro toxicity testing of potential drugs. To provide a solid scientific basis for such assays, it will be important to gain quantitative information on the time course of development and on the underlying regulatory mechanisms by systems biology approaches. Two assays have therefore been tuned here for these requirements. In the UKK test system, human embryonic stem cells (hESC) (or other pluripotent cells) are left to spontaneously differentiate for 14 days in embryoid bodies, to allow generation of cells of all three germ layers. This system recapitulates key steps of early human embryonic development, and it can predict human-specific early embryonic toxicity/teratogenicity, if cells are exposed to chemicals during differentiation. The UKN1 test system is based on hESC differentiating to a population of neuroectodermal progenitor (NEP) cells for 6 days. This system recapitulates early neural development and predicts early developmental neurotoxicity and epigenetic changes triggered by chemicals. Both systems, in combination with transcriptome microarray studies, are suitable for identifying toxicity biomarkers. Moreover, they may be used in combination to generate input data for systems biology analysis. These test systems have advantages over the traditional toxicological studies requiring large amounts of animals. The test systems may contribute to a reduction of the costs for drug development and chemical safety evaluation. Their combination sheds light especially on compounds that may influence neurodevelopment specifically.

  15. Male reproductive toxicity of 1,3,5-trinitrobenzene in the white-footed mouse, Peromyscus leucopus

    SciTech Connect

    Dawes, S.M.

    1995-12-31

    1,3-Dinitrobenzene has been characterized as a testicular toxicant in both laboratory rats and mice. Recently, 1,3,5-trinitrobenzene (TNB) has been shown to elicit testicular toxicity in rats. Given the need for data with which to do ecological risk assessments of munitions waste and by-products (including nitrobenzenes), male white-footed mice were fed a diet containing 0, 1 50, 375, or 750 mg TNB/kg diet (20 animals per treatment) for 90 days. Testis weight and epididymis weight variables exhibited considerable variation at time of animal sacrifice and were found not to differ significantly by ANOVA or by Tukey`s Studentized Range Test (SAS, Cary, NC). Computer-assisted semen analysis (CASA) technology was applied to the measurement of sperm motility. Optimization of the CeliTrak/S{trademark} (Motion Analysis, Santa Rosa, CA) CASA system for tracking sperm heads was performed on sperm from untreated Peromyscus. Cauda epididymal sperm from treated animals were videotaped at 200 frames per second. In addition to the percentage of motile sperm, sperm head curvilinear velocity (VCL), straight-line velocity (VSL), and amplitude of head displacement (ALH) were measured. These measurements were also characterized by considerable within-treatment variation, and again no statistical significance was found. Discussion is made regarding the relevance of this feral rodent model for male reproductive toxicity assessment.

  16. Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs.

    PubMed

    Powles-Glover, Nicola; Mitchard, Terri; Stewart, Jane

    2015-06-01

    In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats. In two time-course investigations, dosed male rats were paired with undosed females after 5, 14, and 28 daily doses and again after 2 and 4 weeks off-dose. Effects on male fertility were undetectable after 5 days. After 14 days, there was no effect on pregnancy rate, but preimplantation losses were increased. Effects on both pregnancy rates and preimplantation losses were clearly detectable after 28 days, but were of lesser magnitude than after 11 weeks of dosing. Fertility recovered rapidly after dose cessation. These studies illustrate the sensitivity of a long premating dose period at revealing hazard and determining the magnitude of effect on male fertility for compounds that are intended for chronic administration and do not affect testicular histopathology. PMID:26194980

  17. How work-place conditions, environmental toxicants and lifestyle affect male reproductive function.

    PubMed

    Bonde, Jens Peter; Storgaard, Lone

    2002-10-01

    Major temporal and geographical shifts in male reproductive function is presently an issue worldwide. The hormonal disruption hypothesis has achieved considerable attention but epidemiological evidence in support of the theory is lacking. Several occupational hazards to male reproductive function are known but exposure prevalences are hardly sufficient to play a role for reduced sperm count in the general male population. Sedentary work may be an exception. Perhaps prolonged time in the sedentary position exhausts the testicular heat regulation. But so far studies addressing implications of the heat hypothesis in the general population are few. Neither change of sexual behaviour nor reduced period of sexual continence seems to be a likely explanation. Tobacco smoking and consumption of caffeine and alcoholic beverages in adulthood have a rather marginal impact on spermatogenesis and can hardly explain major shifts or regional differences in male reproductive health. However, prenatal effects following smoking during pregnancy might play a role because we have witnessed a smoking epidemic among fertile women in some countries during the second half of the twentieth century. Moreover, if genetic factors play more than a marginal role for testicular function and sperm count, pregnancy planning resulting in reduced family size during the past 100 years could possibly explain a decline in semen quality because the most fertile part of the population reproduce less while the subfertile probably continue to get a limited number of children. PMID:12270022

  18. Prediction of the developmental toxicity hazard potential of halogenated drinking water disinfection by-products tested by the in vitro hydra assay

    SciTech Connect

    Fu, L.J.; Johnson, E.M.; Newman, L.M. )

    1990-06-01

    A series of seven randomly selected potential halogenated water disinfection by-products were evaluated in vitro by the hydra assay to determine their developmental toxicity hazard potential. For six of the chemicals tested by this assay (dibromoacetonitrile; trichloroacetonitrile; 2-chlorophenol; 2,4,6-trichlorophenol; trichloroacetic acid; dichloroacetone) it was predicted that they would be generally equally toxic to both adult and embryonic mammals when studied by means of standard developmental toxicity teratology tests. However, the potential water disinfection by-product chloroacetic acid (CA) was determined to be over eight times more toxic to the embryonic developmental portion of the assay than it was to the adults. Because of this potential selectivity, CA is a high-priority item for developmental toxicity tests in pregnant mammals to confirm or refute its apparent unique developmental hazard potential and/or to establish a NOAEL by the route of most likely human exposure.

  19. Influence of sediment composition on PAH toxicity using zebrafish (Danio rerio) and Japanese medaka (Oryzias latipes) embryo-larval assays.

    PubMed

    Perrichon, Prescilla; Le Bihanic, Florane; Bustamante, Paco; Le Menach, Karyn; Budzinski, Hélène; Cachot, Jérôme; Cousin, Xavier

    2014-12-01

    Due to hydrophobic and persistent properties, polycyclic aromatic hydrocarbons (PAHs) have a high capacity to accumulate in sediment. Sediment quality criteria, for the assessment of habitat quality and risk for aquatic life, include understanding the fate and effects of PAHs. In the context of European regulation (REACH and Water Framework Directive), the first objective was to assess the influence of sediment composition on the toxicity of two model PAHs, benzo[a]pyrene and fluoranthene using 10-day zebrafish embryo-larval assay. This procedure was undertaken with an artificial sediment in order to limit natural sediment variability. A suitable sediment composition might be then validated for zebrafish and proposed in a new OECD guideline for chemicals testing. Second, a comparative study of toxicity responses from this exposure protocol was then performed using another OECD species, the Japanese medaka. The potential toxicity of both PAHs was assessed through lethal (e.g., survival, hatching success) and sublethal endpoints (e.g., abnormalities, PMR, and EROD) measured at different developmental stages, adapted to the embryonic development time of both species. Regarding effects observed for both species, a suitable artificial sediment composition for PAH toxicity testing was set at 92.5 % dry weight (dw) silica of 0.2-0.5-mm grain size, 5 % dw kaolin clay without organic matter for zebrafish, and 2.5 % dw blond peat in more only for Japanese medaka. PAH bioavailability and toxicity were highly dependent on the fraction of organic matter in sediment and of the K ow coefficients of the tested compounds. The biological responses observed were also dependent of the species under consideration. Japanese medaka embryos appeared more robust than zebrafish embryos for understanding the toxicity of PAHs following a sediment contact test, due to the longer exposure duration and lower sensitivity of sediment physical properties.

  20. Bisphenol A exposure and healing effects of Adiantum capillus-veneris L. plant extract (APE) in bisphenol A-induced reproductive toxicity in albino rats.

    PubMed

    Yousaf, Balal; Amina; Liu, Guijian; Wang, Ruwei; Qadir, Abdul; Ali, Muhammad Ubaid; Kanwal, Qudsia; Munir, Bushra; Asmatullah; Abbas, Zaigham

    2016-06-01

    The current study presents the bisphenol A exposure and the ameliorative effects of Adiantum capillus-veneris on testicular toxicity induced by bisphenol A. Adult male albino rats were divided into five groups of five animals each: A (control), B (vehicle control), C (toxic), D (protective), and E (ameliorative) were served distilled water, olive oil, bisphenol A (BPA) at 100 mg/kg body weight, A. capillus-veneris plant extract at 25 mg/kg body weight, and BPA + A. capillus-veneris, respectively. All of the doses were administered orally for 15 days, and the rats were then sacrificed. Blood samples for the testosterone assay and both testes were collected for histological examination. The body weight, paired testes weight, relative tissue weight index, Johnsen scoring of tubules, and level of serum testosterone decreased in BPA-treated rats. Similarly, histological examination of the testes in BPA-treated animals revealed a lower number of Leydig cells, an irregular basement membrane, sloughing of germinal layers, vacuolization, a lower number of spermatocytes, and debris in the lumen. However, co-administration of A. capillus-veneris with BPA increased the total antioxidative capacity (330.82 ± 22.46 μmol/mg protein) of the testes and restored the serum testosterone level (1.70 ng/ml); histological features showed restoration in the stages of spermatogenesis. Conclusively, A. capillus-veneris plant extract overcomes the estrogenic effects of BPA on the reproductive system of rats and protects rats' testes against BPA-induced injury/damage via an antioxidative mechanism that appears to be conciliated. PMID:26936479

  1. Bisphenol A exposure and healing effects of Adiantum capillus-veneris L. plant extract (APE) in bisphenol A-induced reproductive toxicity in albino rats.

    PubMed

    Yousaf, Balal; Amina; Liu, Guijian; Wang, Ruwei; Qadir, Abdul; Ali, Muhammad Ubaid; Kanwal, Qudsia; Munir, Bushra; Asmatullah; Abbas, Zaigham

    2016-06-01

    The current study presents the bisphenol A exposure and the ameliorative effects of Adiantum capillus-veneris on testicular toxicity induced by bisphenol A. Adult male albino rats were divided into five groups of five animals each: A (control), B (vehicle control), C (toxic), D (protective), and E (ameliorative) were served distilled water, olive oil, bisphenol A (BPA) at 100 mg/kg body weight, A. capillus-veneris plant extract at 25 mg/kg body weight, and BPA + A. capillus-veneris, respectively. All of the doses were administered orally for 15 days, and the rats were then sacrificed. Blood samples for the testosterone assay and both testes were collected for histological examination. The body weight, paired testes weight, relative tissue weight index, Johnsen scoring of tubules, and level of serum testosterone decreased in BPA-treated rats. Similarly, histological examination of the testes in BPA-treated animals revealed a lower number of Leydig cells, an irregular basement membrane, sloughing of germinal layers, vacuolization, a lower number of spermatocytes, and debris in the lumen. However, co-administration of A. capillus-veneris with BPA increased the total antioxidative capacity (330.82 ± 22.46 μmol/mg protein) of the testes and restored the serum testosterone level (1.70 ng/ml); histological features showed restoration in the stages of spermatogenesis. Conclusively, A. capillus-veneris plant extract overcomes the estrogenic effects of BPA on the reproductive system of rats and protects rats' testes against BPA-induced injury/damage via an antioxidative mechanism that appears to be conciliated.

  2. Predictive Modeling of Chemical Hazard by Integrating Numerical Descriptors of Chemical Structures and Short-term Toxicity Assay Data

    PubMed Central

    Rusyn, Ivan; Sedykh, Alexander; Guyton, Kathryn Z.; Tropsha, Alexander

    2012-01-01

    Quantitative structure-activity relationship (QSAR) models are widely used for in silico prediction of in vivo toxicity of drug candidates or environmental chemicals, adding value to candidate selection in drug development or in a search for less hazardous and more sustainable alternatives for chemicals in commerce. The development of traditional QSAR models is enabled by numerical descriptors representing the inherent chemical properties that can be easily defined for any number of molecules; however, traditional QSAR models often have limited predictive power due to the lack of data and complexity of in vivo endpoints. Although it has been indeed difficult to obtain experimentally derived toxicity data on a large number of chemicals in the past, the results of quantitative in vitro screening of thousands of environmental chemicals in hundreds of experimental systems are now available and continue to accumulate. In addition, publicly accessible toxicogenomics data collected on hundreds of chemicals provide another dimension of molecular information that is potentially useful for predictive toxicity modeling. These new characteristics of molecular bioactivity arising from short-term biological assays, i.e., in vitro screening and/or in vivo toxicogenomics data can now be exploited in combination with chemical structural information to generate hybrid QSAR–like quantitative models to predict human toxicity and carcinogenicity. Using several case studies, we illustrate the benefits of a hybrid modeling approach, namely improvements in the accuracy of models, enhanced interpretation of the most predictive features, and expanded applicability domain for wider chemical space coverage. PMID:22387746

  3. New toxicity determination method that uses fluorescent assay of Escherichia coli.

    PubMed

    Mariscal, A; García, A; Carnero, M; Gómez, E; Fernández-Crehuet, J

    1994-05-01

    We describe a new method that uses a fluorogenic bioassay of the beta-glucuronidase conversion of 4-methylumbelliferyl beta-D-glucuronide (MUG) to 4-methylumbelliferone to evaluate the individual toxic effects on Escherichia coli of Al3+, Cr6+, Hg2+ and Li+. This work was designed to examine the effectiveness of this method to measure the effects of five ionic concentrations of either Al3+, Cr6+, Hg2+ or Li+, on the growth of E. coli in a minimal medium that had MUG as the only source of carbon. This method was simple and fast, and its toxicity detection sensitivity was equal to, or greater than, existing bacterial bioassays. The use of the MUG substrate minimized the danger of interference by bacteria other than E. coli. Evaluations of toxicity in samples of public drinking water proved equally sensitive.

  4. A fluorescence-based hydrolytic enzyme activity assay for quantifying toxic effects of Roundup® to Daphnia magna.

    PubMed

    Ørsted, Michael; Roslev, Peter

    2015-08-01

    Daphnia magna is a widely used model organism for aquatic toxicity testing. In the present study, the authors investigated the hydrolytic enzyme activity of D. magna after exposure to toxicant stress. In vivo enzyme activity was quantified using 15 fluorogenic enzyme probes based on 4-methylumbelliferyl or 7-amino-4-methylcoumarin. Probing D. magna enzyme activity was evaluated using short-term exposure (24-48 h) to the reference chemical K2 Cr2 O7 or the herbicide formulation Roundup®. Toxicant-induced changes in hydrolytic enzyme activity were compared with changes in mobility (International Organization for Standardization standard 6341). The results showed that hydrolytic enzyme activity was quantifiable as a combination of whole body fluorescence of D. magna and the fluorescence of the surrounding water. Exposure of D. magna to lethal and sublethal concentrations of Roundup resulted in loss of whole body enzyme activity and release of cell constituents, including enzymes and DNA. Roundup caused comparable inhibition of mobility and alkaline phosphatase activity with median effective concentration values at 20 °C of 8.7 mg active ingredient (a.i.)/L to 11.7 mg a.i./L. Inhibition of alkaline phosphatase activity by Roundup was lowest at 14 °C and greater at 20 °C and 26 °C. The results suggest that the fluorescence-based hydrolytic enzyme activity assay (FLEA assay) can be used as an index of D. magna stress. Combining enzyme activity with fluorescence measurements may be applied as a simple and quantitative supplement for toxicity testing with D. magna.

  5. An in situ postexposure feeding assay with Carcinus maenas for estuarine sediment-overlying water toxicity evaluations.

    PubMed

    Moreira, Susana M; Moreira-Santos, Matilde; Guilhermino, Lúcia; Ribeiro, Rui

    2006-01-01

    This study developed and evaluated a short-term sublethal in situ toxicity assay for estuarine sediment-overlying waters, with the crab Carcinus maenas (L.) based on postexposure feeding. It consisted of a 48-h in situ exposure period followed by a short postexposure feeding period (30 min). A precise method for quantifying feeding, using the Polychaeta Hediste (Nereis) diversicolor Müller as food source, was first developed. The sensitivity of the postexposure feeding response was verified by comparing it to that of lethality, upon cadmium exposure. The influence of environmental conditions prevailing during exposure (salinity, temperature, substrate, light regime, and food availability) on postexposure feeding was also addressed. The potential of this in situ assay was then investigated by deploying organisms at ten sites, located in reference and contaminated Portuguese estuaries. Organism recovery ranged between 90% and 100% and a significant postexposure feeding depression (16.3-72.7%) was observed at all contaminated sites relatively to references. PMID:16002194

  6. Application of Targeted Functional Assays to Assess a Putative Vascular Disruption Developmental Toxicity Pathway Informed By ToxCast High-Throughput Screening Data

    EPA Science Inventory

    Chemical perturbation of vascular development is a putative toxicity pathway which may result in developmental toxicity. EPA’s high-throughput screening (HTS) ToxCast program contains assays which measure cellular signals and biological processes critical for blood vessel develop...

  7. LAND TREATMENT OF PAH-CONTAMINATED SOIL: PERFORMANCE MEASURED BY CHEMICAL AND TOXICITY ASSAYS

    EPA Science Inventory

    The performance of a soil remediation process can be determined by measuring the reduction in target soil contaminant concentrations and by assessing the treatment's ability to lower soil toxicity. Land treatment of polycyclic armomatic hydrocarbon (PAH)-contaminated soil from a ...

  8. LAND TREATMENT OF PAH-CONTAMINATED SOIL: PERFORMANCE MEASURED BY CHEMICAL AND TOXICITY ASSAYS

    EPA Science Inventory

    The performance of a soil remediation process can be determined by measuring the reduction in target soil contaminant concentrations and by assessing the treatment's ability to lower soil toxicity. Land treatment of polycyclic aromatic hydrocarbon (PAH)-contaminated soil from a ...

  9. Evaluation of toxicity equivalent calculations for use with data from in vitro aromatase inhibition assays

    EPA Science Inventory

    With growing investment in alternatives to traditional animal toxicity tests, the next generation of risk assessment must interpret new streams of data to identify hazards and protect humans and wildlife populations. If the effects of a chemical can be characterized by a battery...

  10. Gaining Acceptance for the use of in vitro Toxicity Assays and QIVIVE in Regulatory Risk Assessment

    EPA Science Inventory

    Testing strategies are anticipated to increasingly rely on in vitro data as a basis to characterize early steps or key events in toxicity at relevant dose levels in human tissues. This requires quantitative in vitro to in vivo extrapolation to characterize dose-response as a bas...

  11. Long-term reproductive and behavioral toxicity of anthracene to fish in the presence of solar ultraviolet radiation

    SciTech Connect

    Hall, A.T.; Oris, J.T.

    1994-12-31

    The long-term, low-level effects of anthracene in the presence of solar ultraviolet radiation (SUVR) were examined in the fathead minnow (Pimephales promelas). Adult fish exposed to anthracene exhibited reduced egg laying capacity, with altered oocyte maturation as a potential mechanism of action. Eggs and larvae maternally exposed to anthracene exhibited reduced hatching success and severe developmental abnormalities when incubated under SUVR. The combination of reduced egg output and developmental effects resulted in an inhibition in reproductive capacity in the range of 70--100%. Maternal transfer of anthracene to eggs was efficient; the BCF was 717 for maternally exposed eggs. However, anthracene deputation from eggs after oviposition with only maternal PAH exposure was rapid; anthracene half-life from eggs equaled 1.3 days. Exposure to anthracene under SUVR altered locomotor activity patterns in fathead minnows by inducing hyperactivity or hypoactivity during the light or dark phases of the photoperiod, respectively. Altered activity patterns indicated potential effects of anthracene on the nervous system and/or pineal gland. These alterations disrupted normal activity patterns and reproductive behaviors, and thus have major implications on a fish`s ability to survive and reproduce. Anthracene, a model phototoxic PAH, has many potential sites of toxic action, and any organism exposed to such contaminants will be an considerable SUVR-enhanced risk in the environment.

  12. Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity.

    PubMed

    Fan, A M; Steinberg, V E

    1996-02-01

    In 1987, an evaluation of the nitrate drinking water standard was performed with a primary focus on the effects of nitrate on methemoglobinemia and reproductive/developmental effects (Fan et al. (1987). Regul. Toxicol. Pharmacol. 7, 135-148). The present review presents an updated overview and evaluation of the available information on the same health effects of nitrate and nitrite with an emphasis on data not included in the previous review, which should be used as a compendium to this report. Recent epidemiologic data have suggested an association between developmental effects in offspring and the maternal ingestion of nitrate from drinking water, but a definite conclusion on the cause and effect relationship cannot be drawn. Animal experimental data have shown reproductive toxicity associated with high exposure levels to nitrate or nitrite, which are not likely to be encountered in drinking water. No teratogenic effects were observed in rats, mice, rabbits, and hamsters tested. Several cases of methemoglobinemia have been reported in infants in the United States using water containing nitrate at levels higher than the current maximum contaminant level (MCL) of 45 ppm (mg/liter) nitrate (NO3) or 10 ppm nitrate-nitrogen (nitrate-N), but none at or lower than the MCL. The uncertainties in the data base are discussed, noting that no uncertainty factor was applied in deriving the MCL in order to account for the uncertainties that exist in the data base.

  13. Lead acetate induced reproductive and paternal mediated developmental toxicity in rats.

    PubMed

    Anjum, M Reshma; Sainath, S B; Suneetha, Y; Reddy, P Sreenivasula

    2011-05-01

    Lead was administered orally to adult male rats at exposure level of 273 or 819 mg/L (0.05% or 0.15% lead acetate, respectively) for 45 days via drinking water. At the end of the exposure period, control and experimental males were mated with untreated females. Of the females mated with treated males, 73.3% in the 0.05% group and 53.33% in the 0.15% group showed copulatory plugs. Significant decrease in number of implantations and pre- and post-implantation loss was also observed in females mated with treated males. Significant decrease in the weight of the reproductive organs, reduction in epididymal sperm count, motile sperm and viable sperm were observed in lead-exposed rats indicating decreased sperm production and deteriorated sperm quality. Significant decrease in serum testosterone levels were also observed in treated rats indicating decreased steroidogenesis. The decreased serum testosterone levels and deteriorated sperm quality might be responsible for the suppressed reproduction in rats after exposure to lead.

  14. Development and validation of an OECD reproductive toxicity test guideline with the pond snail Lymnaea stagnalis (Mollusca, Gastropoda).

    PubMed

    Ducrot, Virginie; Askem, Clare; Azam, Didier; Brettschneider, Denise; Brown, Rebecca; Charles, Sandrine; Coke, Maïra; Collinet, Marc; Delignette-Muller, Marie-Laure; Forfait-Dubuc, Carole; Holbech, Henrik; Hutchinson, Thomas; Jach, Arne; Kinnberg, Karin L; Lacoste, Cédric; Le Page, Gareth; Matthiessen, Peter; Oehlmann, Jörg; Rice, Lynsey; Roberts, Edward; Ruppert, Katharina; Davis, Jessica Elphinstone; Veauvy, Clemence; Weltje, Lennart; Wortham, Ruth; Lagadic, Laurent

    2014-12-01

    The OECD test guideline development program has been extended in 2011 to establish a partial life-cycle protocol for assessing the reproductive toxicity of chemicals to several mollusk species, including the great pond snail Lymnaea stagnalis. In this paper, we summarize the standard draft protocol for a reproduction test with this species, and present inter-comparison results obtained in a 56-day prevalidation ring-test using this protocol. Seven European laboratories performed semi-static tests with cultured snails of the strain Renilys® exposed to nominal concentrations of cadmium chloride (from 53 to 608μgCdL(-1)). Cd concentrations in test solutions were analytically determined to confirm accuracy in the metal exposure concentrations in all laboratories. Physico-chemical and biological validity criteria (namely dissolved oxygen content >60% ASV, water temperature 20±1°C, control snail survival >80% and control snail fecundity >8 egg-masses per snail over the test period) were met in all laboratories which consistently demonstrated the reproductive toxicity of Cd in snails using the proposed draft protocol. Effect concentrations for fecundity after 56days were reproducible between laboratories (68

  15. Reproductive toxicity of ethylene glycol monoethyl ether in Aldh2 knockout mice.

    PubMed

    Wang, Rui-Sheng; Ohtani, Katsumi; Suda, Megumi; Kitagawa, Kyoko; Nakayama, Keiichi; Kawamoto, Toshihiro; Nakajima, Tamie

    2007-08-01

    Ethylene glycol monoethyl ether (EGEE) can cause damage to testes and sperm, and its metabolites are believed to play an important role in its toxicity. Aldehyde dehydrogenase 2 (ALDH2) is involved in the metabolism of this chemical. To investigate whether and how the enzyme affects the toxicity of EGEE, we conducted experiments comparing Aldh2 knockout mice with wild-type mice. Administration of EGEE at 100 and 600 mg/kg/day for one week did not induce any significant change in the weight and body weight ratios of testes, prostate and epididymides in either Aldh2 knockout or wild-type mice. However, motion of sperm from the spermaduct, as analyzed with a Hamilton-Thorne Sperm analyzer, was slightly decreased in the low dose group, and significantly lower in the high dose group; and the percentage of progressive sperm was also reduced in the two EGEE groups. This effect of EGEE treatment was observed in the wild-type, but not in the Aldh2 knockout mice. Sperm motion from the cauda epididymides was not affected. On the other hand, the concentration of ethoxyacetic acid, a metabolite of EGEE, in 24 h pooled urine of EGEE-treated Aldh2 knockout mice was not significantly lower than that of the wild-type mice on most days of urine sampling. These results suggest that inactivation of the ALDH2 enzyme due to gene mutation may be linked to differences in the susceptibility to EGEE-induced sperm toxicity. PMID:17878629

  16. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    PubMed

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS). PMID:25786522

  17. An F1-extended one-generation reproductive toxicity study in Crl:CD(SD) rats with 2,4-dichlorophenoxyacetic acid.

    PubMed

    Marty, Mary Sue; Neal, Barbara H; Zablotny, Carol L; Yano, Barry L; Andrus, Amanda K; Woolhiser, Michael R; Boverhof, Darrell R; Saghir, Shakil A; Perala, Adam W; Passage, Julie K; Lawson, Marie A; Bus, James S; Lamb, James C; Hammond, Larry

    2013-12-01

    2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10-12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

  18. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    PubMed

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  19. The Four Lab Study: Assessment of Reproductive Toxicity of Drinking Water Concentrates in a Multi-Generational Rat Bioassay and Human Placental Cell Cultures

    EPA Science Inventory

    To address concerns raised by epidemiological studies, a multidisciplinary team of scientists from four ORD laboratories (NHEERL, NRMRL, NERL, NCEA) conducted a multigenerational reproductive toxicity study in rats using a “whole” mixture of drinking water disinfection by-product...

  20. A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity.

    PubMed

    Blackburn, Karen; Daston, George; Fisher, Joan; Lester, Cathy; Naciff, Jorge M; Rufer, Echoleah S; Stuard, Sharon B; Woeller, Kara

    2015-07-01

    Alternative methods for full replacement of in vivo tests for systemic endpoints are not yet available. Read across methods provide a means of maximizing utilization of existing data. A limitation for the use of read across methods is that they require analogs with test data. Repeat dose data are more frequently available than are developmental and/or reproductive toxicity (DART) studies. There is historical precedent for using repeat dose data in combination with a database uncertainty factor (UF) to account for missing DART data. We propose that use of the DART decision tree (Wu et al., 2013), in combination with a database UF, provides a path forward for DART data gap filling that better utilizes all of the data. Our hypothesis was that chemical structures identified by the DART tree as being related to structures with known DART toxicity would potentially have lower DART NOAELs compared to their respective repeat dose NOAELs than structures that lacked this association. Our analysis supports this hypothesis and as a result also supports that the DART decision tree can be used as part of weight of evidence in the selection of an appropriate DART database UF factor.

  1. Interlaboratory study of precision: Hyalella azteca and Chironomus tentans freshwater sediment toxicity assays

    USGS Publications Warehouse

    Burton, G.A.; Norberg-King, T. J.; Ingersoll, C.G.; Benoit, D.A.; Ankley, G.T.; Winger, P.V.; Kubitz, J.; Lazorchak, J.M.; Smith, M.E.; Greer, E.; Dwyer, F.J.; Call, D.J.; Day, K.E.; Kennedy, P.; Stinson, M.

    1996-01-01

    Standard 10-d whole-sediment toxicity test methods have recently been developed by the U.S. Environmental Protection Agency (EPA) for the amphipod Hyalella azteca and the midge Chironomus tentans. An interlaboratory evaluation of method precision was performed using a group of seven to 10 laboratories, representing government, academia, and environmental consulting firms. The test methods followed the EPA protocols for 4-d water-only reference toxicant (KCl) testing (static exposure) and for 10-d whole-sediment testing. Test sediments included control sediment, two copper-containing sediments, and a sediment contaminated primarily with polycyclic aromatic hydrocarbons. Reference toxicant tests resulted in H. azteca and C. tentans median lethal concentration (LC50) values with coefficents of variation (CVs) of 15.8 and 19.6%, respectively. Whole sediments which were moderately contaminated provided the best estimates of precision using CVs. Hyalella azteca and C. tentans tests in moderately contaminated sediments exhibited LC50 CVs of 38.9 and 13.5%, respectively. The CV for C. tentans growth was 31.9%. Only 3% (1 of 28) of samples exceeded acceptable interlaboratory precision limits for the H. azteca survival tests. No samples exceeded the intralaboratory precision limit for H. azteca or C. tentans survival tests. However, intralaboratory variability limits for C. tentans growth were exceeded by 80 and 100% of the laboratories for a moderately toxic and control sample, respectively. Interlaboratory variability limits for C. tentans survival were not exceeded by any laboratory. The results showed these test methods to have relatively low variance and acceptable levels of precision in interlaboratory comparisons.

  2. Evaluation of the toxicity and teratogenity of six commercial textile dyes using the frog embryo teratogenesis assay-Xenopus.

    PubMed

    Birhanli, Ayse; Ozmen, Murat

    2005-01-01

    Potential developmental toxicities of six different textile dyes were evaluated using the frog embryo teratogenesis assay-Xenopus (FETAX). Xenopus laevis embryos were exposed to astrazon red FBL, astrazon blue FGRL, remazol red RR, remazol turquoise blue G-A, cibacron red FN-3G, and cibacron blue FN-R from stage 8 to 11 for a 96-h exposure period in static renewal test conditions. A minimum of 17 concentration-response tests were performed with tested dyes, excluding a control group for each dye. Median lethal concentration (LC50), malformation (EC50), non observed adverse effect concentration (NOAEC), and lowest observed adverse effect concentration (LOAEC) were calculated. Also, teratogenic index (TI), minimum concentration to inhibit growth (MCIG), and MCIG/LC50 values were determined for each of the tested dyes. Characteristic abnormalities induced by a given test material were determined by the relationship between concentration and dye in the study. Results from these studies suggested that each tested dye is teratogenic for X. laevis embryos. The lowest LC50 was determined for astrazon red exposure corresponding to a value of 4.73 mg/L. The LC50 value was similar for this dye and astrazon blue; the highest TI was calculated for astrazon blue exposure. Tests with X. laevis indicated that each of the tested compounds possessed teratogenic potential with varying degrees of potency: astrazon blue FGRL > remazol turquoise blue G-A > astrazon red FBL > cibacron blue FN-R > cibacron red FN-3G > remazol red RR. Different types of malformations occurred in the embryos, depending on concentration and dye. From these results, we can suggest that astrazon blue is the most toxic compound, but that the others are also highly toxic and teratogenic substances for X. laevis embryos. Results of the study confirmed that the FETAX assay can be useful in an integrated biological hazard assesment for the preliminary screening of textile dye stuff.

  3. Label-free detection of protein molecules secreted from an organ-on-a-chip model for drug toxicity assays

    NASA Astrophysics Data System (ADS)

    Morales, Andres W.; Zhang, Yu S.; Aleman, Julio; Alerasool, Parissa; Dokmeci, Mehmet R.; Khademhosseini, Ali; Ye, Jing Yong

    2016-03-01

    Clinical attrition is about 30% from failure of drug candidates due to toxic side effects, increasing the drug development costs significantly and slowing down the drug discovery process. This partly originates from the fact that the animal models do not accurately represent human physiology. Hence there is a clear unmet need for developing drug toxicity assays using human-based models that are complementary to traditional animal models before starting expensive clinical trials. Organ-on-a-chip techniques developed in recent years have generated a variety of human organ models mimicking different human physiological conditions. However, it is extremely challenging to monitor the transient and long-term response of the organ models to drug treatments during drug toxicity tests. First, when an organ-on-a-chip model interacts with drugs, a certain amount of protein molecules may be released into the medium due to certain drug effects, but the amount of the protein molecules is limited, since the organ tissue grown inside microfluidic bioreactors have minimum volume. Second, traditional fluorescence techniques cannot be utilized for real-time monitoring of the concentration of the protein molecules, because the protein molecules are continuously secreted from the tissue and it is practically impossible to achieve fluorescence labeling in the dynamically changing environment. Therefore, direct measurements of the secreted protein molecules with a label-free approach is strongly desired for organs-on-a-chip applications. In this paper, we report the development of a photonic crystal-based biosensor for label-free assays of secreted protein molecules from a liver-on-a-chip model. Ultrahigh detection sensitivity and specificity have been demonstrated.

  4. Long-Term Administration of Artesunate Induces Reproductive Toxicity in Male Rats

    PubMed Central

    Olumide, Stephen Akinsomisoye; Raji, Yinusa

    2011-01-01

    Background Artesunate is commonly used in malaria therapy. Many antimalarial drugs have been associated with male reproductive dysfunction. The effect of artesunate on male reproductive activities was studied using in–vivo and in-vitro experimental models. Methods Adult male rats (n=6) were orally given artesunate (2.9 mg/kg body weight) on daily basis for five days. Artesunate (2.9 mg/kg body weight) was administered to another group of rats daily for six weeks, while there was a recovery group of rats too. The control animals received the vehicle only. At the end of the treatment, sperm characteristics, serum follicle stimulating hormone, luteinizing hormone and testosterone levels, testicular and epididymal histology and fertility were assessed. Cultured Sertoli cells were treated with 0.3 µM to 10 µM artesunate for five days after which Sertoli cell viability, double-stranded deoxyribonucleic acid (ds-DNA) integrity and genetic expression of Glial cell line-derived neurotrophic factor (GDNF) and transferrin were assessed. The data were analyzed using Graphpad Instat Statistical software. A probability value of p <0.05 was considered significant. Results Artesunate did not cause any significant effects in short-term administration but significantly reduced the aforesaid parameters in long-term administration. There were visible lesions in the testicular and epididymal histological studies, although fertility was not significantly reduced. These changes were restored in the recovery experiment. In-vitro studies showed dose and duration dependent changes in Sertoli cell viability and ds-DNA integrity. However, transferrin and GDNF gene expressions were normal. Conclusion The results suggest that long-term administration of artesunate could induce reversible infertility in rats which may act via distortion of blood–testis barrier formed by Sertoli cells. PMID:23926511

  5. Toxicity effect of dichlorvos on loach (Misgurnus anguillicaudatus) assessed by micronucleus test, hepatase activity analysis and comet assay.

    PubMed

    Nan, Ping; Yan, Shuaiguo; Li, Li; Chen, Jianjun; Du, Qiyan; Chang, Zhongjie

    2015-06-01

    Pesticides and other chemicals at environmental concentrations often have detrimental effects. Many aquatic species are particularly threatened because of their susceptibility and also because water environment are often polluted. This study preliminarily evaluated the toxicity effect of dichlorvos (DDVP) on loach (Misgurnus anguillicaudatus) using the methods of micronucleus (MN) test, hepatase activity and comet assay. The tested results showed that indeed very little DDVP had strong toxicity effect on loach and its 50% lethal concentration (LC50) at 24 h, 48 h and 96 h was 8.38 μg l(-1), 7.168 μg l(-1) and 6.411 μg l(-1), respectively; The glutamic-pyruvic transaminase (GPT) and glutamic-oxalacetic transaminase (GOT) activity of loach liver decreased; meanwhile, the GPT and GOT activity of loach serum, the MN rate (‰) and three comet parameters of tested fish increased with the increase in the treatment concentration and treatment time of DDVP, and there was significant difference between control group and each treatment group (p < 0.05). These results suggested that DDVP residues might become toxic chemical contaminant in environment and would threaten aquatic and other organisms.

  6. Relative developmental toxicity potencies of retinoids in the embryonic stem cell test compared with their relative potencies in in vivo and two other in vitro assays for developmental toxicity.

    PubMed

    Louisse, Jochem; Gönen, Süleyman; Rietjens, Ivonne M C M; Verwei, Miriam

    2011-05-30

    The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.

  7. Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set

    SciTech Connect

    Makris, Susan L.; Euling, Susan Y.; Gray, L. Earl; Benson, Robert; Foster, Paul M.D.

    2013-09-15

    A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts led to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data.

  8. Toxic Effect of Cadmium Assay in Contaminated Soil Earthworm Cell Using Modified Sensor

    PubMed Central

    Kyung, Lee; Kim, Chae Hwa; Seo, Roma; Lee, Soo Youn; Kim, Lina; Chae, Su min; Choi, Sung Wook; Kim, Ji Yoon

    2015-01-01

    A voltammetric toxic metal of cadmium detection was studied using a fluorine doped graphite pencil electrode (FPE) in a seawater electrolyte. In this study, square wave (SW) stripping and chronoamerometry were used for determination of Cd(II) in seawater. Affordable pencils and an auxiliary electrode were used as reference. All experiments in this study could be performed at reasonable cost by using graphite pencil. The application was performed on the tissue of contaminated soil earthworm. The results show that the method can be applicable for vegetables and in vivo fluid or medicinal diagnosis. PMID:26191388

  9. Reproductive toxicity of the industrial solvent 2-ethoxyethanol in rats and interactive effects of ethanol.

    PubMed Central

    Nelson, B K; Brightwell, W S; Setzer, J V; O'Donohue, T L

    1984-01-01

    The solvent, 2-ethoxyethanol, induced complete embryomortality in pregnant rats exposed to three times the current Federal permissible exposure limit (PEL). Following exposure to ethoxyethanol at a concentration only one-half the current PEL, the offspring evidenced behavioral and neurochemical deviations from controls. Subsequent studies found that ingestion of ethanol with concomitant inhalation of ethoxyethanol vapors early in pregnancy appeared to reduce the number of both behavioral and neurochemical deviations found for ethoxyethanol. In contrast, the concomitant exposure to ethanol and ethoxyethanol later in gestation potentiated the behavioral and neurochemical effects of ethoxyethanol. This research indicates that the industrial solvent 2-ethoxyethanol presents an occupational reproductive hazard and raises the issue of the importance of an interaction of social habits with occupational exposure to such hazards. The results would suggest that occupational physicians should advise pregnant workers in the chemical industry of the adverse effects of ethanol during pregnancy and of the possible interactions with other chemicals and should encourage them to be especially cautious with ethanol consumption since they may be at greater risk. PMID:6499811

  10. Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid.

    PubMed

    Stine, Cynthia B; Reimschuessel, Renate; Keltner, Zachary; Nochetto, Cristina B; Black, Thomas; Olejnik, Nicholas; Scott, Michael; Bandele, Omari; Nemser, Sarah M; Tkachenko, Andriy; Evans, Eric R; Crosby, Tina C; Ceric, Olgica; Ferguson, Martine; Yakes, Betsy J; Sprando, Robert

    2014-06-01

    The industrial chemical melamine was used in 2007 and 2008 to raise the apparent protein content in pet feed and watered down milk, respectively. Because humans may be exposed to melamine via several different routes into the human diet as well as deliberate contamination, this study was designed to characterize the effect of high dose melamine or cyanuric acid oral exposure on the pregnant animal and developing fetus, including placental transfer. Clear rectangular crystals formed following a single triazine exposure which is a different morphology from the golden spherulites caused by combined exposure or the calculi formed when melamine combines with endogenous uric acid. Crystal nephropathy, regardless of cause, induces renal failure which in turn has reproductive sequelae. Specifically, melamine alone-treated dams had increased numbers of early and late fetal deaths compared to controls or cyanuric acid-treated dams. As melamine was found in the amniotic fluid, this study confirms transfer of melamine from mammalian mother to fetus and our study provides evidence that cyanuric acid also appears in the amniotic fluid if mothers are exposed to high doses.

  11. High-Content Assay Multiplexing for Toxicity Screening in Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Hepatocytes.

    PubMed

    Grimm, Fabian Alexander; Iwata, Yasuhiro; Sirenko, Oksana; Bittner, Michael; Rusyn, Ivan

    2015-11-01

    Cell-based high-content screening (HCS) assays have become an increasingly attractive alternative to traditional in vitro and in vivo testing in pharmaceutical drug development and toxicological safety assessment. The time- and cost-effectiveness of HCS assays, combined with the organotypic nature of human induced pluripotent stem cell (iPSC)-derived cells, open new opportunities to employ physiologically relevant in vitro model systems to improve screening for potential chemical hazards. In this study, we used two human iPSC types, cardiomyocytes and hepatocytes, to test various high-content and molecular assay combinations for their applicability in a multiparametric screening format. Effects on cardiomyocyte beat frequency were characterized by calcium flux measurements for up to 90 min. Subsequent correlation with intracellular cAMP levels was used to determine if the effects on cardiac physiology were G-protein-coupled receptor dependent. In addition, we utilized high-content cell imaging to simultaneously determine cell viability, mitochondrial integrity, and reactive oxygen species (ROS) formation in both cell types. Kinetic analysis indicated that ROS formation is best detectable 30 min following initial treatment, whereas cytotoxic effects were most stable after 24 h. For hepatocytes, high-content imaging was also used to evaluate cytotoxicity and cytoskeletal integrity, as well as mitochondrial integrity and the potential for lipid accumulation. Lipid accumulation, a marker for hepatic steatosis, was most reliably detected 48 h following treatment with test compounds. Overall, our results demonstrate how a compendium of assays can be utilized for quantitative screening of chemical effects in iPSC cardiomyocytes and hepatocytes and enable rapid and cost-efficient multidimensional biological profiling of toxicity. PMID:26539751

  12. High-Content Assay Multiplexing for Toxicity Screening in Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Hepatocytes

    PubMed Central

    Grimm, Fabian Alexander; Iwata, Yasuhiro; Sirenko, Oksana; Bittner, Michael

    2015-01-01

    Abstract Cell-based high-content screening (HCS) assays have become an increasingly attractive alternative to traditional in vitro and in vivo testing in pharmaceutical drug development and toxicological safety assessment. The time- and cost-effectiveness of HCS assays, combined with the organotypic nature of human induced pluripotent stem cell (iPSC)-derived cells, open new opportunities to employ physiologically relevant in vitro model systems to improve screening for potential chemical hazards. In this study, we used two human iPSC types, cardiomyocytes and hepatocytes, to test various high-content and molecular assay combinations for their applicability in a multiparametric screening format. Effects on cardiomyocyte beat frequency were characterized by calcium flux measurements for up to 90 min. Subsequent correlation with intracellular cAMP levels was used to determine if the effects on cardiac physiology were G-protein-coupled receptor dependent. In addition, we utilized high-content cell imaging to simultaneously determine cell viability, mitochondrial integrity, and reactive oxygen species (ROS) formation in both cell types. Kinetic analysis indicated that ROS formation is best detectable 30 min following initial treatment, whereas cytotoxic effects were most stable after 24 h. For hepatocytes, high-content imaging was also used to evaluate cytotoxicity and cytoskeletal integrity, as well as mitochondrial integrity and the potential for lipid accumulation. Lipid accumulation, a marker for hepatic steatosis, was most reliably detected 48 h following treatment with test compounds. Overall, our results demonstrate how a compendium of assays can be utilized for quantitative screening of chemical effects in iPSC cardiomyocytes and hepatocytes and enable rapid and cost-efficient multidimensional biological profiling of toxicity. PMID:26539751

  13. In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity.

    PubMed

    Boisvert, Annie; Jones, Steven; Issop, Leeyah; Erythropel, Hanno C; Papadopoulos, Vassilios; Culty, Martine

    2016-10-01

    Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health.

  14. In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity.

    PubMed

    Boisvert, Annie; Jones, Steven; Issop, Leeyah; Erythropel, Hanno C; Papadopoulos, Vassilios; Culty, Martine

    2016-10-01

    Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health. PMID:27423704

  15. Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using lindane.

    PubMed

    Matsuura, Ikuo; Saitoh, Tetsuji; Tani, Einosuke; Wako, Yumi; Iwata, Hiroshi; Toyota, Naoto; Ishizuka, Yoshihito; Namiki, Masato; Hoshino, Nobuhito; Tsuchitani, Minoru; Ikeda, Yasuo

    2005-12-01

    A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases

  16. Evaluation of the developmental and reproductive toxicity of methoxychlor using an anuran (Xenopus tropicalis) chronic exposure model.

    PubMed

    Fort, Douglas J; Thomas, John H; Rogers, Robert L; Noll, Andra; Spaulding, Clinton D; Guiney, Patrick D; Weeks, John A

    2004-10-01

    The chronic toxicity of methoxychlor to the South African clawed frog, Xenopus (Silurana) tropicalis, was evaluated using a life cycle approach. The chronic exposure period ranged from mid-cell blastula stage [NF (Nieuwkoop and Faber, 1994) stage 8] to 90 days of exposure, during which time the organisms generally completed metamorphosis and emerged as juvenile frogs. Methoxychlor concentrations ranged from 1 to 100 micrograms/l. Methoxychlor concentrations >10 micrograms/l caused delayed development. Organisms exposed to 10 micrograms/l methoxychlor for 30 days showed enlarged thyroid glands with follicular hyperplasia. No increase in mortality or external malformation was observed at any of the test concentrations during early embryo-larval development (NF stage 8 to NF stage 46; ca. 2 days exposure). A concentration-dependent increase in external malformations and internal abnormalities of the liver and gonads were noted after 90 days of exposure, however. Skewing of the sex ratio toward the female gender decreased ovary weight and number of oocytes, and increased oocyte immaturity and necrosis were noted at methoxychlor concentrations of 100 micrograms/l. Reductions in testis weight and sperm cell count were also detected at 100 micrograms/l methoxychlor. Results from these studies suggested that methoxychlor was capable of altering the rate of larval development, but did not adversely affect early embryo-larval development (2 days of exposure) as manifested in external malformations. Internal malformations, increases in the ratio of phenotypic females, were induced by chronic methoxychlor exposure. In addition, reproductive endpoints, most notably in the female specimens, were adversely affected by methoxychlor exposure. These studies add to the standardization and validation of a useful amphibian test methods capable of evaluating both reproductive and developmental effects of potential endocrine disrupting chemicals over a life cycle exposure.

  17. Assessment of fertility and reproductive toxicity in adult female mice after long-term exposure to Pueraria mirifica herb.

    PubMed

    Jaroenporn, Sukanya; Malaivijitnond, Suchinda; Wattanasirmkit, Kingkaew; Watanabe, Gen; Taya, Kazuyoshi; Cherdshewasart, Wichai

    2007-10-01

    The present study investigated the effects of long-term administration of Pueraria mirifica (PM) at non-toxic doses on the ovarian function and fertility of adult female mice based on evaluation of hematological and biochemical parameters. Female mice were divided into 4 groups (36 mice/group). Groups 1-3 were orally treated with a dose of 0 (PM-0), 10 (PM-10) or 100 mg/kg BW/day PM (PM-100), and group 4 was subcutaneously injected with 200 mug/kg BW/day of synthetic estrogen diethylstilbestrol (DES). The treatment schedule was separated into treatment and post-treatment periods. The duration of each period was 8 weeks. The PM-10 mice exhibited regular estrous cycles, while the PM-100 and DES treatments induced prolonged estrous cycles. Although no changes were observed in the uterus and ovary weights of the mice after the PM-100 and DES treatments, hyperplasia of the uterine endothelium and a decrease in the number of growing ovarian follicles were detected. The changes in the ovarian histologies of the PM-100 and DES mice were related to reductions in the levels of LH and FSH, which subsequently caused a decrease in mating efficiency. Once the PM mice were able to copulate, they were capable of successfully becoming pregnant and mothering offspring. No abnormalities were observed in the external morphologies and reproductive organ weights of the 50-day-old offspring. In conclusion, our results suggest that long-term exposure to 100 mg/kg BW of PM has adverse effects on the mating efficiency and reproduction of adult female mice and that administration of 10 mg/kg BW of PM does not induce any changes in the hypothalamic-pituitary-ovarian-uterine axis.

  18. Reproductive toxicity evaluation of the dental resin monomer triethylene glycol dimethacrylate (CASRN 109-16-0) in mice.

    PubMed

    Moilanen, Lori H; Dahms, Janell K; Hoberman, Alan M

    2014-01-01

    The reproductive toxicity potential of the resin monomer triethylene glycol dimethacrylate (TEGDMA; Chemical Abstracts Service Registry Number 109-16-0) was investigated in male and female Crl:CD1(ICR) mice, 4 dosage groups, 25 mice/sex/group. Formulations of TEGDMA (0, 0.01, 0.1, or 1.0 mg/kg/d) in reverse osmosis-processed deionized water were intubated once daily beginning 28 days before cohabitation and continuing through mating (males) or through gestation day 17 (females). The following parameters were evaluated: viability, clinical signs, body weights, estrous cyclicity, necropsy observations, organ weights, sperm concentration/motility/morphology, cesarean-sectioning and litter observations, and histopathological evaluation of select tissues. No deaths or clinical signs related to TEGDMA occurred. No significant changes in male and female body weights and body weight gains were recorded for any of the administered dosages of TEGMDA. All mating and fertility parameters and all litter and fetal data were considered to be unaffected by dosages of TEGMDA as high as 1 mg/kg/d. Gross or histopathologic tissue changes attributable to the test article were not observed. Reproductive and developmental no observed adverse effect levels (NOAELs) for TEGMDA were 1.0 mg/kg/d, the highest dose tested. Comparison of conservatively estimated TEGDMA exposures from dental treatments to the NOAEL of 1.0 mg/kg/d identified in this study indicates margins of exposure of at least 120- to 3000-fold depending on the exposure scenario. The results of this study support the continued safe use of TEGDMA in polymeric dental products applied according to the manufacturers' instructions.

  19. High Specificity of a Quantitative PCR Assay Targeting a Saxitoxin Gene for Monitoring Toxic Algae Associated with Paralytic Shellfish Toxins in the Yellow Sea

    PubMed Central

    Gao, Yan; Murray, Shauna A.; Chen, Jian-Hua; Kang, Zhen-Jun; Zhang, Qing-Chun; Kong, Fan-Zhou; Zhou, Ming-Jiang

    2015-01-01

    The identification of core genes involved in the biosynthesis of saxitoxin (STX) offers a great opportunity to detect toxic algae associated with paralytic shellfish toxins (PST). In the Yellow Sea (YS) in China, both toxic and nontoxic Alexandrium species are present, which makes it a difficult issue to specifically monitor PST-producing toxic algae. In this study, a quantitative PCR (qPCR) assay targeting sxtA4, a domain in the sxt gene cluster that encodes a unique enzyme involved in STX biosynthesis, was applied to analyze samples collected from the YS in spring of 2012. The abundance of two toxic species within the Alexandrium tamarense species complex, i.e., A. fundyense and A. pacificum, was also determined with TaqMan-based qPCR assays, and PSTs in net-concentrated phytoplankton samples were analyzed with high-performance liquid chromatography coupled with a fluorescence detector. It was found that the distribution of the sxtA4 gene in the YS was consistent with the toxic algae and PSTs, and the quantitation results of sxtA4 correlated well with the abundance of the two toxic species (r = 0.857). These results suggested that the two toxic species were major PST producers during the sampling season and that sxtA-based qPCR is a promising method to detect toxic algae associated with PSTs in the YS. The correlation between PST levels and sxtA-based qPCR results, however, was less significant (r = 0.552), implying that sxtA-based qPCR is not accurate enough to reflect the toxicity of PST-producing toxic algae. The combination of an sxtA-based qPCR assay and chemical means might be a promising method for monitoring toxic algal blooms. PMID:26231652

  20. High Specificity of a Quantitative PCR Assay Targeting a Saxitoxin Gene for Monitoring Toxic Algae Associated with Paralytic Shellfish Toxins in the Yellow Sea.

    PubMed

    Gao, Yan; Yu, Ren-Cheng; Murray, Shauna A; Chen, Jian-Hua; Kang, Zhen-Jun; Zhang, Qing-Chun; Kong, Fan-Zhou; Zhou, Ming-Jiang

    2015-10-01

    The identification of core genes involved in the biosynthesis of saxitoxin (STX) offers a great opportunity to detect toxic algae associated with paralytic shellfish toxins (PST). In the Yellow Sea (YS) in China, both toxic and nontoxic Alexandrium species are present, which makes it a difficult issue to specifically monitor PST-producing toxic algae. In this study, a quantitative PCR (qPCR) assay targeting sxtA4, a domain in the sxt gene cluster that encodes a unique enzyme involved in STX biosynthesis, was applied to analyze samples collected from the YS in spring of 2012. The abundance of two toxic species within the Alexandrium tamarense species complex, i.e., A. fundyense and A. pacificum, was also determined with TaqMan-based qPCR assays, and PSTs in net-concentrated phytoplankton samples were analyzed with high-performance liquid chromatography coupled with a fluorescence detector. It was found that the distribution of the sxtA4 gene in the YS was consistent with the toxic algae and PSTs, and the quantitation results of sxtA4 correlated well with the abundance of the two toxic species (r=0.857). These results suggested that the two toxic species were major PST producers during the sampling season and that sxtA-based qPCR is a promising method to detect toxic algae associated with PSTs in the YS. The correlation between PST levels and sxtA-based qPCR results, however, was less significant (r=0.552), implying that sxtA-based qPCR is not accurate enough to reflect the toxicity of PST-producing toxic algae. The combination of an sxtA-based qPCR assay and chemical means might be a promising method for monitoring toxic algal blooms.

  1. High Specificity of a Quantitative PCR Assay Targeting a Saxitoxin Gene for Monitoring Toxic Algae Associated with Paralytic Shellfish Toxins in the Yellow Sea.

    PubMed

    Gao, Yan; Yu, Ren-Cheng; Murray, Shauna A; Chen, Jian-Hua; Kang, Zhen-Jun; Zhang, Qing-Chun; Kong, Fan-Zhou; Zhou, Ming-Jiang

    2015-10-01

    The identification of core genes involved in the biosynthesis of saxitoxin (STX) offers a great opportunity to detect toxic algae associated with paralytic shellfish toxins (PST). In the Yellow Sea (YS) in China, both toxic and nontoxic Alexandrium species are present, which makes it a difficult issue to specifically monitor PST-producing toxic algae. In this study, a quantitative PCR (qPCR) assay targeting sxtA4, a domain in the sxt gene cluster that encodes a unique enzyme involved in STX biosynthesis, was applied to analyze samples collected from the YS in spring of 2012. The abundance of two toxic species within the Alexandrium tamarense species complex, i.e., A. fundyense and A. pacificum, was also determined with TaqMan-based qPCR assays, and PSTs in net-concentrated phytoplankton samples were analyzed with high-performance liquid chromatography coupled with a fluorescence detector. It was found that the distribution of the sxtA4 gene in the YS was consistent with the toxic algae and PSTs, and the quantitation results of sxtA4 correlated well with the abundance of the two toxic species (r=0.857). These results suggested that the two toxic species were major PST producers during the sampling season and that sxtA-based qPCR is a promising method to detect toxic algae associated with PSTs in the YS. The correlation between PST levels and sxtA-based qPCR results, however, was less significant (r=0.552), implying that sxtA-based qPCR is not accurate enough to reflect the toxicity of PST-producing toxic algae. The combination of an sxtA-based qPCR assay and chemical means might be a promising method for monitoring toxic algal blooms. PMID:26231652

  2. Regulatory Forum opinion piece: New testing paradigms for reproductive and developmental toxicity--the NTP modified one generation study and OECD 443.

    PubMed

    Foster, Paul M D

    2014-12-01

    The National Toxicology Program (NTP) has developed a new flexible study design, termed the modified one generation (MOG) reproduction study. The MOG study will encompass measurements of developmental and reproductive toxicity parameters as well as enable the setting of appropriate dose levels for a cancer bioassay through evaluation of target organ toxicity that is based on test article exposure that starts during gestation. This study design is compared and contrasted with the new Organization for Economic Co-operation and Development (OECD) 443 test guideline, the extended one generation reproduction study. The MOG study has a number of advantages, with a focus on F 1 animals, the generation of adequately powered, robust data sets that include both pre and postnatal developmental toxicity information, and the measurement of effects on reproductive structure and function in the same animals. This new study design does not employ the use of internal triggers in the design structure for the use of animals already on test and is also consistent with the principles of the 3R's.

  3. Development of screening assays for nanoparticle toxicity assessment in human blood: preliminary studies with charged Au nanoparticles.

    PubMed

    Love, Sara A; Thompson, John W; Haynes, Christy L

    2012-09-01

    As nanoparticles have found increased use in both consumer and medical applications, corresponding increases in possible exposure to humans necessitate studies examining the impacts of these nanomaterials in biological systems. This article examines the effects of approximately 30-nm-diameter gold nanoparticles, with positively and negatively charged surface coatings in human blood. Here, we study the exposure effects, with up to 72 h of exposure to 5, 15, 25 and 50 µg/ml nanoparticles on hemolysis, reactive oxygen species (ROS) generation and platelet aggregation in subsets of cells from human blood. Assessing viability with hemolysis, results show significant changes in a concentration-dependent fashion. Rates of ROS generation were investigated using the dichlorofluorscein diacetate-based assay as ROS generation is a commonly suspected mechanism of nanoparticle toxicity; herein, ROS was not a significant factor. Optical monitoring of platelet aggregation revealed that none of the examined nanoparticles induced aggregation upon short-term exposure.

  4. Kolaviron, a biflavonoid complex from Garcinia kola seeds, ameliorates ethanol-induced reproductive toxicity in male wistar rats.

    PubMed

    Adaramoye, Oluwatosin A; Arisekola, Muritala

    2013-01-01

    In previous studies, we established that kolaviron (KV) (a biflavonoid from Garcinia kola seeds) elicited anti-oxidative and hepatoprotective effects in Wistar rats chronically treated with ethanol. The present study investigates the possible ameliorative effect of KV against ethanol-induced reproductive toxicity in male Wistar rats. Twenty-eight rats were randomly divided into four groups of seven animals each; Group 1 (control) was administered corn oil, group 2 was given 45%v/v ethanol at 3g/kg body weight, group 3 received ethanol and KV (200mg/kg) simultaneously and group 4 received KV alone. All drugs were given daily by oral gavage for 21 consecutive days. Ethanol treatment resulted in a significant (p<0.05) decrease in relative weight of testis of the animals. In the spermatozoa, ethanol intoxication resulted in 54%, 21% and 38% decreases in testicular protein content, sperm motility and count, respectively. In addition, ethanol administration enhanced lipid peroxidation (LPO) process assessed by the accumulation of malondialdehyde (MDA) in the testis. Precisely, MDA level was increased by 121% in the testis of ethanol-treated rats relative to the control. Furthermore, levels of testicular glutathione and activities of testicular antioxidant enzymes such as superoxide dismutase and catalase were significantly (p<0.05) reduced in ethanol-treated rats. Histopathology showed extensive degenerative changes in seminiferous tubules and defoliation of spermatocytes in testis of ethanol-treated rats. Interestingly, co-administration of KV with ethanol led to almost complete inhibition of testicular LPO thereby enhancing antioxidant status of the testis. Overall, KV ameliorates ethanol-induced toxic assault on testis and improves seminal qualities of the rats. PMID:23955400

  5. The interactive effects of cytoskeleton disruption and mitochondria dysfunction lead to reproductive toxicity induced by microcystin-LR.

    PubMed

    Chen, Liang; Zhang, Xuezhen; Zhou, Wenshan; Qiao, Qin; Liang, Hualei; Li, Guangyu; Wang, Jianghua; Cai, Fei

    2013-01-01

    The worldwide occurrence of cyanobacterial blooms evokes profound concerns. The presence of microcystins (MCs) in waters and aquatic food increases the risk to human health. Some recent studies have suggested that the gonad is the second most important target organ of MCs, however, the potential toxicity mechanisms are still unclear. For a better understanding of reproductive toxicity of MCs on animals, we conducted the present experimental investigation. Male rats were intraperitoneally injected with MC-LR for 50 d with the doses of 1 and 10 µg/kg body weight per day. After prolonged exposure to MC-LR, the testes index significantly decreased in 10 µg/kg group. Light microscope observation indicated that the space between the seminiferous tubules was increased. Ultrastructural observation showed some histopathological characteristics, including cytoplasmic shrinkage, cell membrane blebbing, swollen mitochondria and deformed nucleus. Using Q-PCR methods, the transcriptional levels of some cytoskeletal and mitochondrial genes were determined. MC-LR exposure affected the homeostasis of the expression of cytoskeletal genes, causing possible dysfunction of cytoskeleton assembly. In MC-LR treatments, all the 8 mitochondrial genes related with oxidative phosphorylation (OXPHOS) significantly increased. The reactive oxygen species (ROS) level significantly increased in 10 µg/kg group. The mitochondria swelling and DNA damage were also determined in 10 µg/kg group. Hormone levels of testis significantly changed. The present study verified that both cytoskeleton disruption possibly due to cytoskeletal reorganization or depolymerization and mitochondria dysfunction interact with each other through inducing of reactive oxygen species and oxidative phosphorylation, and jointly result in testis impairment after exposure to MC-LR.

  6. Reversibility of the toxic effect of lead on the male reproductive axis.

    PubMed

    Sokol, R Z

    1989-01-01

    The present study investigates the reversibility of the toxic effects of lead on the hypothalamic-pituitary-testicular axis in prepubertal and pubertal male rats. Male Wistar rats, 27 days and 52 days old, were given ad libitum access to 0.0% or 0.6% lead acetate containing water. Groups of animals were sacrificed at the end of 30 days of exposure or after a 30-day recovery period. Blood lead and free erythrocyte porphyrin (FEP) levels in the lead-treated groups were significantly higher than in the control animals (P less than 0.001). The animals in the recovery groups had lower, albeit not normal, blood lead and FEP levels 30 days after discontinuing treatment. Serum testosterone, intratesticular sperm counts, and sperm production rates were suppressed in the lead-treated groups (P less than 0.001). Serum testosterone and sperm parameters normalized at the end of the recovery period in the prepubertal animals but not in the pubertal animals.

  7. Toxic compounds and health and reproductive effects in St. Lawrence Beluga Whales

    SciTech Connect

    Beland, P.; Michaud, R. ); DeGuise, S. Faculte de Medecine Veterinaire, St-Hyacinthe, Quebec ); Girard, C.; Lagace, A. ); Martineau, D. Cornell Univ., Ithaca, NY ); Muir, D.C.G. ); Norstorm, R.J. ); Pelletier, E. ); Ray, S. )

    1993-01-01

    An epidemiologic study was carried out over a period of 9 years on an isolated population of beluga whales (Delphinapterus leucas) residing in the St. Lawrence estuary (Quebec, Canada). More than 100 individual deaths were aged, and/or autopsied and analyzed for toxic compounds, and the population was surveyed for size and structure. Arctic belugas and other species of whales and seals from the St. Lawrence were used for comparison. Population dynamics: Population size appeared to be stable and modeling showed this stable pattern to result from low calf production and/or low survival to adulthood. Toxicology: St. Lawrence belugas had higher or much higher levels of mercury, lead, PCBs, DDT, Mirex, benzo[a]pyrene metabolites, equivalent levels of dioxins, furans, and PAH metabolites, and much lower levels of cadmium than Arctic belugas. In other St. Lawrence cetaceans, levels of PCBs and DDT were inversely related to body size, as resulting from differences in metabolic rate, diet, and trophic position, compounded by length of residence in the St. Lawrence basin. St. Lawrence belugas had much higher levels than predicted from body size alone; levels increased with age in both sexes, although unloading by females through the placenta and/or lactation was evidenced by overall lower levels in females and very high burdens in some calves. 45 refs., 4 figs., 5 tabs.

  8. Celery oil modulates DEHP-induced reproductive toxicity in male rats.

    PubMed

    Helal, Mona A M

    2014-09-01

    The objective of the study was to investigate the protective effect of Apium graveolens (AP) against di-(2-ethylhexyl) phthalate (DEHP)-induced testes injury in rats. Adult rats were divided into nine groups: (1) control group (no treatment); (2) corn oil (60 μg/kg body weight - bwt); (3) AP (50 μg/kg bwt); (4) 300 mg DEHP/kg bwt; (5) 500 mg DEHP/kg bwt; (6) 1000 mg DEHP/kg bwt; (7) 300 mg DEHP/kg bwt+AP; (8) 500 mg DEHP/kg bwt+AP; and (9) 1000 mg DEHP/kg bwt+AP. Oral administration of treatments was performed daily for 6 weeks. DEHP decreased (p<0.01) body weight, testis weight and serum concentrations of testosterone, cholesterol and total proteins. Moreover, DEHP increased (p<0.001) total antioxidant capacity in the testis and plasma DEHP level. In addition, DEHP decreased mRNA expression of two testicular steroidogenic enzymes: 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. DEHP also caused atrophy, vacuolar degeneration and aspermia of the seminiferous tubules. AP administered concurrently with DEHP effectively alleviated most of the DEHP-induced effects. In conclusion, in male rats, DEHP had adverse effects on the testis including inhibition of androgen production. A concurrent administration of A. graveolens (celery oil) protected the testis against DEHP-induced toxicity.

  9. DNA damage in earthworms from highly contaminated soils: assessing resistance to arsenic toxicity by use of the Comet assay.

    PubMed

    Button, Mark; Jenkin, Gawen R T; Bowman, Karen J; Harrington, Chris F; Brewer, Tim S; Jones, George D D; Watts, Michael J

    2010-02-01

    Earthworms native to the former mine site of Devon Great Consols (DGC), UK reside in soils highly contaminated with arsenic (As). These earthworms are considered to have developed a resistance to As toxicity. The mechanisms underlying this resistance however, remain unclear. In the present study, non-resistant, commercially sourced Lumbricus terrestris were exposed to a typical DGC soil in laboratory mesocosms. The earthworms bio-accumulated As from the soil and incurred DNA-damage levels significantly above those observed in the control mesocosm (assessed using the Comet assay). A dose response was observed between DNA damage (% tail DNA) and As concentration in soil (control, 98, 183, 236, 324 and 436mgkg(-1)). As-resistant earthworms (Lumbricus rubellus, Dendrodrilus rubidus and L. terrestris) collected from contaminated soils at DGC (203 to 9025mgkg(-1) As) had also bio-accumulated high levels of As from their host soils, yet demonstrated low levels of DNA damage compared with earthworms from uncontaminated sites. The results demonstrate that the As-contaminated soils at DGC are genotoxic to non-native earthworms and much less so to earthworms native to DGC, thus providing further evidence of an acquired resistance to As toxicity in the native earthworms. PMID:20015476

  10. DNA damage in earthworms from highly contaminated soils: assessing resistance to arsenic toxicity by use of the Comet assay.

    PubMed

    Button, Mark; Jenkin, Gawen R T; Bowman, Karen J; Harrington, Chris F; Brewer, Tim S; Jones, George D D; Watts, Michael J

    2010-02-01

    Earthworms native to the former mine site of Devon Great Consols (DGC), UK reside in soils highly contaminated with arsenic (As). These earthworms are considered to have developed a resistance to As toxicity. The mechanisms underlying this resistance however, remain unclear. In the present study, non-resistant, commercially sourced Lumbricus terrestris were exposed to a typical DGC soil in laboratory mesocosms. The earthworms bio-accumulated As from the soil and incurred DNA-damage levels significantly above those observed in the control mesocosm (assessed using the Comet assay). A dose response was observed between DNA damage (% tail DNA) and As concentration in soil (control, 98, 183, 236, 324 and 436mgkg(-1)). As-resistant earthworms (Lumbricus rubellus, Dendrodrilus rubidus and L. terrestris) collected from contaminated soils at DGC (203 to 9025mgkg(-1) As) had also bio-accumulated high levels of As from their host soils, yet demonstrated low levels of DNA damage compared with earthworms from uncontaminated sites. The results demonstrate that the As-contaminated soils at DGC are genotoxic to non-native earthworms and much less so to earthworms native to DGC, thus providing further evidence of an acquired resistance to As toxicity in the native earthworms.

  11. Systematic Evaluation of Nanomaterial Toxicity: Utility of Standardized Materials and Rapid Assays

    PubMed Central

    2011-01-01

    The challenge of optimizing both performance and safety in nanomaterials hinges on our ability to resolve which structural features lead to desired properties. It has been difficult to draw meaningful conclusions about biological impacts from many studies of nanomaterials due to the lack of nanomaterial characterization, unknown purity, and/or alteration of the nanomaterials by the biological environment. To investigate the relative influence of core size, surface chemistry, and charge on nanomaterial toxicity, we tested the biological response of whole animals exposed to a matrix of nine structurally diverse, precision-engineered gold nanoparticles (AuNPs) of high purity and known composition. Members of the matrix include three core sizes and four unique surface coatings that include positively and negatively charged headgroups. Mortality, malformations, uptake, and elimination of AuNPs were all dependent on these parameters, showing the need for tightly controlled experimental design and nanomaterial characterization. Results presented herein illustrate the value of an integrated approach to identify design rules that minimize potential hazard. PMID:21609003

  12. Predicting relative toxicity and interactions of divalent metal ions: Microtox{reg_sign} bioluminescence assay

    SciTech Connect

    Newman, M.C.; McCloskey, J.T.

    1996-03-01

    Both relative toxicity and interactions between paired metal ions were predicted with least-squares linear regression and various ion characteristics. Microtox{reg_sign} 15 min EC50s (expressed as free ion) for Ca(II), Cd(II), Cu(II), Hg(II), Mg(II), Mn(II), Ni(II), Pb(II), and Zn(II) were most effectively modeled with the constant for the first hydrolysis (K{sub H} for M{sup n+} + H{sub 2}O {yields} MOH{sup a{minus}1} + H{sup +}) although other ion characteristics were also significant in regression models. The {vert_bar}log K{sub H}{vert_bar} is correlated with metal ion affinity to intermediate ligands such as many biochemical functional groups with O donor atoms. Further, ordination of metals according to ion characteristics, e.g., {vert_bar}log K{sub H}{vert_bar} facilitated prediction of paired metal interactions. Pairing metals with strong tendencies to complex with intermediate or soft ligands such as those with O or S donor atoms resulted in strong interactions.

  13. The marine hard substrate community as an assay for toxicity of CCA-treated wood

    SciTech Connect

    Weis, J.S.; Weis, P. |

    1994-12-31

    Panels of chromated copper arsenate (CCA) pressure-treated wood and control (untreated) wood were placed into an estuary and examined after one month for settlement of organisms. The community on the CCA wood exhibited greatly reduced species richness, biomass, and diversity. When the community was removed and the boards replaced into the estuary, the epibiota settling during the following month showed a smaller difference between the CCA panels and the control wood. After removal of the community and immersion of the wood for a third month, there were no statistically significant differences in the community that formed on the two materials. However, qualitative differences were still visible, particularly in the growth of the alga Enteromorpha and the bryozoan Conopeum. Differences in algal and bryozoan cover persisted after a year of submersion. Bioaccumulation of the metals in the epibiota on the CCA wood generally declined over time, but remained far above control levels, however. The decreased toxicity of the CCA wood with repeated trials is probably related to decreased rate of leaching, as observed earlier in laboratory experiments, and suggests that the treated wood would have reduced environmental impact if it were soaked out on site at the treatment facility before being marketed for use in the aquatic environment.

  14. Artichoke induces genetic toxicity in the cytokinesis-block micronucleus (CBMN) cytome assay.

    PubMed

    Jacociunas, Laura Vicedo; de Andrade, Heloisa Helena Rodrigues; Lehmann, Mauricio; de Abreu, Bianca Regina Ribas; Ferraz, Alexandre de Barros Falcão; da Silva, Juliana; Grivicich, Ivana; Dihl, Rafael Rodrigues

    2013-05-01

    Artichoke leaves are used in traditional medicine as an herbal medicament for the treatment of hepatic related diseases, as well as choleretic and diuretic. The aim of the present study was to evaluate the capacity of Cynara scolymus L. leaves extract (LE) to cause chromosomal instability and cytotoxicity in Chinese hamster ovary cells (CHO) employing the cytokinesis-block micronucleus (CBMN) cytome assay. Cells were treated with four concentrations of C. scolymus for two exposure times: 1h and 24h. Our findings showed that LE did not increase the frequencies of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, all concentrations of the extract produced increments in micronuclei frequencies (MNi) in both exposure times, when compared to the negative control. No significant differences were observed in the nuclear division cytotoxicity index (NDCI), reflecting the absence of cytotoxic effects associated to LE. The results demonstrated the ability of C. scolymus LE to promote chromosomal mutations which are, probably, a result of the pro-oxidant activity of LE constituents such as flavonoids and chlorogenic acids. The data obtained in this study suggests that high concentrations of artichoke can pose a risk associated to its consumption. PMID:23274746

  15. Real-time Assay of Toxic Lead in In Vivo Living Plant Tissue.

    PubMed

    Ly, Suwyoung; Kim, Nack Joo; Youn, Minsang; Kim, Yongwook; Sung, Yeolmin; Kim, Dohoon; Chung, Tackhyun

    2013-12-31

    A method of detecting lead was developed using square wave anodic stripping voltammetry (SWASV) with DNA-carbon nanotube paste electrode (CNTPE). The results indicated a sensitive oxidation peak current of lead on the DNA-CNTPE. The curves were obtained within a concentration range of 50 ngL(-1)-20 mgL(-1) with preconcentration time of 100, 200, and 400 sec at the concentration of mgL(-1), μgL(-1), and ngL(-1), respectively. The observed relative standard deviation was 0.101% (n = 12) in the lead concentration of 30.0 μgL(-1) under optimum conditions. The low detection limit (S/N) was pegged at 8 ngL(-1) (2.6 × 10(-8) M). Results showed that the developed method can be used in real-time assay in vivo without requiring any pretreatment and pharmaceutical samples, and food samples, as well as other materials requiring water source contamination analyses. PMID:24578800

  16. Real-time Assay of Toxic Lead in In Vivo Living Plant Tissue.

    PubMed

    Ly, Suwyoung; Kim, Nack Joo; Youn, Minsang; Kim, Yongwook; Sung, Yeolmin; Kim, Dohoon; Chung, Tackhyun

    2013-12-31

    A method of detecting lead was developed using square wave anodic stripping voltammetry (SWASV) with DNA-carbon nanotube paste electrode (CNTPE). The results indicated a sensitive oxidation peak current of lead on the DNA-CNTPE. The curves were obtained within a concentration range of 50 ngL(-1)-20 mgL(-1) with preconcentration time of 100, 200, and 400 sec at the concentration of mgL(-1), μgL(-1), and ngL(-1), respectively. The observed relative standard deviation was 0.101% (n = 12) in the lead concentration of 30.0 μgL(-1) under optimum conditions. The low detection limit (S/N) was pegged at 8 ngL(-1) (2.6 × 10(-8) M). Results showed that the developed method can be used in real-time assay in vivo without requiring any pretreatment and pharmaceutical samples, and food samples, as well as other materials requiring water source contamination analyses.

  17. Real-time Assay of Toxic Lead in In Vivo Living Plant Tissue

    PubMed Central

    Kim, Nack Joo; Youn, Minsang; Kim, Yongwook; Sung, Yeolmin; Kim, Dohoon

    2013-01-01

    A method of detecting lead was developed using square wave anodic stripping voltammetry (SWASV) with DNA-carbon nanotube paste electrode (CNTPE). The results indicated a sensitive oxidation peak current of lead on the DNA-CNTPE. The curves were obtained within a concentration range of 50 ngL−1-20 mgL−1 with preconcentration time of 100, 200, and 400 sec at the concentration of mgL−1, μgL−1, and ngL−1, respectively. The observed relative standard deviation was 0.101% (n = 12) in the lead concentration of 30.0 μgL−1 under optimum conditions. The low detection limit (S/N) was pegged at 8 ngL−1 (2.6 × 10−8 M). Results showed that the developed method can be used in real-time assay in vivo without requiring any pretreatment and pharmaceutical samples, and food samples, as well as other materials requiring water source contamination analyses. PMID:24578800

  18. Artichoke induces genetic toxicity in the cytokinesis-block micronucleus (CBMN) cytome assay.

    PubMed

    Jacociunas, Laura Vicedo; de Andrade, Heloisa Helena Rodrigues; Lehmann, Mauricio; de Abreu, Bianca Regina Ribas; Ferraz, Alexandre de Barros Falcão; da Silva, Juliana; Grivicich, Ivana; Dihl, Rafael Rodrigues

    2013-05-01

    Artichoke leaves are used in traditional medicine as an herbal medicament for the treatment of hepatic related diseases, as well as choleretic and diuretic. The aim of the present study was to evaluate the capacity of Cynara scolymus L. leaves extract (LE) to cause chromosomal instability and cytotoxicity in Chinese hamster ovary cells (CHO) employing the cytokinesis-block micronucleus (CBMN) cytome assay. Cells were treated with four concentrations of C. scolymus for two exposure times: 1h and 24h. Our findings showed that LE did not increase the frequencies of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, all concentrations of the extract produced increments in micronuclei frequencies (MNi) in both exposure times, when compared to the negative control. No significant differences were observed in the nuclear division cytotoxicity index (NDCI), reflecting the absence of cytotoxic effects associated to LE. The results demonstrated the ability of C. scolymus LE to promote chromosomal mutations which are, probably, a result of the pro-oxidant activity of LE constituents such as flavonoids and chlorogenic acids. The data obtained in this study suggests that high concentrations of artichoke can pose a risk associated to its consumption.

  19. Reproductive toxicity of chromium in adult bonnet monkeys (Macaca radiata Geoffrey). Reversible oxidative stress in the semen

    SciTech Connect

    Subramanian, Senthivinayagam . E-mail: subbi100@yahoo.co.uk; Rajendiran, Gopalakrishnan; Sekhar, Pasupathi; Gowri, Chandrahasan; Govindarajulu, Pera; Aruldhas, Mariajoseph Michael

    2006-09-15

    The present study was designed to test the hypothesis that oxidative stress mediates chromium-induced reproductive toxicity. Monthly semen samples were collected from adult monkeys (Macaca radiata), which were exposed to varying doses (50, 100, 200 and 400 ppm) of chromium (as potassium dichromate) for 6 months through drinking water. Chromium treatment decreased sperm count, sperm forward motility and the specific activities of antioxidant enzymes, superoxide dismutase and catalase, and the concentration of reduced glutathione in both seminal plasma and sperm in a dose- and duration-dependent manner. On the other hand, the quantum of hydrogen peroxide in the seminal plasma/sperm from monkeys exposed to chromium increased with increasing dose and duration of chromium exposure. All these changes were reversed after 6 months of chromium-free exposure period. Simultaneous supplementation of vitamin C (0.5 g/L; 1.0 g/L; 2.0 g/L) prevented the development of chromium-induced oxidative stress. Data support the hypothesis and show that chronic chromium exposure induces a reversible oxidative stress in the seminal plasma and sperm by creating an imbalance between reactive oxygen species and antioxidant system, leading to sperm death and reduced motility of live sperm.

  20. Reproductive toxicity of chromium in adult bonnet monkeys (Macaca radiata Geoffrey). Reversible oxidative stress in the semen.

    PubMed

    Subramanian, Senthivinayagam; Rajendiran, Gopalakrishnan; Sekhar, Pasupathi; Gowri, Chandrahasan; Govindarajulu, Pera; Aruldhas, Mariajoseph Michael

    2006-09-15

    The present study was designed to test the hypothesis that oxidative stress mediates chromium-induced reproductive toxicity. Monthly semen samples were collected from adult monkeys (Macaca radiata), which were exposed to varying doses (50, 100, 200 and 400 ppm) of chromium (as potassium dichromate) for 6 months through drinking water. Chromium treatment decreased sperm count, sperm forward motility and the specific activities of antioxidant enzymes, superoxide dismutase and catalase, and the concentration of reduced glutathione in both seminal plasma and sperm in a dose- and duration-dependent manner. On the other hand, the quantum of hydrogen peroxide in the seminal plasma/sperm from monkeys exposed to chromium increased with increasing dose and duration of chromium exposure. All these changes were reversed after 6 months of chromium-free exposure period. Simultaneous supplementation of vitamin C (0.5 g/L; 1.0 g/L; 2.0 g/L) prevented the development of chromium-induced oxidative stress. Data support the hypothesis and show that chronic chromium exposure induces a reversible oxidative stress in the seminal plasma and sperm by creating an imbalance between reactive oxygen species and antioxidant system, leading to sperm death and reduced motility of live sperm. PMID:16678873

  1. Evaluation of possible toxic effects of spearmint (Mentha spicata) on the reproductive system, fertility and number of offspring in adult male rats

    PubMed Central

    Nozhat, Fatemeh; Alaee, Sanaz; Behzadi, Khodabakhsh; Azadi Chegini, Najmeh

    2014-01-01

    Objective: In this study we investigated the effects of spearmint (Mentha spicata Labiatae) on the reproductive system, fertility and number of offspring in adult male rats. Materials and Methods: Adult Wistar male rats in one control (C) and three experimental groups (I, II and III) received 0, 10, 20 and 40 mg/kg spearmint extract orally for 45 days, respectively. Following this treatment, the animals’ weights, and the standard weight of reproductive tissues, sperm count, sperm motility and serum testosterone concentration were measured, and reproductive tissues were examined histopathologically. To evaluate the effects of spearmint on fertility of male rats and growth of their offspring, male rats of the control and experimental groups mated with untreated female rats. Results: Results showed that spearmint did not affect the rats’ body and reproductive tissue weights. The sperm count, fast and slow progressive motility of sperm and serum testosterone concentration decreased while number of non-progressive sperm and immotile sperm increased in the experimental groups compared to the control group, but none of these changes were statistically significant. Histopathological studies showed no severe changes in reproductive tissues between control and experimental groups. Number and growth of offspring born from mating of male rats with untreated female rats showed no difference. Conclusion: We concluded that spearmint has no significant toxic effect on the reproductive system, fertility and number of offspring in adult male rats at the above mentioned dose levels. However high levels of this extract may have adverse effects on male fertility. PMID:25386406

  2. Scientific and regulatory policy committee (SRPC) paper: Assessment of Circulating Hormones in Nonclinical Toxicity Studies. III Female Reproductive Hormones

    EPA Science Inventory

    Hormonally mediated effects on the female reproductive system may manifest in pathologic changes of endocrine-responsive organs and altered reproductive function. Identification of these effects requires proper assessment, which may include investigative studies of female reprod...

  3. Toxicity of Pb and of Pb/Cd combination on the springtail Folsomia candida in natural soils: reproduction, growth and bioaccumulation as indicators.

    PubMed

    Bur, T; Crouau, Y; Bianco, A; Gandois, L; Probst, A

    2012-01-01

    The toxicity of Pb and Cd+Pb was assessed on the Collembola F. candida in two cultivated soils (SV and AU) with low organic matter (OM) content and circumneutral to basic pH, and an acid forested soil (EPC) with high OM content. Collembola reproduction and growth as well as metal content in Collembola body, in soil, exchangeable fraction and soil solutions, pH and DOC were investigated. Pb and Cd+Pb were the highest in exchangeable fraction and soil solution of the acidic soils. Soil solution pH decreased after metal spiking in every soil due to metal adsorption, which was similar for Cd and the highest in AU for Pb. With increasing Pb and Cd+Pb, the most important reproduction decrease was in EPC soil. The LOEC for reproduction after metal addition was 2400 (Pb) and 200/2400 (Cd/Pb), 1200 and 100/1200, 300 and 100/1200 μg g(-1) for AU, SV and EPC, respectively. The highest and the lowest Pb toxicity was observed for EPC and AU bulk soil, respectively. The metal in Collembola increased with increasing soil concentration, except in AU, but the decreasing BF(solution) with increasing concentrations indicates a limited metal transfer to Collembola or an increased metal removal. Loading high Pb concentrations decreases Cd absorption by the Collembola, but the reverse was not true. The highest Pb toxicity in EPC can be explained by pH and OM content. Because of metal complexation, OM might have a protective role but its ingestion by Collembola lead to higher toxicity. Metal bioavailability in Collembola differs from soil solution indicating that soil solution is not sufficient to evaluate toxicity in soil organisms. The toxicity as a whole decreased when metals were combined, except for Pb in AU, due to adsorption competition between Cd and Pb on clay particles and OM sites in AU and EPC soils, respectively. PMID:22113108

  4. Hospital waste incinerator bottom ash leachate induced cyto-genotoxicity in Allium cepa and reproductive toxicity in mice.

    PubMed

    Akinbola, Temitayo I; Adeyemi, Adetutu; Morenikeji, Olajumoke A; Bakare, Adekunle A; Alimba, Chibuisi G

    2011-07-01

    The potentials of hospital incinerator bottom ash leachate (HIBAL) to induce cyto-genotoxicity in Allium cepa and reproductive anomalies in the mouse were investigated. The leachate obtained from simulation of the bottom ash was analyzed for some physico-chemical parameters. The A. cepa, mouse sperm morphology and histopathological tests were carried out at concentrations ranging from 1% to 50% of the leachate sample. In A. cepa, HIBAL caused significant (p < 0.05) inhibition of root growth and induction of chromosomal aberrations. In the animal assays, there was 100% mortality at the 50% concentrations. The leachate caused insignificant (p > 0.05) concentration-dependent induction of various types of sperm morphology. There was accumulation of fluid in the seminiferous tubule lumen and necrosis of stem cells in the testes. These effects were believed to be provoked by the somatic and germ cell genotoxins, particularly the heavy metals in the leachate. Our finding is of environmental and public health significance. PMID:21343229

  5. Acute, reproductive toxicity and two-generation teratology studies of a standardized quassinoid-rich extract of Eurycoma longifolia Jack in Sprague-Dawley rats.

    PubMed

    Low, Bin-Seng; Das, Prashanta Kumar; Chan, Kit-Lam

    2014-07-01

    The roots of Eurycoma longifolia Jack are popularly sought as herbal medicinal supplements to improve libido and general health amongst the local ethnic population. The major quassinoids of E. longifolia improved spermatogenesis and fertility but toxicity studies have not been well documented. The reproductive toxicity, two generation of foetus teratology and the up-and-down acute toxicity were investigated in Sprague-Dawley rats orally treated with quassinoid-rich E. longifolia extract (TAF273). The results showed that the median lethal dose (LD50 ) of TAF273 for female and male rats was 1293 and >2000 mg/kg, respectively. Fertility index and litter size of the TAF273 treated were significantly increased when compared with those of the non-treated animals. The TAF273-treated dams decreased in percentage of pre-implantation loss, post-implantation loss and late resorption. No toxic symptoms were observed on the TAF273-treated pregnant female rats and their foetuses were normal. The no-observed adverse effect level (NOAEL) obtained from reproductive toxicity and teratology studies of TAF273 in rats was 100 mg/kg body weight/day, being more than 10-fold lower than the LD50 value. Thus, any human dose derived from converting the rat doses of 100 mg/kg and below may be considered as safe for further clinical studies. PMID:24318772

  6. Acute, reproductive toxicity and two-generation teratology studies of a standardized quassinoid-rich extract of Eurycoma longifolia Jack in Sprague-Dawley rats.

    PubMed

    Low, Bin-Seng; Das, Prashanta Kumar; Chan, Kit-Lam

    2014-07-01

    The roots of Eurycoma longifolia Jack are popularly sought as herbal medicinal supplements to improve libido and general health amongst the local ethnic population. The major quassinoids of E. longifolia improved spermatogenesis and fertility but toxicity studies have not been well documented. The reproductive toxicity, two generation of foetus teratology and the up-and-down acute toxicity were investigated in Sprague-Dawley rats orally treated with quassinoid-rich E. longifolia extract (TAF273). The results showed that the median lethal dose (LD50 ) of TAF273 for female and male rats was 1293 and >2000 mg/kg, respectively. Fertility index and litter size of the TAF273 treated were significantly increased when compared with those of the non-treated animals. The TAF273-treated dams decreased in percentage of pre-implantation loss, post-implantation loss and late resorption. No toxic symptoms were observed on the TAF273-treated pregnant female rats and their foetuses were normal. The no-observed adverse effect level (NOAEL) obtained from reproductive toxicity and teratology studies of TAF273 in rats was 100 mg/kg body weight/day, being more than 10-fold lower than the LD50 value. Thus, any human dose derived from converting the rat doses of 100 mg/kg and below may be considered as safe for further clinical studies.

  7. Characteristics and Applications of the ToxRefDB In Vivo Datasets from Chronic, Reproductive and Developmental Assays

    EPA Science Inventory

    ToxRefDB was developed to store data from in vivo animal toxicity studies. The initial focus was populating ToxRefDB with pesticide registration toxicity data that has been historically stored as hard-copy and scanned documents by the Office of Pesticide Programs. A significant p...

  8. The reproductive toxicity on the rotifer Brachionus plicatilis induced by BDE-47 and studies on the effective mechanism based on antioxidant defense system changes.

    PubMed

    Wang, Hong; Tang, Xuexi; Sha, Jingjing; Chen, Hongmei; Sun, Tianli; Wang, You

    2015-09-01

    2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), a low-brominated Tetra-BDE that is widely distributed in the marine ecosystem, was selected to investigate the reproductive toxicity on the rotifer, Brachionus plicatilis, and the possible mechanism based on antioxidant defense system changes were studied. The results showed the following: (1) A low concentration of BDE-47 had a slight effect on the egg production of individual females and the egg production rate (EPR) of the population. In fact, BDE-47 exerted reproductive inhibition effects in a time- and concentration-dependent manner. The obtained life tables indicated that BDE-47 at a high concentration prolonged the generation time, whereas low and moderate concentrations of BDE-47 had the opposite effects. BDE-47 at a medium concentration significantly decreased the life expectancy and net reproductive rate (P<0.05). Additionally, a high concentration of BDE-47 markedly decreased the net reproductive rate and intrinsic increase rate (P<0.05). The ultra-structure of the ovary showed that BDE-47 severely damaged the ovary. (2) BDE-47 stress elevated the ROS level in B. plicatilis. The GST activity was induced significantly by the low concentration of BDE-47 and inhibited by the highest concentration tested. The GPx activity and GSH content were significant decreased in all the tested groups, and GR activity was induced. GST and GSH appeared to be sensitive to oxidative stress, and all of the glutathione-related enzymes were found to play an important role in maintaining the antioxidant/pro-oxidant balance based on Pearson's correlation analysis. The results indicated that BDE-47 causes reproductive toxicity in B. plicatilis and that the ROS-mediated pathway is responsible for the observed toxicity.

  9. Nicotine-induced reproductive toxicity, oxidative damage, histological changes and haematotoxicity in male rats: the protective effects of green tea extract.

    PubMed

    Mosbah, Rachid; Yousef, Mokhtar Ibrahim; Mantovani, Alberto

    2015-03-01

    Nicotine is an active substance present in tobacco that causes oxidative stress and tissues damages leading to several diseases. Natural antioxidants that prevent or slow the progression and severity of nicotine toxicity may have a significant health impact. We have analyzed the effects of green tea extract (GTE) on nicotine (NT)-induced reproductive toxicity, oxidative damage and haematotoxicity in adult Wistar male rats. Thirty-two rats were randomly divided into four groups: control, nicotine (NT, 1mg/kg i.p.), green tea extract (GTE, 2% w/v as the sole beverage) and (NT+GTE) group. After 2 months of treatment, blood samples were collected for measuring the haematological and oxidative stress parameters and testosterone level, while the reproductive organs were weighed and used for the semen analysis and histopathology. NT induced oxidative damage as indicated by a significant reduction in the activities of antioxidant enzymes and an elevation in TBARS levels. NT also caused reproductive toxicity as shown by a decline in testosterone levels, the weights of reproductive organs and sperm characteristics; the histological examination of testes revealed atrophy, degenerative alterations and perturbation of spermatogenesis in several seminiferous tubules, together with increased interstitial spaces and reduced number of Leydig cells. Both NT and GTE altered white blood cell count and red blood cells parameters, albeit with somewhat different effect, no protective action being seen upon NT+GTE treatment. On the contrary, GTE played a protective role against NT-induced oxidative stress as well as the reproductive effects by improving the oxidative status, semen quality and the testicular histological damage.

  10. EVALUATION OF THE AROMATASE INHIBITOR FADROZOLE IN A SHORT-TERM REPRODUCTION ASSAY WITH THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

    EPA Science Inventory

    Cytochrome P450 aromatase is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such a B-estradiol (E2). The objective of this study was to assess effects of the CYP inhibitor fadrozole on fathead minnow reproductive endocrinol...

  11. Chronic toxicity of tributyltin on development and reproduction of the hermaphroditic snail Physa fontinalis: Influence of population density.

    PubMed

    Leung, Kenneth M Y; Morley, Neil J; Grist, Eric P M; Morritt, David; Crane, Mark

    2004-01-01

    Tributyltin (TBT) is toxic to aquatic organisms and occurs widely in sediments and surface waters of American and European rivers and lakes. This study investigated TBT effects on development and population growth rate (r) of the common, hermaphroditic European freshwater snail Physa fontinalis. Egg ropes of similar age (1-3 days old) were exposed to a control (solvent only) and nominal concentrations of 0.01, 1.0 and 10 microg TBT l(-1) in triplicate. Hatching and mortality were recorded during 0-40 days of exposure. At day 40, 18 juveniles were randomly selected from each concentration (i.e., six from each test vessel) and individually exposed to the same concentration of TBT in 50 ml beakers. A cohort of 20 juveniles was allowed to continue developing in the original test vessels, so that individual and grouped results could be compared. Mortality and reproduction were recorded at 48-h intervals throughout the study period (110 days). Abnormal embryonic development was observed at 1 and 10 microg TBT l(-1). Although 50% of eggs hatched at 10 microg TBT l(-1), all these hatchlings failed to survive. Survivorship of hatchlings was significantly reduced by TBT at 1 microgl(-1). In general, there was a delay in egg production in isolated snails when compared with the grouped snails. Survival, fecundity and population growth rate (r) were reduced in both individual and grouped P. fontinalis at 1.0 microg TBT l(-1). Only a decline in r was observed in snails exposed individually to 0.01 microg TBT l(-1).

  12. Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of a distillate from light alkylate naphtha.

    PubMed

    Bui, Q Q; Burnett, D M; Breglia, R J; Koschier, F J; Lapadula, E S; Podhasky, P I; Schreiner, C A; White, R D; Dalbey, W E; Feuston, M H

    1998-01-23

    A distillate of light alkylate naphtha (CAS number 64741-66-8; LAN distillate) was administered via inhalation, 6 h/d, 7 d/wk to 4 groups of Sprague-Dawley rats (10/sex/dose) at target concentrations of 0 (filtered air control), 5, 12.5, or 25 g/m3 with the highest dose exceeding 60% of the lower explosive limit of LAND. Exposure began 2 wk prior to mating and continued throughout gestation until postnatal d 4 for females or for 8 consecutive weeks for males. No apparent clinical signs indicative of systemic toxicity were observed in the F0 and F1 animals of either sex. Inhalation exposure to LAND up to and including the 25 g/m3 dose level had no effect on parental food consumption, body weights, absolute and relative organ weights, and reproductive indices. All groups had comparable delivery data and a fertility index > or 80%. Pups in all groups showed comparable birth weights, weight gain, a viability index (postnatal d 4) for all groups of > or = 97%, and no histopathological changes. In the dams, there were no significant differences in the mean numbers of corpora lutea, implantation sites, and resorptions recorded at necropsy. In the males, the only remarkable findings at necropsy were a small right epididymis and testis seen in one mid-dose male and an abscess on the right epididymis of a high-dose male. In both cases, the dams that had been bred to these males produced normal litters. There were no test material-related microscopic changes observed in the testes and epididymis of the F0 male rats or ovaries of the F0 female rats exposed to LAND. Under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for LAND via inhalation in rats is established at greater than 24.7 g/m3 (analytical concentration).

  13. A semiquinone glucoside derivative provides protection to male reproductive system of the mice against gamma radiation toxicity.

    PubMed

    Patel, Dev Dutt; Bansal, Deen Dayal; Mishra, Saurabh; Arora, Rajesh; Sharma, Rakesh Kumar; Jain, Swatantra Kumar; Kumar, Raj

    2014-05-01

    Present investigation was carried out to evaluate the radioprotective efficacy of a novel Semiquinone glucoside derivative (SQGD), isolated from Bacillus sp. INM-1, in the male reproductive system of BALB/c mice. Animals were administered 50 mg/kg b.wt. (i.p.) SQGD 2 h before whole body γ-irradiation (10 Gy). Radiation-induced cellular toxicity and its modulation by SQGD pretreatment was evaluated in the mice testes by quantitative histological and protein expression analysis. SQGD pretreatment protects irradiated mice from radiation-induced testicular atrophy and germ cells degeneration, which may lead to emptiness of seminiferous tubules. Significant decrease in P53 and P21((Cip/WAF-1)) expression was observed in the irradiated mice pretreated (2 h) by SQGD at 6 h compared with only irradiated mice. However, contrary to P53, expressions of P21 at latter time, that is, 24-72 h was found to be increased significantly in the irradiated mice pretreated by SQGD. Significant increase in the intact PARP-1 protein expression were observed in the testes of the mice pretreated by SQGD 2 h before irradiation at 24-72 h compared with the only irradiated mice, whereas significant increase in PARP-1 cleaved fragment was noticed at 24 h. Similarly, significant increase in NF-kB and BCL-2/BAX expressions ratio was noticed in SQGD-treated mice (± irradiation) compared with irradiated mice, suggested a role of SQGD in the activation of prosurvival signaling in the testicular germinal cells population of the irradiated mice and thus contributed to protection against lethal γ-irradiation.

  14. Comparison of Birth-and Conception-Based Definitions of Postnatal Age in Developmental and Reproductive Rodent Toxicity Studies: Influence of Gestation Length and Timing of Neonatal Examinations on Litter Data in Controls

    EPA Science Inventory

    Laboratories conducting developmental and reproductive toxicity studies with rodents use varied protocols for determining the timing of neonatal litter examinations and subsequent measurements. Most laboratories determine timing based on the day of birth (DOB); l.e., gestation le...

  15. Relative Impact of Incorporating Pharmacokinetics on Predicting In Vivo Hazard and Mode of Action from High-Throughput In Vitro Toxicity Assays

    EPA Science Inventory

    The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing. In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals. Computational in vitro-to-in vivo e...

  16. Introducing Environmental Toxicology in Instructional Labs: The Use of a Modified Amphibian Developmental Toxicity Assay to Support Inquiry-Based Student Projects

    ERIC Educational Resources Information Center

    Sauterer, Roger; Rayburn, James R.

    2012-01-01

    Introducing students to the process of scientific inquiry is a major goal of high school and college labs. Environmental toxins are of great concern and public interest. Modifications of a vertebrate developmental toxicity assay using the frog Xenopus laevis can support student-initiated toxicology experiments that are relevant to humans. Teams of…

  17. High-throughput Screening of ToxCast™ Phase I Chemicals in a Mouse Embryonic Stem Cell (mESC) Assay Reveals Disruption of Potential Toxicity Pathways

    EPA Science Inventory

    Little information is available regarding the potential for many commercial chemicals to induce developmental toxicity. The mESC Adherent Cell Differentiation and Cytoxicity (ACDC) assay is a high-throughput screen used to close this data gap. Thus, ToxCast™ Phase I chemicals wer...

  18. Toxicity assessment of diesel- and metal-contaminated soils through elutriate and solid phase assays with the slime mold Dictyostelium discoideum.

    PubMed

    Rodríguez-Ruiz, Amaia; Dondero, Francesco; Viarengo, Aldo; Marigómez, Ionan

    2016-06-01

    A suite of organisms from different taxonomical and ecological positions is needed to assess environmentally relevant soil toxicity. A new bioassay based on Dictyostelium is presented that is aimed at integrating slime molds into such a testing framework. Toxicity tests on elutriates and the solid phase developmental cycle assay were successfully applied to a soil spiked with a mixture of Zn, Cd, and diesel fuel freshly prepared (recently contaminated) and after 2 yr of aging. The elutriates of both soils provoked toxic effects, but toxicity was markedly lower in the aged soil. In the D. discoideum developmental cycle assay, both soils affected amoeba viability and aggregation, with fewer multicellular units, smaller fruiting bodies and, overall, inhibition of fruiting body formation. This assay is quick and requires small amounts of test soil, which might facilitate its incorporation into a multispecies multiple-endpoint toxicity bioassay battery suitable for environmental risk assessment in soils. Environ Toxicol Chem 2016;35:1413-1421. © 2015 SETAC.

  19. Toxicity assessment of diesel- and metal-contaminated soils through elutriate and solid phase assays with the slime mold Dictyostelium discoideum.

    PubMed

    Rodríguez-Ruiz, Amaia; Dondero, Francesco; Viarengo, Aldo; Marigómez, Ionan

    2016-06-01

    A suite of organisms from different taxonomical and ecological positions is needed to assess environmentally relevant soil toxicity. A new bioassay based on Dictyostelium is presented that is aimed at integrating slime molds into such a testing framework. Toxicity tests on elutriates and the solid phase developmental cycle assay were successfully applied to a soil spiked with a mixture of Zn, Cd, and diesel fuel freshly prepared (recently contaminated) and after 2 yr of aging. The elutriates of both soils provoked toxic effects, but toxicity was markedly lower in the aged soil. In the D. discoideum developmental cycle assay, both soils affected amoeba viability and aggregation, with fewer multicellular units, smaller fruiting bodies and, overall, inhibition of fruiting body formation. This assay is quick and requires small amounts of test soil, which might facilitate its incorporation into a multispecies multiple-endpoint toxicity bioassay battery suitable for environmental risk assessment in soils. Environ Toxicol Chem 2016;35:1413-1421. © 2015 SETAC. PMID:26450765

  20. Assessment of the reproductive and developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater.

    PubMed

    Heindel, J J; Chapin, R E; Gulati, D K; George, J D; Price, C J; Marr, M C; Myers, C B; Barnes, L H; Fail, P A; Grizzle, T B

    1994-05-01

    Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage

  1. Short-term fish reproduction assays with methyl tertiary butyl ether with zebrafish and fathead minnow: Implications for evaluation of potential for endocrine activity.

    PubMed

    Mihaich, Ellen; Erler, Steffen; Le Blanc, Gerald; Gallagher, Sean

    2015-09-01

    The authors report on short-term fish reproduction assays in zebrafish and fathead minnow conducted to examine the potential for methyl tertiary butyl ether (MTBE) to cause effects on the endocrine system. Both studies were performed under good laboratory practice and in accordance with Organisation for Economic Co-operation and Development and US Environmental Protection Agency test guidelines. The results of the first study demonstrated that exposure to a high test concentration (147 mg/L) of MTBE impaired reproductive output of female zebrafish, evident by a reduction in fecundity. Based on the endpoints evaluated in the present study however, there was no supporting evidence to indicate that this effect was caused by disruption of or interaction with the endocrine system. In the second study, fathead minnows exposed to a wider but lower range of test concentrations showed no effects on any reproductive parameter of male or female fish, at the maximum recommended testing concentration of 100 mg/L (62 mg/L measured). The results of these 2 guideline studies indicate that MTBE does not interact with the hypothalamic-pituitary-gonadal axis of zebrafish or fathead minnow. PMID:25866897

  2. Short-term fish reproduction assays with methyl tertiary butyl ether with zebrafish and fathead minnow: Implications for evaluation of potential for endocrine activity.

    PubMed

    Mihaich, Ellen; Erler, Steffen; Le Blanc, Gerald; Gallagher, Sean

    2015-09-01

    The authors report on short-term fish reproduction assays in zebrafish and fathead minnow conducted to examine the potential for methyl tertiary butyl ether (MTBE) to cause effects on the endocrine system. Both studies were performed under good laboratory practice and in accordance with Organisation for Economic Co-operation and Development and US Environmental Protection Agency test guidelines. The results of the first study demonstrated that exposure to a high test concentration (147 mg/L) of MTBE impaired reproductive output of female zebrafish, evident by a reduction in fecundity. Based on the endpoints evaluated in the present study however, there was no supporting evidence to indicate that this effect was caused by disruption of or interaction with the endocrine system. In the second study, fathead minnows exposed to a wider but lower range of test concentrations showed no effects on any reproductive parameter of male or female fish, at the maximum recommended testing concentration of 100 mg/L (62 mg/L measured). The results of these 2 guideline studies indicate that MTBE does not interact with the hypothalamic-pituitary-gonadal axis of zebrafish or fathead minnow.

  3. A high-throughput three-dimensional cell migration assay for toxicity screening with mobile device-based macroscopic image analysis

    PubMed Central

    Timm, David M.; Chen, Jianbo; Sing, David; Gage, Jacob A.; Haisler, William L.; Neeley, Shane K.; Raphael, Robert M.; Dehghani, Mehdi; Rosenblatt, Kevin P.; Killian, T. C.; Tseng, Hubert; Souza, Glauco R.

    2013-01-01

    There is a growing demand for in vitro assays for toxicity screening in three-dimensional (3D) environments. In this study, 3D cell culture using magnetic levitation was used to create an assay in which cells were patterned into 3D rings that close over time. The rate of closure was determined from time-lapse images taken with a mobile device and related to drug concentration. Rings of human embryonic kidney cells (HEK293) and tracheal smooth muscle cells (SMCs) were tested with ibuprofen and sodium dodecyl sulfate (SDS). Ring closure correlated with the viability and migration of cells in two dimensions (2D). Images taken using a mobile device were similar in analysis to images taken with a microscope. Ring closure may serve as a promising label-free and quantitative assay for high-throughput in vivo toxicity in 3D cultures. PMID:24141454

  4. A high-throughput three-dimensional cell migration assay for toxicity screening with mobile device-based macroscopic image analysis.

    PubMed

    Timm, David M; Chen, Jianbo; Sing, David; Gage, Jacob A; Haisler, William L; Neeley, Shane K; Raphael, Robert M; Dehghani, Mehdi; Rosenblatt, Kevin P; Killian, T C; Tseng, Hubert; Souza, Glauco R

    2013-01-01

    There is a growing demand for in vitro assays for toxicity screening in three-dimensional (3D) environments. In this study, 3D cell culture using magnetic levitation was used to create an assay in which cells were patterned into 3D rings that close over time. The rate of closure was determined from time-lapse images taken with a mobile device and related to drug concentration. Rings of human embryonic kidney cells (HEK293) and tracheal smooth muscle cells (SMCs) were tested with ibuprofen and sodium dodecyl sulfate (SDS). Ring closure correlated with the viability and migration of cells in two dimensions (2D). Images taken using a mobile device were similar in analysis to images taken with a microscope. Ring closure may serve as a promising label-free and quantitative assay for high-throughput in vivo toxicity in 3D cultures. PMID:24141454

  5. A high-throughput three-dimensional cell migration assay for toxicity screening with mobile device-based macroscopic image analysis

    NASA Astrophysics Data System (ADS)

    Timm, David M.; Chen, Jianbo; Sing, David; Gage, Jacob A.; Haisler, William L.; Neeley, Shane K.; Raphael, Robert M.; Dehghani, Mehdi; Rosenblatt, Kevin P.; Killian, T. C.; Tseng, Hubert; Souza, Glauco R.

    2013-10-01

    There is a growing demand for in vitro assays for toxicity screening in three-dimensional (3D) environments. In this study, 3D cell culture using magnetic levitation was used to create an assay in which cells were patterned into 3D rings that close over time. The rate of closure was determined from time-lapse images taken with a mobile device and related to drug concentration. Rings of human embryonic kidney cells (HEK293) and tracheal smooth muscle cells (SMCs) were tested with ibuprofen and sodium dodecyl sulfate (SDS). Ring closure correlated with the viability and migration of cells in two dimensions (2D). Images taken using a mobile device were similar in analysis to images taken with a microscope. Ring closure may serve as a promising label-free and quantitative assay for high-throughput in vivo toxicity in 3D cultures.

  6. Sediment toxicity in the Duluth-Superior Harbor: Use of Microtox{reg_sign} and Mutatox{reg_sign} as screening assays

    SciTech Connect

    Schubauer-Berigan, M.; Hubbard, C.; Schubauer-Berigan, J.; Tesser, G.

    1995-12-31

    Sediment toxicity tests were conducted in the Duluth-Superior Harbor at 40 sites as part of an integrated sediment assessment during the fall of 1993. Two rapid assays conducted with Photobacterium phosphoreum (Microtox{reg_sign} and Mutatox{reg_sign}) were compared with three standard US EPA sediment toxicity tests: Hyalella azteca (acute tests) and Chironomus tentans (acute and sub-lethal tests). The response in the two microbial assays was also evaluated for sensitivity to various contaminants analyzed simultaneously in the Duluth-Superior Harbor sediments. Microtox{reg_sign} and Mutatox{reg_sign} were found to be sensitive to approximately one-third and one-half the sediments, respectively; Chironomus tentans was sensitive to 15% of the sediments (either acutely or sub-lethally), while Hyalella azteca was not sensitive to any of the sediments. In almost all cases, Microtox{reg_sign} and Mutatox{reg_sign} correctly identified samples that were toxic to the chironomid, making it useful as a screening tool for toxicity, to reduce the number of sites to be tested with the benthic organisms. The subsequent application of Microtox{reg_sign} as a screen for sediment toxicity in an EMAP survey in the St. Louis River (MN) estuary will be discussed. Correlation of Microtox{reg_sign} and Mutatox{reg_sign} toxicity to environmental contaminants found in the sediments will be presented.

  7. Reproductive toxicity of binary and ternary mixture combinations of nickel, zinc, and lead to Ceriodaphnia dubia is best predicted with the independent action model.

    PubMed

    Nys, Charlotte; Janssen, Colin R; Blust, Ronny; Smolders, Erik; De Schamphelaere, Karel A C

    2016-07-01

    Metals occur as mixtures in the environment. Risk assessment procedures for metals currently lack a framework to incorporate chronic metal mixture toxicity. In the present study, the toxicity of binary and ternary mixture combinations of Ni, Zn, and Pb was investigated in 3 large-scale experiments using the standard chronic (7-d) Ceriodaphnia dubia reproductive toxicity test. These metals were selected because of anticipated differences in mode of action. The toxicity of the metals in most mixtures, expressed as either free metal ion activities or as dissolved metal concentrations, were antagonistic relative to the concentration addition model, whereas no significant (p < 0.05) interactive effects were observed relative to the independent action model. The only exception was the binary Pb-Zn mixture, for which mixture effects were noninteractive based on the dissolved concentrations, but antagonistic based on free ion activities all relative to the independent action model. Overall, the independent action model fitted the observed toxicity better than the concentration addition model, which is consistent with the different modes of action of these metals. The concentration addition model mostly overestimated toxicity. Finally, the present study warns against extrapolation of the type of interactive effects between species, even when they are closely related. Environ Toxicol Chem 2016;35:1796-1805. © 2015 SETAC. PMID:26648335

  8. Reproductive toxicity of a single dose of 1,3-dinitrobenzene in two ages of young adult male rats

    EPA Science Inventory

    These studies evaluated the reproductive response and the possible influence of testicular maturation on the reproductive parameters, in male rats treated with 1,3-dinitrobenzene (m-DNB). Young adult male rats (75 or 105 days of age) were given a single oral dose of 0, 8, 16, 24,...

  9. Histone H3 lysine 27 and 9 hypermethylation within the Bad promoter region mediates 5-Aza-2'-deoxycytidine-induced Leydig cell apoptosis: implications of 5-Aza-2'-deoxycytidine toxicity to male reproduction.

    PubMed

    Choi, Ji-Young; Lee, Sangmi; Hwang, Soojin; Jo, Sangmee Ahn; Kim, Miji; Kim, Young Ju; Pang, Myung-Geol; Jo, Inho

    2013-01-01

    5-Aza-2'-deoxycitidine (5-Aza), an anticancer agent, results in substantial toxicity to male reproduction, causing a decline in sperm quality associated with reduced testosterone. Here, we report that 5-Aza increased the apoptotic protein Bad epigenetically in the testosterone-producing mouse TM3 Leydig cell line. 5-Aza decreased cell viability in a dose- and time-dependent manner with concomitant increase in Bad protein. This increase is accompanied by increased cleavages of both poly ADP ribose polymerase and caspase-3. Flow cytometric analysis further supported 5-Aza-derived apoptosis in TM3 cells. Bisulfite sequencing analysis failed to identify putative methylcytosine site(s) in CpG islands of the Bad promoter. A chromatin immunoprecipitation assay revealed decreased levels of trimethylation at lysine 27 of histone H3 (H3K27-3me) and H3K9-3me in the Bad promoter region in response to 5-Aza treatment. Knock-down by siRNA of enhancer of zeste homologue 2 (EZH2), a histone methyltransferase responsible for H3K27-3me, or demethylation of H3K9-3me by BIX-01294 showed significantly increased levels in Bad expression and consequent Leydig cell apoptosis. In conclusion, our results demonstrate for the first time that Bad expression is regulated at least by EZH2-mediated H3K27-3me or G9a-like protein/euchromatic histone methyltransferase 1 (GLP/Eu-HMTase1)-mediated H3K9-3me in mouse TM3 Leydig cells, which may be implicated in 5-Aza-derived toxicity to male reproduction.

  10. Grape juice concentrate protects reproductive parameters of male rats against cadmium-induced damage: a chronic assay.

    PubMed

    Pires, Vanessa Cardoso; Gollücke, Andréa Pittelli Boiago; Ribeiro, Daniel Araki; Lungato, Lisandro; D'Almeida, Vânia; Aguiar, Odair

    2013-12-14

    The aim of the present study was to investigate the effects of long-term grape juice concentrate (GJC) consumption, in two dosages, on the reproductive parameters of cadmium-exposed male rats. The effects of the concentrate on body mass gain, plasma testosterone levels, reproductive organ weights, daily sperm production, sperm morphology, testis histopathological and histomorphometrical parameters, and testicular antioxidant markers were investigated. Wistar rats (n 54) were distributed into six groups: CdCl2; cadmium and grape juice I (1·18 g/kg per d); cadmium and grape juice II (2·36 g/kg per d); grape juice I (1·18 g/kg per d); grape juice II (2·36 g/kg per d); control. A single dose of CdCl2 (1·2 mg/kg body weight (BW)) was injected intraperitoneally and the grape juice was administered orally for 56 d. The results indicated that cadmium changed all reproductive and antioxidant parameters. At dosage I (1·18 g/kg BW), GJC consumption did not show the effects against cadmium-induced damages. In contrast, at dosage II (2·36 g/kg BW), the GJC improved the gonadosomatic index (P= 0·003), serum testosterone levels (P= 0·001), the relative weight of epididymis (P= 0·013) and ventral prostate (P= 0·052), the percentage of normal sperm (P= 0·001), and histopathological and histomorphometrical parameters. In addition, at this dosage, normalisation of the enzymatic activity of superoxide dismutase (P= 0·001) and of testicular levels of glutathione (P= 0·03) were observed. The parameters of the non-exposed rats did not depict significant alterations. In conclusion, the product was able to act as a protector of reproductive function against cadmium-induced damage. Such a property was expressed in a dose-dependent manner as the more effective dose was dosage II. The GJC acted possibly by antioxidant mechanisms. PMID:23656754

  11. Assessment by Ames test and comet assay of toxicity potential of polymer used to develop field-capable rapid-detection device to analyze environmental samples

    NASA Astrophysics Data System (ADS)

    Hebert, Amanda; Bishop, Michelle; Bhattacharyya, Dhiman; Gleason, Karen; Torosian, Stephen

    2015-08-01

    There is need for devices that decrease detection time of food-borne pathogens from days to real-time. In this study, a rapid-detection device is being developed and assessed for potential cytotoxicity. The device is comprised of melt-spun polypropylene coupons coated via oxidative chemical vapor deposition (oCVD) with 3,4-Ethylenedioxythiophene (EDOT), for conductivity and 3-Thiopheneethanol (3TE), allowing antibody attachment. The Ames test and comet assay have been used in this study to examine the toxicity potentials of EDOT, 3TE, and polymerized EDOT-co-3TE. For this study, Salmonella typhimurium strain TA1535 was used to assess the mutagenic potential of EDOT, 3TE and the copolymer. The average mutagenic potential of EDOT, 3TE and copolymer was calculated to be 0.86, 0.56, and 0.92, respectively. For mutagenic potential, on a scale from 0 to 1, close to 1 indicates low potential for toxicity, whereas a value of 0 indicates a high potential for toxicity. The comet assay is a single-cell gel electrophoresis technique that is widely used for this purpose. This assay measures toxicity based on the area or intensity of the comet-like shape that DNA fragments produce when DNA damage has occurred. Three cell lines were assessed; FRhK-4, BHK-21, and Vero cells. After averaging the results of all three strains, the tail intensity of the copolymer was 8.8 % and tail moment was 3.0, and is most similar to the untreated control, with average tail intensity of 5.7 % and tail moment of 1.7. The assays conducted in this study provide evidence that the copolymer is non-toxic to humans.

  12. Final report on the reproductive toxicity of n'(hydroxymethyl)-acrylamide (HACR) (CAS No. 924-42-5) in CD-1 (trade name) swiss mice. Laboratory supplement. Report for 1 June 1990-1 April 1991

    SciTech Connect

    Not Available

    1993-01-01

    The document is the laboratory supplement to a report studying the reproductive toxicity of N'(hydroxymethyl)-acrylamide and contains data on conduct of animal testing, as well as information in support of the research effort. Included are background toxicity data, chemical handling information, animal husbandry methods, and the data collection and statistical methods used.

  13. Investigation of olive mill wastewater (OMW) ozonation efficiency with the use of a battery of selected ecotoxicity and human toxicity assays.

    PubMed

    Siorou, Sofia; Vgenis, Theodoros T; Dareioti, Margarita A; Vidali, Maria-Sophia; Efthimiou, Ioanna; Kornaros, Michael; Vlastos, Dimitris; Dailianis, Stefanos

    2015-07-01

    The effects of olive mill wastewater (OMW) on a battery of biological assays, before and during the ozonation process, were investigated in order to assess ozone's efficiency in removing phenolic compounds from OMW and decreasing the concomitant OMW toxicity. Specifically, ozonated-OMW held for 0, 60, 120, 300, 420, 540min in a glass bubble reactor, showed a drastic reduction of OMW total phenols (almost 50%) after 300min of ozonation with a concomitant decrease of OMW toxicity. In particular, the acute toxicity test primarily performed in the fairy shrimp Thamnocephalus platyurus (Thamnotoxkit F™ screening toxicity test) showed a significant attenuation of OMW-induced toxic effects, after ozonation for a period of 120 and in a lesser extent 300min, while further treatment resulted in a significant enhancement of ozonated-OMW toxic effects. Furthermore, ozonated-OMW-treated mussel hemocytes showed a significant attenuation of the ability of OMW to cause cytotoxic (obtained by the use of NRRT assay) effects already after an ozonation period of 120 and to a lesser extent 300min. In accordance with the latter, OMW-mediated oxidative (enhanced levels of superoxide anions and lipid peroxidation by-products) and genotoxic (induction of DNA damage) effects were diminished after OMW ozonation for the aforementioned periods of time. The latter was also revealed by the use of cytokinesis block micronucleus (CBMN) assay in human lymphocytes exposed to different concentrations of both raw- and ozonated-OMW for 60, 120 and 300min. Those findings revealed for a first time the existence of a critical time point during the OMW ozonation process that could be fundamentally used for evaluating OMW ozonation as a pretreatment method of OMW.

  14. Characterization and preliminary toxicity assay of nano-titanium dioxide additive in sugar-coated chewing gum.

    PubMed

    Chen, Xin-Xin; Cheng, Bin; Yang, Yi-Xin; Cao, Aoneng; Liu, Jia-Hui; Du, Li-Jing; Liu, Yuanfang; Zhao, Yuliang; Wang, Haifang

    2013-05-27

    Nanotechnology shows great potential for producing food with higher quality and better taste through including new additives, improving nutrient delivery, and using better packaging. However, lack of investigations on safety issues of nanofood has resulted in public fears. How to characterize engineered nanomaterials in food and assess the toxicity and health impact of nanofood remains a big challenge. Herein, a facile and highly reliable separation method of TiO2 particles from food products (focusing on sugar-coated chewing gum) is reported, and the first comprehensive characterization study on food nanoparticles by multiple qualitative and quantitative methods is provided. The detailed information on nanoparticles in gum includes chemical composition, morphology, size distribution, crystalline phase, particle and mass concentration, surface charge, and aggregation state. Surprisingly, the results show that the number of food products containing nano-TiO2 (<200 nm) is much larger than known, and consumers have already often been exposed to engineered nanoparticles in daily life. Over 93% of TiO2 in gum is nano-TiO2 , and it is unexpectedly easy to come out and be swallowed by a person who chews gum. Preliminary cytotoxicity assays show that the gum nano-TiO2 particles are relatively safe for gastrointestinal cells within 24 h even at a concentration of 200 μg mL(-1) . This comprehensive study demonstrates accurate physicochemical property, exposure, and cytotoxicity information on engineered nanoparticles in food, which is a prerequisite for the successful safety assessment of nanofood products. PMID:23065899

  15. Reference genes for qPCR assays in toxic metal and salinity stress in two flatworm model organisms.

    PubMed

    Plusquin, Michelle; DeGheselle, Olivier; Cuypers, Ann; Geerdens, Ellen; Van Roten, Andromeda; Artois, Tom; Smeets, Karen

    2012-03-01

    The flatworm species Schmidtea mediterranea and Macrostomum lignano have become new and innovative model organisms in stem cell, regeneration and tissue homeostasis research. Because of their unique stem cell system, (lab) technical advantages and their phylogenetic position within the Metazoa, they are also ideal candidate model organisms for toxicity assays. As stress and biomarker screenings are often performed at the transcriptional level, the aim of this study was to establish a set of reference genes for qPCR experiments for these two model organisms in different stress situations. We examined the transcriptional stability of nine potential reference genes (actb, tubb, ck2, cox4, cys, rpl13, gapdh, gm2ap, plscr1) to assess those that are most stable during altered stress conditions (exposure to carcinogenic metals and salinity stress). The gene expression stability was evaluated by means of geNorm and NormFinder algorithms. Sets of best reference genes in these analyses varied between different stress situations, although gm2ap and actb were stably transcribed during all tested combinations. In order to demonstrate the impact of bad normalisation, the stress-specific gene hsp90 was normalised to different sets of reference genes. In contrast to the normalisation according to GeNorm and NormFinder, normalisation of hsp90 in Macrostomum lignano during cadmium stress did not show a significant difference when normalised to only gapdh. On the other hand an increase of variability was noticed when normalised to all nine tested reference genes together. Testing appropriate reference genes is therefore strongly advisable in every new experimental condition.

  16. An evaluation of fish early life stage tests for predicting reproductive and longer-term toxicity from plant protection product active substances.

    PubMed

    Wheeler, James R; Maynard, Samuel K; Crane, Mark

    2014-08-01

    The chronic toxicity of chemicals to fish is routinely assessed by using fish early life stage (ELS) test results. Fish full life cycle (FLC) tests are generally required only when toxicity, bioaccumulation, and persistence triggers are met or when there is a suspicion of potential endocrine-disrupting properties. This regulatory approach is based on a relationship between the results of fish ELS and FLC studies first established more than 35 yrs ago. Recently, this relationship has been challenged by some regulatory authorities, and it has been recommended that more substances should undergo FLC testing. In addition, a project proposal has been submitted to the Organisation for Economic Cooperation and Development (OECD) to develop a fish partial life cycle (PLC) test including a reproductive assessment. Both FLC and PLC tests are animal- and resource-intensive and technically challenging and should therefore be undertaken only if there is clear evidence that they are necessary for coming to a regulatory decision. The present study reports on an analysis of a database of paired fish ELS and FLC endpoints for plant protection product active substances from European Union draft assessment reports and the US Environmental Protection Agency Office of Pesticide Programs Pesticide Ecotoxicity Database. Analysis of this database shows a clear relationship between ELS and FLC responses, with similar median sensitivity across substances when no-observed-effect concentrations (NOECs) are compared. There was also no indication that classification of a substance as a mammalian reproductive toxicant leads to more sensitive effects in fish FLC tests than in ELS tests. Indeed, the response of the ELS tests was generally more sensitive than the most sensitive reproduction NOEC from a FLC test. This analysis indicates that current testing strategies and guidelines are fit for purpose and that there is no need for fish full or partial life cycle tests for most plant protection

  17. A one-generation reproductive toxicity study of 3,4-methylenedioxy-n-methamphetamine (MDMA, Ecstasy), an amphetamine derivative, in C57BL/6 mice.

    PubMed

    Kwack, Seung Jun; Yoon, Kyung Sil; Lim, Seong Kwang; Gwak, Hyo-Min; Kim, Ji Yun; Um, Yoon Mi; Lee, Jung Dae; Hyeon, Ji Hyeon; Kim, Yeon Joo; Kim, Hyung Sik; Lee, Byung-Mu

    2014-01-01

    3,4-Methylenedioxy-N-methamphetamine (MDMA, ecstasy) is an amphetamine derivative and is a popular type of drug that is abused due to its effects on the central nervous system (CNS), including alertness and euphoria. However, life-threatening (brain edema, heart failure, and coma) and fatal hyperthermia sometimes occur in some individuals taking MDMA. In a one-generation reproductive toxicity study, the potential toxicity of chronic exposure of MDMA was investigated on the reproductive capabilities of parental mice (F0), as well as the survival/development of their subsequent offspring (F1). Male and female C57BL/6 mice were administered orally MDMA at 0, 1.25, 5 or 20 mg/kg body weight (b.w.) throughout the study, beginning at the premating period, through mating, gestation, and lactation periods. MDMA did not produce any apparent clinical signs in F0 or F1 mice, and produced no significant changes in body weight, feed/water intake, or organ weights. In contrast, administration of MDMA produced external abnormalities in fetuses, stillbirth and labored delivery, and diminished viability and weaning indices in offspring, but these data were not significant. In addition, physical development of F1 mice was not markedly influenced by MDMA treatment. Nonetheless, serum biochemistry markers showed that levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) were markedly elevated in a dose-dependent manner from 5 mg and higher MDMA/kg b.w., whereas levels of triglycerides (TG), potassium (K), and uric acid (UA) were reduced. Data suggest that MDMA may exert a weak reproductive and developmental toxicity, and the no-observed-adverse-effect level (NOAEL) of MDMA is estimated to be 1.25 mg/kg b.w./d.

  18. An evaluation of fish early life stage tests for predicting reproductive and longer-term toxicity from plant protection product active substances.

    PubMed

    Wheeler, James R; Maynard, Samuel K; Crane, Mark

    2014-08-01

    The chronic toxicity of chemicals to fish is routinely assessed by using fish early life stage (ELS) test results. Fish full life cycle (FLC) tests are generally required only when toxicity, bioaccumulation, and persistence triggers are met or when there is a suspicion of potential endocrine-disrupting properties. This regulatory approach is based on a relationship between the results of fish ELS and FLC studies first established more than 35 yrs ago. Recently, this relationship has been challenged by some regulatory authorities, and it has been recommended that more substances should undergo FLC testing. In addition, a project proposal has been submitted to the Organisation for Economic Cooperation and Development (OECD) to develop a fish partial life cycle (PLC) test including a reproductive assessment. Both FLC and PLC tests are animal- and resource-intensive and technically challenging and should therefore be undertaken only if there is clear evidence that they are necessary for coming to a regulatory decision. The present study reports on an analysis of a database of paired fish ELS and FLC endpoints for plant protection product active substances from European Union draft assessment reports and the US Environmental Protection Agency Office of Pesticide Programs Pesticide Ecotoxicity Database. Analysis of this database shows a clear relationship between ELS and FLC responses, with similar median sensitivity across substances when no-observed-effect concentrations (NOECs) are compared. There was also no indication that classification of a substance as a mammalian reproductive toxicant leads to more sensitive effects in fish FLC tests than in ELS tests. Indeed, the response of the ELS tests was generally more sensitive than the most sensitive reproduction NOEC from a FLC test. This analysis indicates that current testing strategies and guidelines are fit for purpose and that there is no need for fish full or partial life cycle tests for most plant protection

  19. NTP-CERHR EXPERT PANEL UPDATE ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DI(2-ETHYLHEXYL) PHTHALATE.

    EPA Science Inventory

    The purpose of the Center is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed.

  20. Probe-free real-time reverse transcription polymerase chain reaction assays for the detection and typing of porcine reproductive and respiratory syndrome virus in Canada

    PubMed Central

    Eschbaumer, Michael; Li, Wansi (May); Wernike, Kerstin; Marshall, Frank; Czub, Markus

    2015-01-01

    Porcine reproductive and respiratory syndrome (PRRS) has tremendous impact on the pork industry in North America. The molecular diagnosis of infection with PRRS virus (PRRSV) is hampered by its considerable strain diversity. In this study, 43 previously published or newly developed primers for probe-free real-time reverse transcription polymerase chain reaction (RT-PCR) were evaluated on their sensitivity, specificity, reproducibility, and repeatability, using a diverse panel of 36 PRRSV strains as well as other arteriviruses and unrelated porcine viruses. Three primer pairs had excellent diagnostic and analytical sensitivity on par with a probe-based reference assay, absolute specificity to virus genotype and species, as well as over 95% reproducibility and repeatability across a wide dynamic range. PMID:26130848

  1. Probe-free real-time reverse transcription polymerase chain reaction assays for the detection and typing of porcine reproductive and respiratory syndrome virus in Canada.

    PubMed

    Eschbaumer, Michael; Li, Wansi May; Wernike, Kerstin; Marshall, Frank; Czub, Markus

    2015-07-01

    Porcine reproductive and respiratory syndrome (PRRS) has tremendous impact on the pork industry in North America. The molecular diagnosis of infection with PRRS virus (PRRSV) is hampered by its considerable strain diversity. In this study, 43 previously published or newly developed primers for probe-free real-time reverse transcription polymerase chain reaction (RT-PCR) were evaluated on their sensitivity, specificity, reproducibility, and repeatability, using a diverse panel of 36 PRRSV strains as well as other arteriviruses and unrelated porcine viruses. Three primer pairs had excellent diagnostic and analytical sensitivity on par with a probe-based reference assay, absolute specificity to virus genotype and species, as well as over 95% reproducibility and repeatability across a wide dynamic range.

  2. Fish multigeneration test with preliminary short-term reproduction assay for estrone using Japanese medaka (Oryzias latipes).

    PubMed

    Nakamura, Ataru; Tamura, Ikumi; Takanobu, Hitomi; Yamamuro, Masumi; Iguchi, Taisen; Tatarazako, Norihisa

    2015-01-01

    The most potent chemicals potentially causing adverse effects on fish species are estrogens in human waste.Sewage is a source of these estrogens and it is difficult to reduce. In particular, although the bioactivity of estrone is estimated to be about half of that of estradiol, multiple studies report that more than 100 ng l(–1) of estrone can be detected in urban rivers, including discharges from sewage treatment works; approximately two times as high as estradiol. Few studies have been conducted to investigate the long-term effects of estrone on wildlife; therefore, we conducted fish multigeneration test using Japanese medaka (Oryzias latipes). Medaka were exposed to estrone for 27 weeks across three generations in environmentally relevant concentrations, being 5.74, 11.4, 24.0, 47.1 and 91.4 ng l(–1). No effects on reproduction were observed in the first generation; however, a decline in egg production and fertility was observed in the second generation exposed to 91.4 ng l(–1) estrone, which is lower than some known environmental concentrations in urban environments. Furthermore, histopathological abnormalities were observed in the third generation exposed to both 47.1 and 91.4 ng l(–1), suggesting that estrone possibly exerts severe effects on the third or later generations. However, appearances of testis–ova were observed in the second and third generation they were not consistent with actual effects on reproduction, notwithstanding the testis-ovais regarded as the key evidence for endocrine disruption. Accordingly, we consider that qualitative measurement of abnormalities using histopathological observations is required for appropriate evaluation of endocrine disruption. PMID:25580481

  3. Testing environmental pollutants on soil organisms: A simple assay to investigate the toxicity of environmental pollutants on soil organisms, using CdCl2 and nematodes

    SciTech Connect

    van Kessel, W.H.; Brocades Zaalberg, R.W.; Seinen, W. )

    1989-10-01

    Juvenile stages of Caenorhabditis elegans (nematoda) were isolated and grown in an axenic medium containing various concentrations of CdCl2. Growth of the organisms was significantly reduced from a level of 1 microM CdCl2. Reproduction of the nematodes was also reduced from that 1 microM exposure level. At levels of 160 and 320 microM, growth was retarded at the early juvenile stages and the organisms did not reach the adult stage and could therefore not reproduce. The test system turned out to be simple and reproducible and is therefore suitable for the investigation of the toxicity of compounds to soil nematodes.

  4. Rapid aquatic toxicity assay using incorporation of tritiated-thymidine into sea urchin, Arbacia punctulata, embryo: evaluation of toxicant exposure procedures

    SciTech Connect

    Nacci, D.E.; Jackim, E.

    1985-01-01

    Toxicity of substances in seawater was measured using growth inhibition of embryonic sea urchins during a short period after fertilization. Growth of Arbacia punctulata embryos was monitored by incorporation of tritium-labeled thymidine. The paper presents a comparison of toxicant exposure procedures using the Arbacia embryo thymidine incorporation test. Toxicant exposure began before, at the time of, or after fertilization and continued for 4 h following fertilization. In addition to the eight organic chemicals tested for comparison to acute toxicity values for other species, several chemicals with embryotoxic potentials (tumor promoters and teratogens) were tested to determine differential sensitivities of exposed life-stages: unfertilized egg, fertilization, and early embryo. EC50 values for any one substance were not significantly changed by exposure modification. Toxicity values for exposures that included fertilization as well as early embryo growth were at least as sensitive as post-fertilization exposure values for all compounds tested except one. Because of technical ease and potential sensitivity, toxicant exposure that includes fertilization as well as early embryo growth (but not unfertilized egg exposure) is recommended for future testing.

  5. Comparison of Toxicity of CdSe: ZnS Quantum Dots on Male Reproductive System in Different Stages of Development in Mice

    PubMed Central

    Amiri, Gholamreza; Valipoor, Akram; Parivar, Kazem; Modaresi, Mehrdad; Noori, Ali; Gharamaleki, Hamideh; Taheri, Jafar; Kazemi, Ali

    2016-01-01

    Background Quantum dots (QDs) are new types of fluorescent materials for biological labeling. QDs toxicity study is an essential requirement for future clinical applications. Therefore, this study aimed to evaluate cytotoxic effects of CdSe: ZnS QDs on male reproductive system. Materials and Methods In this experimental study, the different concentrations of CdSe: ZnS QDs (10, 20 and 40 mg/kg) were injected to 32 male mice (adult group) and 24 pregnant mice (embryo group) on day 8 of gestation. The histological changes of testis and epididymis were studied by a light microscopy, and the number of seminiferous tubules between two groups was compared. One-way analysis of variance (one-way Anova) using the Statistical Package for the Social Sciences (SPSS, SPSS Inc., USA) version 16 were performed for statistical analysis. Results In adult group, histological studies of testis tissues showed a high toxicity of CdSe: ZnS in 40 mg/kg dose followed by a decrease in lamina propria; destruction in interstitial tissue; deformation of seminiferous tubules; and a reduction in number of spermatogonia, spermatocytes, and spermatids. However, there was an interesting result in fetal testis development, meaning there was no significant effect on morphology and structure of the seminiferous tubules and number of sperm stem cells. Also histological study of epididymis tissues in both groups (adult and embryo groups) showed no significant effect on morphology and structure of tubule and epithelial cells, but there was a considerable reduction in number of spermatozoa in the lumen of the epididymal duct in 40 mg/kg dose of adult group. Conclusion The toxicity of QDs on testicular tissue of the mice embryo and adult are different before and after puberty. Due to lack of research in this field, this study can be an introduction to evaluate the toxicity of QDs on male reproduction system in different stages of development. PMID:26985339

  6. An aqueous platinum nanotube based fluorescent immuno-assay for porcine reproductive and respiratory syndrome virus detection.

    PubMed

    Chen, Lu; Ye, Shiyi; Cai, Kai; Zhang, Cuiling; Zhou, Guohua; He, Zhike; Han, Heyou

    2015-11-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) has been a significant pathogen towards global swine industry upon its emergence in the late 1980s and since then has exemplified a rapidly evolving, widely spreading pathogen. It is urgently important to develop a simple, rapid and cost effective method to detect this pathogen when virus outbreaks. In the present work, it was found that virus antibody modified platinum nanotubes (Pt-Ab) could act as a superquencher to CdTe:Zn(2+) quantum dots (CdTe:Zn(2+) QDs) fluorescence by Stern-Volmer constants nearly 10(9) M(-1) without any aggregation, the CdTe:Zn(2+) QDs fluorescence will recover as the Pt-Ab goes away by antibody and antigen interaction when virus was added into the probe solution, releasing CdTe:Zn(2+) QDs from the surface of Pt-Ab. By the recovery fluorescence intensity, it can realize qualitative and quantitative detection of PRRSV. This method gives a fast response to PRRSV concentration and provides a sensitive detection limit (2.4 ng/mL). Moreover, it can be applied in infected porcine serum samples and obtain satisfied results.

  7. Assessment of the Endocrine Toxicity of the Fungicide Prochloraz using the Larval Amphibian Growth and Development Assay

    EPA Science Inventory

    Prochloraz is a broad spectrum fungicide that acts by inhibiting ergosterol biosynthesis in target species. Toxicity results in non-target vertebrate species suggest this toxicant acts as an endocrine disruptor that inhibits aromatase, the enzyme responsible for the conversion of...

  8. Protein electron transfer (mechanism and reproductive toxicity): iminium, hydrogen bonding, homoconjugation, amino acid side chains (redox and charged), and cell signaling.

    PubMed

    Kovacic, Peter

    2007-03-01

    This contribution presents novel biochemical perspectives of protein electron transfer (ET) with focus on the iminium nature of the peptide link, along with relationships to reproductive toxicity. The favorable influence of hydrogen bonding on protein ET has been widely documented. Hydrogen bonding of the zwitterionic peptide enhances iminium character. A wide array of such bonding agents is available in vivo, with many reports on the peptide link itself. ET proceeds along the backbone, due in part, to homoconjugation. Redox amino acids (AAs), mainly tyrosine (Tyr), tryptophan (Typ), histidine (His), cysteine (Cys), disulfide, and methionine (Met), are involved in the competing processes for radical formation: direct hydrogen atom abstraction versus electron and proton loss. It appears that the radical or radical cation generated during the redox process is capable of interacting with n-electrons of the backbone. Beneficial effects of cationic AAs impact the conduction process. A relationship apparently exists involving cell signaling, protein conduction, and radicals or electrons. In addition, the link between protein ET and reproductive toxicity is examined. A key element is the role of reactive oxygen species (ROS) generated by protein ET. There is extensive evidence for involvement of ROS in generation of birth defects. The radical species arise in protein mainly by ET transformations by enzymes, as illustrated in the case of alcoholism.

  9. Protective role of N-Acetyl L-Cysteine against reproductive toxicity due to interaction of lead and cadmium in male Wistar rats

    PubMed Central

    Kumar, Banothu Anil; Reddy, Alla Gopala; Kumar, Pentela Ravi; Reddy, Yerradoddi Ramana; Rao, Thirtham Madava; Haritha, Chiluka

    2013-01-01

    Introduction: One of the target organs of heavy metals is testis and many authors proposed that oxidative stress could be responsible to induce their toxicity. An experimental study was conducted to evaluate the molecular mechanisms of lead (Pb) and cadmium (Cd) toxicity, their toxicodynamic interaction and to evaluate therapeutic potential of N-Acetyl L-cysteine (NAC) against the reproductive toxicity in male Wistar rats. Material and methods: rats were randomly divided into 8 groups comprising of 6 rats in each. Group 1 and 2 were syam and NAC control, Group 3, 4 and 5 were kept as toxic control groups such as lead, cadmium and lead + cadmium respectively, where as Group 6, 7 and 8 were therapeutic groups with NAC. The experiment scheduled for 3 months. Body weights, anti-oxidant profile (GSH, GST, TBARS and protein carbonyls) in testis, testis weight, testicular LDH, sperm count and histopathology were conducted. And also, interaction of Pb and Cd with zinc (Zn) and copper (Cu) in testis was assessed. Results: The present study revealed significant alterations in body weights, anti-oxidant profile, weights of testes, testicular LDH, sperm count, and concentration of Zn and Cu in toxic control groups 3, 4 and 5 as compared to control and NAC-treated groups. The toxic combination (Pb+Cd) group 5 showed significant alterations in protein carbonyls, GST levels and testicular LDH as compared to Pb and Cd alone administered groups and these results are substantiated with marked changes in the histopathology. All the NAC-treated groups revealed significant improvement in all the parameters. Conclusion: The results of the investigation revealed that Pb, Cd and their combination induces toxicity to the biological system due to the excess generation of free radicals and impairment of anti-oxidant defenses. Toxic effects were more pronounced in the group that received a combination of Pb and Cd, suggesting positive toxicodynamic interaction. Use of NAC countered the

  10. Allethrin induced toxicity in the male reproductive tract of rats contributes to disruption in the transcription of genes involved in germ cell production.

    PubMed

    Madhubabu, Golla; Yenugu, Suresh

    2014-11-01

    Pyrethroids are known to be neurotoxic. However, their toxic effects including that of allethrin on the male reproductive tract are not elucidated. Adult male rats were treated orally with 25, 50, 100, and 150 mg/kg body weight allethrin every day for 60 days. Lipid peroxidation was increased (p < 0.001) in the caput, cauda, and testes. Nitric oxide production was increased (p < 0.001) in the caput, but unaltered in the cauda and testes. The activities of catalase, glutathione peroxidase, glutathione-S-transferase, and superoxide dismutase were decreased in the caput and cauda where as a decrease was observed in the testis obtained from allethrin treated rats. In the epididymides and testes, damage to tubular architecture, congestion, degeneration of epithelial cell lining, intestinal edema, and presence of dead or degenerating spermatids were observed in a dose dependent manner. The expression profile of genes involved in spermatogenesis (Tgf-beta1), sperm maturation (Spag11e), and sperm function (Defb22) were reduced (p < 0.001) in allethrin rats. The expression of p53 gene was decreased and increased phosphorylation of MAPK (p42/p44) expression was observed the male reproductive tract tissues of allethrin treated rats. Although earlier studies have reported the effects of allethrin inhalation because of the use of mosquito coils and vaporizers, our results for the first time prove that oral exposure to allethrin could affect fertility and may contribute to deregulation of cell cycle in the male reproductive tract.

  11. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 19). Effects of two-week repeated dosing of enoxacin on the male reproductive organs.

    PubMed

    Kizawa, K; Furubo, S; Sanzen, T; Kawamura, Y

    2000-10-01

    The toxicity of Enoxacin (ENX), a fluoroquinolone antibacterial agent, on the testis and epididymis was studied in rats. ENX was administered to 5 male rats orally once daily for 2 weeks at the dose level of 3000 mg/kg/day. ENX-treated rats showed a marked decrease in body weight, and two of them died on Day 10. At the end of the dosing period, absolute weights of the epididymis were decreased; in contrast, relative weights of testis were increased in the ENX-treated group. On histopathological examination, testis of ENX-treated rats exhibited the following regressive changes: degeneration of spermatids and spermatocytes, retention of Step 19 spermatids, chromatin margination in nuclei of spermatids, multinucleated giant cell formation, and/or vacuolar degeneration of Sertoli cells. Additionally, desquamated cell debris was observed in the epididymis. Degenerative spermatids and spermatocytes were strongly positive by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). From these results, it is concluded that a 2-week treatment is sufficient to detect toxic effects of ENX on reproductive organs in male rats, and that testicular toxicity induced by ENX is associated with germ cell apoptosis.

  12. A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrine-disrupting chemicals.

    PubMed

    Ankley, Gerald T; Jensen, Kathleen M

    2014-11-01

    The fish short-term reproduction assay (FSTRA) is a key component of the US Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP), which uses a weight-of-evidence analysis based on data from several assays to identify the potential for chemicals to act as agonists or antagonists of the estrogen or androgen receptors (ER and AR), or inhibitors of steroidogenic enzymes. The FSTRA considers a variety of mechanistic and apical responses in 21-d exposures with the fathead minnow (Pimephales promelas), including plasma steroid and vitellogenin (VTG; egg yolk protein) concentrations, secondary sex characteristics, gonad size and histopathology, and egg production. Although the FSTRA initially was described several years ago, recent data generation associated with implementation of the EDSP highlighted the need for more formal guidance regarding evaluation of information from the assay. The authors describe a framework for interpretation of FSTRA data relative to perturbation of endocrine pathways of concern to the EDSP. The framework considers end points individually and as suites of physiologically related responses relative to pathway identification. Sometimes changes in single end points can be highly diagnostic (e.g., induction of VTG in males by ER agonists, production of male secondary sex characteristics in females by AR agonists); in other instances, however, multiple, related end points are needed to reliably assess pathway perturbation (e.g., AR antagonism, steroid synthesis inhibition). In addition to describing an interpretive framework, the authors demonstrate its practical utility using publicly available FSTRA data for a wide range of known and hypothesized endocrine-disrupting chemicals. Environ Toxicol Chem 2014;33:2529-2540. Published 2014 Wiley Periodicals Inc., on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

  13. A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrine-disrupting chemicals.

    PubMed

    Ankley, Gerald T; Jensen, Kathleen M

    2014-11-01

    The fish short-term reproduction assay (FSTRA) is a key component of the US Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP), which uses a weight-of-evidence analysis based on data from several assays to identify the potential for chemicals to act as agonists or antagonists of the estrogen or androgen receptors (ER and AR), or inhibitors of steroidogenic enzymes. The FSTRA considers a variety of mechanistic and apical responses in 21-d exposures with the fathead minnow (Pimephales promelas), including plasma steroid and vitellogenin (VTG; egg yolk protein) concentrations, secondary sex characteristics, gonad size and histopathology, and egg production. Although the FSTRA initially was described several years ago, recent data generation associated with implementation of the EDSP highlighted the need for more formal guidance regarding evaluation of information from the assay. The authors describe a framework for interpretation of FSTRA data relative to perturbation of endocrine pathways of concern to the EDSP. The framework considers end points individually and as suites of physiologically related responses relative to pathway identification. Sometimes changes in single end points can be highly diagnostic (e.g., induction of VTG in males by ER agonists, production of male secondary sex characteristics in females by AR agonists); in other instances, however, multiple, related end points are needed to reliably assess pathway perturbation (e.g., AR antagonism, steroid synthesis inhibition). In addition to describing an interpretive framework, the authors demonstrate its practical utility using publicly available FSTRA data for a wide range of known and hypothesized endocrine-disrupting chemicals. Environ Toxicol Chem 2014;33:2529-2540. Published 2014 Wiley Periodicals Inc., on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID:25098918

  14. miR-541 Contributes to Microcystin-LR-Induced Reproductive Toxicity through Regulating the Expression of p15 in Mice.

    PubMed

    Meng, Xiannan; Zhang, Ling; Chen, Xiang; Xiang, Zou; Li, Dongmei; Han, Xiaodong

    2016-01-01

    Microcystin-leucine arginine (MC-LR) is a harmful cyanotoxin produced by cyanobacteria. MC-LR can exert endocrine-disrupting activities in many organisms. We have previously demonstrated that MC-LR exerts both acute and chronic reproductive toxicity in male mice, resulting in a decline in sperm quality and damage to testicular structure. Moreover, we also observed extensive alterations in a panel of microRNAs in spermatogonial cells after exposure to MC-LR. In this study, we have confirmed that miR-541 was significantly increased both in GC-1 cells (in vitro) and in mouse testes (in vivo) after exposure to MC-LR. Our data support that p15 was the target gene of miR-541. Increase in miR-541 led to a reduction of p15 and murine double minute2 (MDM2), promoting the activation of p53 signaling and MC-LR-mediated cell apoptosis. Moreover, cells responded to MC-LR with reduced viability and increased apoptosis. Consistently, inhibiting miR-541 could upregulate the expression of p15 and MDM2, resulting in the downregulation of phospho-p53. Downregulation of miR-541 promoted cell viability by reducing MC-LR-induced cell apoptosis. In conclusion, we demonstrate here a crucial role for miR-541 in MC-LR-induced toxic effects on the reproductive system, in an attempt to provide a rational strategy for the diagnosis and treatment of MC-LR-induced impairment in the reproductive system. PMID:27608041

  15. miR-541 Contributes to Microcystin-LR-Induced Reproductive Toxicity through Regulating the Expression of p15 in Mice

    PubMed Central

    Meng, Xiannan; Zhang, Ling; Chen, Xiang; Xiang, Zou; Li, Dongmei; Han, Xiaodong

    2016-01-01

    Microcystin-leucine arginine (MC-LR) is a harmful cyanotoxin produced by cyanobacteria. MC-LR can exert endocrine-disrupting activities in many organisms. We have previously demonstrated that MC-LR exerts both acute and chronic reproductive toxicity in male mice, resulting in a decline in sperm quality and damage to testicular structure. Moreover, we also observed extensive alterations in a panel of microRNAs in spermatogonial cells after exposure to MC-LR. In this study, we have confirmed that miR-541 was significantly increased both in GC-1 cells (in vitro) and in mouse testes (in vivo) after exposure to MC-LR. Our data support that p15 was the target gene of miR-541. Increase in miR-541 led to a reduction of p15 and murine double minute2 (MDM2), promoting the activation of p53 signaling and MC-LR-mediated cell apoptosis. Moreover, cells responded to MC-LR with reduced viability and increased apoptosis. Consistently, inhibiting miR-541 could upregulate the expression of p15 and MDM2, resulting in the downregulation of phospho-p53. Downregulation of miR-541 promoted cell viability by reducing MC-LR-induced cell apoptosis. In conclusion, we demonstrate here a crucial role for miR-541 in MC-LR-induced toxic effects on the reproductive system, in an attempt to provide a rational strategy for the diagnosis and treatment of MC-LR-induced impairment in the reproductive system. PMID:27608041

  16. Food Emulsifier Glycerin Monostearate Increases Internal Exposure Levels of Six Priority Controlled Phthalate Esters and Exacerbates Their Male Reproduct