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Sample records for reproductive toxicity assay

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

    PubMed

    Knapen, Dries; Vergauwen, Lucia; Villeneuve, Daniel L; Ankley, Gerald T

    2015-08-15

    Historically, the prediction of reproductive and 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 mechanistic information from existing assays. However, a single AOP may not capture all events that contribute to any relevant toxic effect, even in single chemical exposure scenarios. AOP networks, defined as sets of AOPs sharing at least one common element, are capable of more realistically representing potential chemical effects. They provide information on interactions between AOPs and have the potential to reveal previously unknown links between biological pathways. Analysis of these AOP networks can aid the prioritization of assay development, whether the goal is to develop a single assay with predictive utility of multiple outcomes, or development of assays that are highly specific for a particular mode of action. This paper provides a brief overview of the AOPs related to reproductive and developmental toxicity currently available in the AOP Wiki (http://aopwiki.org), and gives an example of an AOP network based on five reproductive and developmental toxicity-related AOPs for fish to illustrate how AOP networks can be used for assay development and refinement.

  2. 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.

  3. 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

  4. 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...

  5. Results of testing fifteen glycol ethers in a short-term in vivo reproductive toxicity assay.

    PubMed

    Schuler, R L; Hardin, B D; Niemeier, R W; Booth, G; Hazelden, K; Piccirillo, V; Smith, K

    1984-08-01

    Fifteen glycol ethers were investigated for their potential to cause adverse reproductive toxic effects using an in vivo mouse screening bioassay. Pregnant mice were orally dosed once per day on days 7 through 14 of gestation at concentrations causing 0 to 41% maternal mortality. Reproductive endpoints included pup survival in utero (percent of live litters/pregnant survivors), pup perinatal and postnatal survival (number of live pups per litter, number of dead pups per litter, and pup survival to 2.5 days of age), and pup body weight statistics (weight at birth and weight at 2.5 days of age). The study was conducted in two phases: a dose range-finding phase using nonpregnant female mice, and a definitive reproductive phase using time-mated mice. The range-finding phase sought to identify, for each chemical, the maternal LD10 as the target dose. However, based upon reproductive phase results, such an exact dose was impractical to achieve. Thus, a range from the LD5 to the LD20 was considered a sufficient challenge dose that would not affect results due to high mortality, i.e., greater than the LD20. Glycol ethers were assigned to groups having different priorities for further testing based upon whether a sufficient challenge dose was administered and the degree of effects recorded for each chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. An in vitro high-throughput assay for screening reproductive and toxic effects of anticancer compounds.

    PubMed

    Edwards, Vicki; Benkendorff, Kirsten; Young, Fiona

    2014-01-01

    An in vitro assay was developed that simultaneously tested the effects of anticancer drug candidates on cytotoxicity, hormone synthesis, and gonadotrophin responsiveness using the choriocarcinoma JAr cell line. JAr culture conditions were optimized and then cells were exposed to a marine mollusc extract in the presence and absence of hCG. The intra- and interassay coefficients of variation of the optimized 1 H thiazolyl blue tetrazolium bromide assay were 11.3% and 10.9%, respectively. hCG (1,000 mIU/mL) increased progesterone (P4) synthesis after 24 H (P<0.05). The mollusc extract significantly decreased cell viability, with the IC50 affected by incubation time, but not hCG. P4 synthesis was inhibited at low concentrations of the anticancer extract, but stimulated at the highest concentration, and complex interactions of P4 were also found with hCG. In conclusion, the optimized assay is useful to characterize the effects of novel drugs on cytotoxicity, basal, and gonadotrophin-stimulated P4 synthesis in vitro, and can be used to inform subsequent in vivo studies.

  7. 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.

  8. Nordic criteria for reproductive toxicity.

    PubMed

    Taskinen, H K

    1995-08-01

    Scientific criteria for assessment of the reproductive toxicity of chemicals have been proposed by a Nordic group of experts and regulatory representatives. The criteria take into account the results of clinical studies as well as of experimental research. The criteria should be useful in, for example, product control and labeling and planning of a safe work environment. The proposed Nordic criteria and examples of the assessment of the reproductive toxicity of some chemicals are presented.

  9. 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...

  10. Guidelines for Reproductive Toxicity Risk Assessment

    EPA Pesticide Factsheets

    These guidelines discuss the scientific basis for concern about exposure to agents that cause reproductive toxicity and describe the principles and procedures to be followed in conducting risk assessments for reproductive toxicity.

  11. Test systems to identify reproductive toxicants.

    PubMed

    Riecke, K; Stahlmann, R

    2000-09-01

    Experience with drugs and other xenobiotics indicates that both animal testing and epidemiological studies are necessary to provide adequate data for an estimation of risks that might be associated with exposure to a chemical substance. In this review, the pros and cons of test systems for reproductive toxicity are discussed. Usually, several studies are performed to cover the different phases of the reproductive cycle. In the preclinical development of drugs, the three so-called 'segment testing protocols' have been used for several decades now. More recently, new testing concepts have been accepted internationally which include more flexibility in implementation. Several examples of compounds with the potential for reproductive toxicity are presented in more detail in a discussion of some pitfalls of the tests for fertility (phthalates and fluoroquinolones), teratogenicity (acyclovir and protease inhibitors) and postnatal developmental toxicity (fluoroquinolones). In addition, important aspects of kinetics and metabolism as a prerequisite for a rational interpretation of results from toxicological studies are briefly discussed. In vitro assays are useful for supplementing the routinely used in vivo approaches or for studying an expected or defined effect, but they are not suitable for revealing an unknown effect of a chemical on the complex reproductive process.

  12. 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...

  13. TOXIC RESPONSES OF THE REPRODUCTIVE SYSTEM

    EPA Science Inventory

    Fish reproduction is arguably one of the most sensitive indicators of exposure to environmental chemicals. Reproductive toxicity can simply be referred to as an alteration in reproductive success. It can occur at several developmental stages (larval, juvenile, and adult) with le...

  14. 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...

  15. 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.

  16. 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.

  17. ASSESSMENT OF MALE REPRODUCTIVE TOXICITY

    EPA Science Inventory

    This chapter reviews the subject of risk assessment in male reproductive toxicology. After providing an overview of the risk assessment process, laboratory test protocols, including those specified by EPA and used by NIEHS are summarized and discussed in detail with respect to t...

  18. 7 day chronic ceriodaphnia toxicity test -- reproductive

    SciTech Connect

    Not Available

    1989-01-01

    This toxicity test was conducted to determine if the effluent causes death (acute toxicity) or reduction in the reproduction of the test organisms (chronic toxicity) during a seven day period. A series of dilutions of the effluent are set to determine how much the effluent must be diluted before toxic effects are no longer noted. Acute toxicity is checked by statistically analyzing whether significantly more organisms die in the effluent dilutions than in the control treatment, and, if significantly more die, how much the effluent must be diluted so as to kill only 50% of the test organisms (the LC50). Chronic toxicity is checked by statistically analyzing whether significantly fewer young are produced by test organisms exposed to the effluent dilutions. Results indicate the lowest effluent concentration which shows a toxic effect (the LOEC) and the highest effluent concentration which does not demonstrate an effect (NOEC).

  19. Developmental Toxicity Assays Using the Drosophila Model

    PubMed Central

    Rand, Matthew D.; Montgomery, Sara L.; Prince, Lisa; Vorojeikina, Daria

    2014-01-01

    The fruit fly (Drosophila melanogaster) has long been a premier model for developmental biologists and geneticists. The utility of Drosophila for toxicology studies has only recently gained broader recognition as a tool to elaborate molecular genetic mechanisms of toxic substances. In this article two practical applications of Drosophila for developmental toxicity assays are described. The first assay takes advantage of newly developed methods to render the fly embryo accessible to small molecules, toxicants and drugs. The second assay engages straightforward exposures to developing larvae and easy to score outcomes of adult development. With the extensive collections of flies that are publicly available and the ease with which to create transgenic flies, these two assays have a unique power for identifying and characterizing molecular mechanisms and cellular pathways specific to the mode of action of a number of toxicants and drugs. PMID:24789363

  20. Thyroid toxicants: assessing reproductive health effects.

    PubMed Central

    Jahnke, Gloria D; Choksi, Neepa Y; Moore, John A; Shelby, Michael D

    2004-01-01

    A thyroid toxicant workshop sponsored by the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction convened on 28-29 April 2003 in Alexandria, Virginia. The purpose of this workshop was to examine and discuss chemical-induced thyroid dysfunction in experimental animals and the relevance of reproductive and developmental effects observed for prediction of adverse effects in humans. Presentations highlighted and compared reproductive and developmental effects of thyroid hormones in humans and rodents. Rodent models of thyroid system dysfunction were presented. Animal testing protocols were reviewed, taking into account protocol designs that allow extrapolation to possible human health effects. Potential screening methods to assess toxicant-induced thyroid dysfunction were outlined, and postnatal bioassays of thyroid-related effects were discussed. PMID:14998754

  1. 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.

  2. 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…

  3. 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...

  4. 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

  5. Alternative Models of Developmental and Reproductive Toxicity in Pharmaceutical Risk Assessment and the 3Rs.

    PubMed

    Brannen, Kimberly C; Chapin, Robert E; Jacobs, Abigail C; Green, Maia L

    2016-12-01

    In the pharmaceutical industry, preclinical developmental and reproductive toxicity studies are conducted in laboratory animals in order to predict and prevent adverse effects of drugs on human reproductive health and development. However, these studies require a relatively large number of animals and are usually conducted late in the drug development process. Early, simple, and inexpensive screening assays could facilitate smarter decisions, reductions in animal use, and development of safe drugs. The current state and future needs for alternative models of developmental and reproductive toxicity are reviewed here. The most popular predictive developmental toxicity assays are embryonic stem cells, rodent whole embryo culture, and zebrafish, each of which involves fairly well-developed techniques with demonstrated utility in drug discovery and development. In vitro or ex vivo methods for male and female reproductive toxicity are less established, but there are promising assays available or being developed that may be useful in drug development, especially for elucidating mechanisms or screening backup compounds. While a number of challenges remain, much progress has been made in alternative developmental and reproductive toxicity models to date, and there is a strong collective enthusiasm in the industry to continue moving them forward. Therefore, it appears that these approaches may be widely used in the near future.

  6. 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...

  7. 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

  8. Mercury vapor and female reproductive toxicity.

    PubMed

    Davis, B J; Price, H C; O'Connor, R W; Fernando, R; Rowland, A S; Morgan, D L

    2001-02-01

    Epidemiological studies finding menstrual cycle abnormalities among women occupationally exposed to Hg degrees prompted us to investigate the mechanisms of reproductive toxicity of Hg degrees in the female rat. Nose-only Hg degrees vapor inhalation exposures were conducted on regularly cycling rats 80-90 days of age in dose-response and acute time-course studies, which have previously proven useful as a model to identify ovarian toxicants. Vaginal smears were evaluated daily and serum hormone levels were correlated with cycle and with ovarian morphology at necropsy. Exposure concentration-related effects of Hg degrees were evaluated by exposing rats to 0, 1, 2, or 4 mg/m3 Hg degrees vapor 2 h/day for 11 consecutive days. Tissue Hg levels correlated with exposure concentration and duration. Exposure of rats to 4 mg/m3 (but not 1 or 2 mg/m3) Hg vapor for 11 days resulted in significant decreases in body weights relative to controls. Estrous cycles were slightly prolonged in the 2 and 4 mg/m3 dose groups, and serum estradiol and progesterone levels were significantly different in the 4 mg/m3 group compared to controls. The alterations in cycle and hormones at the 4 mg/m3 exposure concentration were attributed to body weight loss and generalized toxicity. In the time-course study, rats were exposed to 2 mg/m3 Hg degrees or air beginning in metestrus and evaluated daily for 8 days. A lengthening of the cycle was detected and morphological changes were observed in the corpora lutea (CL) after exposure for 6 days. To determine if changes in the CL and cyclicity correlated with a functional defect, rats were exposed to Hg degrees vapor and evaluated for pregnancy outcome. There were no significant effects on pregnancy rate or numbers of implantation sites when rats were exposed to 1 or 2 mg/m3 Hg degrees for 8 days prior to breeding, or when exposed for 8 days after breeding. These studies indicate that exposure to Hg degrees vapor altered estrous cyclicity, but had no

  9. 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.

  10. Assaying environmental nickel toxicity using model nematodes.

    PubMed

    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.

  11. 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

  12. 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...

  13. 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...

  14. 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...

  15. Development of a Reproductive Toxicity Test Using Xenopus.

    DTIC Science & Technology

    2000-05-01

    of the present study was to develop and validate a reproductive toxicity test using Xenopus laevis which measures effects on gametogenesis...reproductive performance, and development fitness of the progeny. Sexually mature female and male Xenopus laevis were exposed to varying concentrations of

  16. 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...

  17. Reproductive toxicity in boron exposed workers in Bandirma, Turkey.

    PubMed

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

    2012-06-01

    Boric acid and sodium borates have been considered as being "toxic to reproduction and development", following results of animal studies with high doses. However unfavorable effects of boron exposure on reproduction and development have not been proved in epidemiological studies so far. The aim of the present study was to investigate the reproductive toxicity indicators in highly exposed workers employed in a boric acid production plant in Bandırma, Turkey. Two hundred and four workers participated in this study. The mean blood boron concentration of the high exposure group of workers was 223.89 ± 69.49 (152.82-454.02)ng/g. Unfavorable effects of boron exposure on the reproductive toxicity indicators were not observed.

  18. 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

  19. 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...

  20. 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.

  1. 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

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  2. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  3. 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

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  4. 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

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  5. 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

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  6. 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.

  7. 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.

  8. 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.

  9. Reproductive and developmental toxicity of dioxin in fish.

    PubMed

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

    2012-05-06

    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.

  10. 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

  11. 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.

  12. 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.

  13. 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...

  14. 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...

  15. 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...

  16. 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.

  17. 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.

  18. 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.

  19. 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...

  20. 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.

  1. Impacts of environmental toxicants on male reproductive dysfunction

    PubMed Central

    Wong, Elissa W.P.; Cheng, C. Yan

    2011-01-01

    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, leading to reproductive dysfunction, such as reduced sperm count and semen quality in men. 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 can possibly 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 elucidate fully the underlying molecular mechanism(s) by which these toxicants disrupt male reproductive function. PMID:21324536

  2. 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.

  3. A DNA-based assay for toxic chemicals in wastewater.

    PubMed

    Foreman, Amy L; Phillips, Leo; Kanellis, Vangelis G; Hammoudeh, Daoud; Naumann, Christoph; Wong, Henri; Chisari, Robert; Hibbert, D Brynn; Lee, Garry S H; Patra, Ronald; Julli, Moreno; Chapman, John; Cooke, A Roger; dos Remedios, Cristobal G

    2011-08-01

    Chemical toxicants, particularly metal ions, are a major contaminant in global waterways. Live-organism bioassays used to monitor chemical toxicants commonly involve measurements of activity or survival of a freshwater cladoceran (Ceriodaphnia dubia) or light emitted by the marine bacterium Vibrio fischeri, used in the commercial Microtox® bioassay. Here we describe a novel molecule-based assay system employing DNA as the chemical biosensor. Metals bind to DNA, causing structural changes that expel a bound (intercalated) fluorescent reporter dye. Analyses of test data using 48 wastewater samples potentially contaminated by metal ions show that the DNA-dye assay results correlate with those from C. dubia and Microtox bioassays. All three assays exhibit additive, antagonistic, and synergistic responses that cannot be predicted by knowing individual metal concentrations. Analyses of metals in these samples imply the presence of chemical toxicants other than metal ions. The DNA-dye assay is robust, has a 12-month shelf life, and is only slightly affected by sample pH in the range 4 to 9. The assay is completed in a matter of minutes, and its portability makes it well suited as a screening assay for use in the field. We conclude that the DNA-dye test is a surrogate bioassay suitable for screening chemical toxicity.

  4. Bioluminescent toxicity assay of synfuel by-product waters

    SciTech Connect

    Delistraty, D.

    1984-05-01

    Large amounts of complex by-product waters, potentially toxic to biological systems, are generated during in situ recovery of fuels from oil shale, coal, and tar sand deposits. Since these by-product waters may contain a broad spectrum of organic and inorganic pollutants, analysis of individual compounds may not always be practical. Separation of complex by-product water into environmentally interpretable hydrophilic (HP) and organophilic (OP) fractions can, however, provide a useful approach for initial toxicity evaluation. The Microtox assay was developed by Beckman Microbics Operations. For this assay, reduction of bacterial luminescence upon exposure to potential inhibitors was used as an index of toxicity. This paper presents results of the Microtox assay on eight whole waters and their HP and OP fractions, derived from oil shale, coal, and tar sand recovery processes.

  5. 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.

  6. 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).

  7. 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

  8. 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.

  9. Reproductive toxicity of nanoscale graphene oxide in male mice.

    PubMed

    Liang, Shanlu; Xu, Shun; Zhang, Ding; He, Junmin; Chu, Maoquan

    2015-02-01

    In the past few years, much work has been performed to explore the biomedical applications and toxicity of nano-graphene and its derivatives. However, the reproductive toxicity of those carbon nanomaterials has been rarely studied. In this study, we report on the male reproductive toxicity of nanoscale graphene oxide (GO) using a mouse model. The results showed that the adult male mice injected with high dosages of GO (25 mg/kg mouse) via the tail vein exhibited normal sex hormone secretion and retained normal reproductive activity. All untreated female mice mated with the GO-treated male mice could produce healthy pups. There were no significant differences in pup numbers, sex ratio, weights, pup survival rates or pup growth over time between the GO-treated and control groups. Furthermore, these GO-treated male mice could produce a second, third, fourth and even fifth litter of healthy offspring when they lived with the untreated female mice. The testicular and epididymal histology as well as the activities of several important epididymal enzymes including α-glucosidase, lactate dehydrogenase, glutathione peroxidase and acid phosphatase were not affected by GO treatment. In addition, no damaging effects were seen at high dose rates of GO (total 300 mg/kg male mouse, 60 mg/kg every 24 h for 5 days) via intra-abdominal injection. Thus, GO showed very low or nearly no toxicity for male reproduction. This work will greatly enable future investigations of GO nanosheets for in vivo biomedical applications.

  10. Reproductive and Developmental Toxicity of Formaldehyde: A Systematic Review

    PubMed Central

    Duong, Anh; Steinmaus, Craig; McHale, Cliona M.; Vaughan, Charles P.; Zhang, Luoping

    2011-01-01

    Formaldehyde, the recently classified carcinogen and ubiquitous environmental contaminant, has long been suspected of causing adverse reproductive and developmental effects, but previous reviews were inconclusive, due in part, to limitations in the design of many of the human population studies. In the current review, we systematically evaluated evidence of an association between formaldehyde exposure and adverse reproductive and developmental effects, in human populations and in vivo animal studies, in the peer-reviewed literature. The mostly retrospective human studies provided evidence of an association of maternal exposure with adverse reproductive and developmental effects. Further assessment of this association by meta-analysis revealed an increased risk of spontaneous abortion (1.76, 95% CI 1.20–2.59, p=0.002) and of all adverse pregnancy outcomes combined (1.54, 95% CI 1.27–1.88, p<0.001), in formaldehyde-exposed women, although differential recall, selection bias, or confounding cannot be ruled out. Evaluation of the animal studies including all routes of exposure, doses and dosing regimens studied, suggested positive associations between formaldehyde exposure and reproductive toxicity, mostly in males. Potential mechanisms underlying formaldehyde-induced reproductive and developmental toxicities, including chromosome and DNA damage (genotoxicity), oxidative stress, altered level and/or function of enzymes, hormones and proteins, apoptosis, toxicogenomic and epigenomic effects (such as DNA methylation), were identified. To clarify these associations, well-designed molecular epidemiologic studies, that include quantitative exposure assessment and diminish confounding factors, should examine both reproductive and developmental outcomes associated with exposure in males and females. Together with mechanistic and animal studies, this will allow us to better understand the systemic effect of formaldehyde exposure. PMID:21787879

  11. 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

  12. Allethrin toxicity causes reproductive dysfunction in male rats.

    PubMed

    Madhubabu, Golla; Yenugu, Suresh

    2017-02-09

    Pyrethroids are widely used for domestic and agricultural purposes and their use is increasing, especially in developing countries. Uncontrolled use of these insecticides resulted in their entry into the food chain thereby causing toxicity to different organ systems. Allethrin is one of the widely used pyrethroids, but its toxicological effects are underreported when compared to other pyrethroids. Further, its effects on the male reproductive tract remain uncharacterized. In this study, its toxicity on the male reproductive tract was evaluated by administering 25-150 mg/kg body weight allethrin to adult rats for 60 days. The mRNA expression of factors that are important in spermatogenesis (Scf, c-Kit, Hsf2, Ovol1, Brdt, Kdm3A, Ybx-2, and Grth) and steroidogenesis (StAR, 3β-HSD, 17β-HSD) was significantly downregulated. Decreased levels of testosterone, reduced sperm count and daily sperm production was also observed due to allethrin toxicity. However, sperm quality parameters assessed by computer-assisted sperm analyzer were not affected. Spermatozoa obtained from allethrin-treated rats failed to undergo acrosome reaction. Results of this study indicate that allethrin affects spermatogenesis and sperm function, thus lending further support to the growing evidence of its toxicity.

  13. 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...

  14. 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

  15. 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.

  16. 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.

  17. Ochratoxin A: developmental and reproductive toxicity-an overview.

    PubMed

    Malir, Frantisek; Ostry, Vladimir; Pfohl-Leszkowicz, Annie; Novotna, Eva

    2013-12-01

    Ochratoxin A (OTA) is nephrotoxic, hepatotoxic, reprotoxic, embryotoxic, teratogenic, neurotoxic, immunotoxic, and carcinogenic for laboratory and farm animals. Male and female reproductive health has deteriorated in many countries during the last few decades. A number of toxins in environment are suspected to affect reproductive system in male and female. OTA is one of them. OTA has been found to be teratogenic in several animal models including rat, mouse, hamster, quail, and chick, with reduced birth weight and craniofacial abnormalities being the most common signs. The presence of OTA also results in congenital defects in the fetus. Neither the potential of OTA to cause malformations in human nor its teratogenic mode of action is known. Exposure to OTA leads to increased embryo lethality manifested as resorptions or dead fetuses. The mechanism of OTA transfer across human placenta (e.g., which transporters are involved in the transfer mechanism) is not fully understood. Some of the toxic effects of OTA are potentiated by other mycotoxins or other contaminants. Therefore, OTA exposure of pregnant women should be minimized. OTA has been shown to be an endocrine disruptor and a reproductive toxicant, with abilities of altering sperm quality. Other studies have shown that OTA is a testicular toxin in animals. Thus, OTA is a biologically plausible cause of testicular cancer in man.

  18. Effectivity of advanced wastewater treatment: reduction of in vitro endocrine activity and mutagenicity but not of in vivo reproductive toxicity.

    PubMed

    Giebner, Sabrina; Ostermann, Sina; Straskraba, Susanne; Oetken, Matthias; Oehlmann, Jörg; Wagner, Martin

    2016-09-06

    Conventional wastewater treatment plants (WWTPs) have a limited capacity to eliminate micropollutants. One option to improve this is tertiary treatment. Accordingly, the WWTP Eriskirch at the German river Schussen has been upgraded with different combinations of ozonation, sand, and granulated activated carbon filtration. In this study, the removal of endocrine and genotoxic effects in vitro and reproductive toxicity in vivo was assessed in a 2-year long-term monitoring. All experiments were performed with aqueous and solid-phase extracted water samples. Untreated wastewater affected several endocrine endpoints in reporter gene assays. The conventional treatment removed the estrogenic and androgenic activity by 77 and 95 %, respectively. Nevertheless, high anti-estrogenic activities and reproductive toxicity persisted. All advanced treatment technologies further reduced the estrogenic activities by additional 69-86 % compared to conventional treatment, resulting in a complete removal of up to 97 %. In the Ames assay, we detected an ozone-induced mutagenicity, which was removed by subsequent filtration. This demonstrates that a post treatment to ozonation is needed to minimize toxic oxidative transformation products. In the reproduction test with the mudsnail Potamopyrgus antipodarum, a decreased number of embryos was observed for all wastewater samples. This indicates that reproductive toxicants were eliminated by neither the conventional nor the advanced treatment. Furthermore, aqueous samples showed higher anti-estrogenic and reproductive toxicity than extracted samples, indicating that the causative compounds are not extractable or were lost during extraction. This underlines the importance of the adequate handling of wastewater samples. Taken together, this study demonstrates that combinations of multiple advanced technologies reduce endocrine effects in vitro. However, they did not remove in vitro anti-estrogenicity and in vivo reproductive toxicity. This

  19. Exposure-based validation list for developmental toxicity screening assays.

    PubMed

    Daston, George P; Beyer, Bruce K; Carney, Edward W; Chapin, Robert E; Friedman, Jan M; Piersma, Aldert H; Rogers, John M; Scialli, Anthony R

    2014-12-01

    Validation of alternative assays requires comparison of the responses to toxicants in the alternative assay with in vivo responses. Chemicals have been classified as "positive" or "negative" in vivo, despite the fact that developmental toxicity is conditional on magnitude of exposure. We developed a list of positive and negative developmental exposures, with exposure defined by toxicokinetic data, specifically maternal plasma Cmax . We selected a series of 20 chemicals that caused developmental toxicity and for which there were appropriate toxicokinetic data. Where possible, we used the same chemical for both positive and negative exposures, the positive being the Cmax at a dose level that produced significant teratogenicity or embryolethality, the negative being the Cmax at a dose level not causing developmental toxicity. It was not possible to find toxicokinetic data at the no-effect level for all positive compounds, and the negative exposure list contains Cmax values for some compounds that do not have developmental toxicity up to the highest dose level tested. This exposure-based reference list represents a fundamentally different approach to the evaluation of alternative tests and is proposed as a step toward application of alternative tests in quantitative risk assessment.

  20. 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

  1. [Ethylene glycol and propylene glycol ethers - Reproductive and developmental toxicity].

    PubMed

    Starek-Świechowicz, Beata; Starek, Andrzej

    2015-01-01

    Both ethylene and propylene glycol alkyl ethers (EGAEs and PGAEs, respectively) are widely used, mainly as solvents, in industrial and household products. Some EGAEs demonstrate gonadotoxic, embriotoxic, fetotoxic and teratogenic effects in both humans and experimental animals. Due to the noxious impact of these ethers on reproduction and development of organisms EGAEs are replaced for considerably less toxic PGAEs. The data on the mechanisms of testicular, embriotoxic, fetotoxic and teratogenic effects of EGAEs are presented in this paper. Our particular attention was focused on the metabolism of some EGAEs and their organ-specific toxicities, apoptosis of spermatocytes associated with changes in the expression of various genes that code for oxidative stress factors, protein kinases and nuclear hormone receptors.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. The reproductive and developmental toxicity of High Flash Aromatic Naphtha.

    PubMed

    McKee, R H; Wong, Z A; Schmitt, S; Beatty, P; Swanson, M; Schreiner, C A; Schardein, J L

    1990-01-01

    Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent--High Flash Aromatic Naphtha. A program was initiated to assess the toxicological properties of High Flash Aromatic Naphtha since there may be human exposure through inhalation or external body contact. The current study was conducted to assess the potential for developmental toxicity in the mouse and for reproductive toxicity in the rat. In the developmental toxicity study in CD-1 mice, exposure of dams by inhalation to near lethal levels (1500 ppm) resulted in fetal mortality, reduced weight, delayed ossification, and an increased incidence of cleft palate. At 500 ppm, a level at which maternal weight gain was slightly reduced, fetal weight gain was also reduced, but there was no other evidence of developmental effects. The lowest exposure level (100 ppm) did not cause any maternal or developmental toxicity. There was no consistent evidence of reproductive toxicity in rats, even at exposure levels which resulted in significantly reduced parental weight gain. In addition, when parental exposure was stopped on GD (gestation day) 20, birth weights as well as postnatal survival were generally similar to control values, even in the 1500 ppm exposure group. Postnatal weight gain was also similar to controls early in weaning, but, if maternal exposure was reinitiated, weight gain was reduced in the high exposure group. However, when exposure was continued until delivery, pups in the high exposure group exhibited reduced litter size, birth weight and poor survival. Thus it was likely that the reduction in fetal weight

  8. Reproductive Toxicities Caused by Swainsonine from Locoweed in Mice

    PubMed Central

    Feng, Ke; Lu, Dezhang; Yan, Dujian; Han, Tiesuo

    2016-01-01

    Swainsonine is the primary toxin in locoweeds. It causes intention tremors, reproductive dysfunction, emaciation, and death. The objective of the present study was to evaluate the potential reproductive and developmental toxicities caused by swainsonine in mice. The treatment groups consisting of three generations of mice were given a range of concentrations of swainsonine by intraperitoneal injection (2.50 mg/kg body weight (BW), 1.20 mg/kg BW, 0.60 mg/kg BW, and 0 mg/kg BW). The 0 mg/kg BW group exhibited significantly fewer estrous cycles and an increased number of estrous ones compared to the 2.50 mg/kg BW, 1.20 mg/kg BW, and 0.60 mg/kg BW groups (P < 0.05). All three generations of mice treated with swainsonine had significantly higher spleen, liver, and kidney indices and significantly lower body weights compared to the 0 mg/kg BW group (P < 0.05). For the first and second generations of treatment group, the copulation indices and the numbers of live pups on postnatal days (PND) 0, 4, and 15 were significantly decreased compared to those of the 0 mg/kg BW group (P < 0.05). The fertility and gestation indices of the treatment group of the first generation were significantly increased compared to the 2.50 mg/kg BW, 1.20 mg/kg BW, and 0.60 mg/kg BW groups of the second generation (P < 0.05). Cumulatively, these results indicate that swainsonine may cause reproductive and developmental toxicities in mice in both parents and offspring. PMID:27999809

  9. 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.

  10. 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.

  11. 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

  12. Nanoscale zerovalent iron (nZVI) at environmentally relevant concentrations induced multigenerational reproductive toxicity in Caenorhabditis elegans.

    PubMed

    Yang, Ying-Fei; Chen, Pei-Jen; Liao, Vivian Hsiu-Chuan

    2016-05-01

    Nanoscale zerovalent iron (nZVI) is widely used with large scale for environmental remediation for in situ or ex situ applications. The potential impact of nZVI on biota at environmentally relevant concentrations needs to be elucidated. In this study, the reproductive toxicities of three irons species: carboxymethyl cellulose (CMC)-stabilized nZVI, nanoscale iron oxide (nFe3O4), and ferrous ion (Fe(II)aq) in the soil-dwelling nematode Caenorhabditis elegans were examined. In addition, the generational transfer of reproductive toxicity of CMC-nZVI on C. elegans was investigated. The results showed that CMC-nZVI, nFe3O4, and Fe(II)aq did not cause significant mortality after 24 h exposure at the examined concentrations. Reproductive toxicity assays revealed that CMC-nZVI, nFe3O4, and Fe(II)aq significantly decreased offsprings in parental generation (F0) in accompany with the increased intracellular reactive oxygen species (ROS). Furthermore, the reproductive toxicity of CMC-nZVI at environmentally relevant concentrations was transferrable from the F0 to the F1 and F2 generations, but then recovered in the F3 and F4 generations. Further evidence showed that total irons were accumulated in the F0 and F1 generations of C. elegans after CMC-nZVI parental exposure. This study demonstrated that environmentally relevant concentrations of CMC-nZVI induced multigenerational reproductive toxicity which can be ascribed to its high production of ROS in F0 generation, toxicity of Fe(II)aq, and iron accumulation in C. elegans. Since nZVI is widely used for environmental remediation, considering the multigenerational toxicity, this study thus implicates a potential environmental risk of nZVI-induced nanotoxicity in the environment.

  13. Incorporating potency into EU classification for carcinogenicity and reproductive toxicity.

    PubMed

    Hennes, C; Batke, M; Bomann, W; Duhayon, S; Kosemund, K; Politano, V; Stinchcombe, S; Doe, J

    2014-11-01

    Although risk assessment, assessing the potential harm of each particular exposure of a substance, is desirable, it is not feasible in many situations. Risk assessment uses a process of hazard identification, hazard characterisation, and exposure assessment as its components. In the absence of risk assessment, the purpose of classification is to give broad guidance (through the label) on the suitability of a chemical in a range of use situations. Hazard classification in the EU is a process involving identification of the hazards of a substance, followed by comparison of those hazards (including degree of hazard) with defined criteria. Classification should therefore give guidance on degree of hazard as well as hazard identification. Potency is the most important indicator of degree of hazard and should therefore be included in classification. This is done for acute lethality and general toxicity by classifying on dose required to cause the effect. The classification in the EU for carcinogenicity and reproductive toxicity does not discriminate across the wide range of potencies seen (6 orders of magnitude) for carcinogenicity and for developmental toxicity and fertility. Therefore potency should be included in the classification process. The methodology in the EU guidelines for classification for deriving specific concentration limits is a rigorous process for assigning substances which cause tumours or developmental toxicity and infertility in experimental animals to high, medium or low degree of hazard categories by incorporating potency. Methods are suggested on how the degree of hazard so derived could be used in the EU classification process to improve hazard communication and in downstream risk management.

  14. Weight-of-the-evidence review of acrylonitrile reproductive and developmental toxicity studies.

    PubMed

    Neal, Barbara H; Collins, James J; Strother, Dale E; Lamb, James C

    2009-01-01

    Risk assessment of acrylonitrile (AN) toxicity to humans has focused on potential carcinogenicity and acute toxicity. Epidemiological studies from China reported reproductive and developmental effects in AN workers, including infertility, birth defects, and spontaneous abortions. A weight-of-the-evidence (WoE) evaluation of the AN database assessed study strength, characterized toxicity, and identified no-observed-adverse-effect levels (NOAELs). The epidemiological studies do not demonstrate causality and are not sufficiently robust to be used for risk assessment. Rodent developmental studies showed fetotoxicity and malformations at maternally toxic levels; there was no unique developmental susceptibility. NOAELs for oral and inhalation exposures were 10 mg/kg/day and 12 ppm (6 h/day), respectively. Drinking-water and inhalation reproductive toxicity studies showed no clear effects on reproductive performance or fertility. Maternally toxic concentrations caused decreased pup growth. The drinking-water reproductive NOAEL was 100 ppm (moderate confidence due to study limitations). The inhalation exposure reproductive and neonatal toxicity high confidence NOAEL was 45 ppm (first generation 90 ppm) (6 h/day). The inhalation reproductive toxicity study provides the most robust data for risk assessment. Based on the WoE evaluation, AN is not expected to be a developmental or reproductive toxicant in the absence of significant maternal toxicity.

  15. Current developments in reproductive toxicity testing of pesticides.

    PubMed

    Cooper, Ralph L

    2009-09-01

    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 Assessment (ACSA) Technical Committee. Since the original publication, several international groups have provided public comment on conducting the test. The extended one-generation reproductive toxicity test is now under consideration as a potential test guideline. The protocol uses a flexible approach that is markedly different from the current multigenerational guidelines. It encourages the use of toxicokinetics when setting the doses, evaluates more than one rat per sex per litter in the F1 offspring and does not necessarily require mating of the F1 to produce an F2 (F1 mating may be triggered by the presence of effects in the P0 and developing F1 rats). A number of additional reproductive endpoints, and the neurotoxicity and immunotoxicity cohorts are included. The ACSA protocol was developed with the goal of assuring that the methods are scientifically appropriate and the toxicological endpoints and exposure durations are relevant for risk assessment. Compared to existing testing strategies, the proposed approach uses substantially fewer animals, provides additional information on the neonate, juvenile and pubertal animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required. In this paper, the evolution of the protocol since the 2006 publication is discussed. These changes reflect the collective input of a U.S. expert panel of government and industrial scientist convened in 2007 and discussions of an OECD expert group held in Paris, France (October, 2008).

  16. 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.

  17. Amodiaquine-induced reproductive toxicity in adult male rats.

    PubMed

    Niu, Yan-Ru; Wei, Bing; Chen, Bi; Xu, Li-Hua; Jing, Xia; Peng, Cai-Ling; Ma, Tian-Zhong

    2016-02-01

    Amodiaquine (AQ) is routinely prescribed as an anti-malarial drug. Here, we evaluated AQ-induced toxicity in the male reproductive system. Eighty adult male Sprague-Dawley rats were randomly divided into four groups that received distilled water (control) or daily doses of 5 mg/kg body weight, 10 mg/kg, or 15 mg/kg AQ for 2 weeks. Testes morphology was analyzed using hematoxylin-and-eosin staining, terminal dUTP nicked-end labeling (TUNEL), and immunostaining whereas protein expression was determined by Western blotting. AQ dose-dependently led to abnormal spermatogenesis. Disruption of the blood-testis barrier and increased germ cell apoptosis were observed in all three AQ-treated groups. Interestingly, AQ-induced damage of spermatogenesis recovered over time, based on the survival of promyelocytic leukemia zinc-finger (PLZF)-positive, undifferentiated spermatogonia. Serum levels of luteinizing hormone and testosterone, as well as testicular testosterone levels, were not significantly altered in AQ-treated groups compared with controls. Collectively, our study suggests that AQ exerts substantial acute side effects on the reproductive systems of adult male rats by inducing the apoptosis of differentiating spermatogenic cells and disruption of blood-testis barrier function.

  18. 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.

  19. 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.

  20. Highly Sensitive Protein Translation Assay for Trichothecene Toxicity in Airborne Particulates: Comparison with Cytotoxicity Assays

    PubMed Central

    Yike, Iwona; Allan, Terry; Sorenson, William G.; Dearborn, Dorr G.

    1999-01-01

    Screening assays for environmental mycotoxins in bulk samples currently use cytotoxicity in cell cultures, but their application to air particulate samples often lacks sensitivity and specificity for fungal spores. An assay based on inhibition of protein synthesis using translation of firefly luciferase in a rabbit reticulocyte system has been developed for the detection of trichothecene mycotoxins found in the spores of toxigenic fungi. Ethanol extracts of air particulates trapped on polycarbonate filters are ultrafiltered and applied at several dilutions to a translation reaction mixture. The activity of translated luciferase is measured directly in a luminometer, eliminating the need for radioisotopes and time-consuming sample processing. Parallel standard curves using a commercially available trichothecene provide for expression of the results in T-2 toxin equivalents per cubic meter of air. The assay can be completed in 2 h and is readily applicable to multiple samples. Comparison to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay indicates a 400-fold increase in sensitivity of trichothecene detection in addition to a much higher specificity for these toxins. Initial field testing indicates a strong correlation between the measured level of toxicity and the presence of toxigenic fungi detected with microbiological methods. In conclusion, this luciferase translation assay offers a rapid and highly sensitive and specific method for quantitative detection of trichothecene mycotoxin activity in air particulate samples. PMID:9872764

  1. Predicting fish acute toxicity using a fish gill cell line-based toxicity assay.

    PubMed

    Tanneberger, Katrin; Knöbel, Melanie; Busser, Frans J M; Sinnige, Theo L; Hermens, Joop L M; Schirmer, Kristin

    2013-01-15

    The OECD test guideline 203 for determination of fish acute toxicity requires substantial numbers of fish and uses death as an apical end point. One potential alternative are fish cell lines; however, several studies indicated that these appear up to several orders of magnitude less sensitive than fish. We developed a fish gill cell line-based (RTgill-W1) assay, using several measures to improve sensitivity. The optimized assay was applied to determine the toxicity of 35 organic chemicals, having a wide range of toxicity to fish, mode of action and physicochemical properties. We found a very good agreement between in vivo and in vitro effective concentrations. For up to 73% of the tested compounds, the difference between the two approaches was less than 5-fold, covering baseline toxicants but as well compounds with presumed specific modes of action, including reactivity, inhibition of acetylcholine esterase or uncoupling of oxidative phosphorylation. Accounting for measured chemical concentrations eliminated two outliers, the hydrophobic 4-decylaniline and the volatile 2,3-dimethyl-1,3-butadiene, with an outlier being operationally defined as a substance showing a more than 10-fold difference between in vivo/in vitro effect concentrations. Few outliers remained. The most striking were allyl alcohol (2700-fold), which likely needs to be metabolically activated, and permethrin (190-fold) and lindane (63-fold), compounds acting, respectively, on sodium and chloride channels in the brain of fish. We discuss further developments of this assay and suggest its use beyond predicting acute toxicity to fish, for example, as part of adverse outcome pathways to replace, reduce, or refine chronic fish tests.

  2. 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.

  3. Assessing the toxicity of TBBPA and HBCD by zebrafish embryo toxicity assay and biomarker analysis.

    PubMed

    Hu, Jun; Liang, Yong; Chen, Minjie; Wang, Xiaorong

    2009-08-01

    Tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCD) are two of the most widely used brominated flame retardants (BFRs). The biological toxicity effect of TBBPA and HBCD was studied by means of zebrafish embryo toxicity assays in combination with three biomarkers, including superoxide dismutase (SOD), lipid peroxidation, (LPO), and heat shock protein (Hsp70). The standard zebrafish embryo assay showed that high concentrations of TBBPA (> or =0.75 mg/L) can cause lethality or malformation. For HBCD within the concentration range (0.002-10 mg/L), no endpoint was observed. Furthermore, SOD activities of zebrafish embryos exposed to TBBPA were increased with the increasing concentrations. SOD activities in the group treated by HBCD showed an increase followed by a decline. Regardless of TBBPA or HBCD, LPO were increased along with the increase of the concentration. The change pattern of Hsp70 levels was the same with LPO. All these results showed that TBBPA and HBCD could cause oxidative stress and Hsp70 overexpression, inducing acute toxicity to zebrafish embryo in a short-term exposure. The study also indicates that the zebrafish embryo assay in combination with the biomarkers is effective in aquatic environmental toxicology and risk assessment.

  4. Chronic toxicity, reproductive, and teratogenic studies of hexazinone.

    PubMed

    Kennedy, G L; Kaplan, A M

    1984-12-01

    Hexazinone [3-cyclohexyl-6-(dimethylamino)-1-methyl-1,3,5-triazine 2,4(1H,3H)-dione; CAS 51235-04-2] was tested for oral toxicity in rats (both 90-day and 2-year feeding studies), mice (8-week and 2-year feeding studies), and dogs (90-day feeding study). The teratogenic potential was evaluated in rabbits and rats and functional reproductive capacity was studied in rats. Ninety-day feeding of up to 1000 ppm produced no signs of a toxic response in rats. Rats fed 5000 ppm had growth curves slightly inferior to those of the controls as the only detectable difference. Extending the feeding period to 2 years produced decreased body weights in males fed 2500 ppm (top level tested) and in females fed either 1000 or 2500 ppm. All other indices of response, including the type and distribution of tumors, were similar in the test and control rats with the no-effect level being 200 ppm. Eight-week feeding of up to 10,000 ppm in mice produced increased liver weight only at the highest level without any other changes. Two-year feeding of either 200, 2500, or 10,000 ppm resulted in sloughing of the distal tip of the tail and increased liver weights among mice fed 10,000 ppm. Hypertrophy of centrilobular hepatocytes and hyperplasic nodules were increased in mice fed either 2500 or 10,000 ppm. No evidence of a tumorigenic response was evident. The no-effect level was 200 ppm. Dogs fed 5000 ppm for 90 days had decreased rate of body weight gain with clinical enzyme changes suggestive of liver damage. Microscopic examination of the liver failed to reveal any alterations and dogs fed either 200 or 1000 ppm were indistinguishable from controls. The no-effect level in the dog was 1000 ppm. No evidence of a teratogenic response was seen in either rats or rabbits and reproduction capacity in rats fed up to 2500 ppm for three generations was unaffected.

  5. 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.

  6. REPRODUCTIVE TOXICITY OF EXPOSURE TO CONAZOLE FUNGICIDES IN THE FEMALE RAT

    EPA Science Inventory

    Conazole fungicides are used extensively in pharmaceutical and agricultural applications. Although some conazoles have been investigated extensively for toxicological effects, there is little published information on the reproductive toxicity of many of the agriculturally importa...

  7. 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...

  8. 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.

  9. [Effect of zinc on reproductive toxicity in rats].

    PubMed

    Wei, Qing; Fan, Ruiquan; Yang, Xingfen; Chen, Tiejiang

    2003-11-01

    The purpose of this study was to explore the effect of zinc on reproductive function in rats. The results revealed that the sperm count, sperm motility and reproductive function appeared to be enhanced in male rats by 60 days successive administration of low dose zinc (12 mg/kg) or medium dose zinc (120 mg/kg), whereas reproductive system damages characterized by lowering of reproductive function would be resulted by high dose zinc(240 mg/kg). However, no effect on the growth and development of the second generation was shown, suggesting that the injury was just limited to certain extent.

  10. 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.

  11. Validation of Screening Assays for Developmental Toxicity: An Exposure-Based Approach

    EPA Science Inventory

    There continue to be widespread efforts to develop assay methods for developmental toxicity that are shorter than the traditional Segment 2 study and use fewer or no animals. As with any alternative test method, novel developmental toxicity assays must be validated by evaluating ...

  12. USING THE MEDAKA EMBRYO ASSAY TO INVESTIGATE DEVELOPMENTAL ETHANOL TOXICITY.

    EPA Science Inventory

    Ethanol (EtOH) is a well-known developmental toxicant that produces a range of abnormal phenotypes. While the toxic potential of developmental EtOH exposure is well characterized, the effect of the timing of exposure on the extent of toxicity remains unknown. Fish models such as ...

  13. Triorganotin as a compound with potential reproductive toxicity in mammals.

    PubMed

    Delgado Filho, V S; Lopes, P F I; Podratz, P L; Graceli, J B

    2011-09-01

    Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks, called "imposex". However, little is known about the capability of triorganotin compounds, such as tributyltin and triphenyltin, to cause disorders in the sexual development and reproductive functions of mammals, including humans and rodents. Moreover, these compounds can act as potential competitive inhibitors of aromatase enzyme and other steroidogenic enzymes, affecting the reproductive capacity of male and female mammals. In this review, we discuss the cellular, biochemical, and molecular mechanisms by which triorganotin compounds induce adverse effects in the mammalian reproductive function.

  14. [Study advance on reproductive and developmental toxicity of haloacetic acids in drinking water].

    PubMed

    Xiang, Hong; Lu, Xiwu

    2008-03-01

    Haloacetic acids (HAAs) are major by-products of water disinfection of chlorination, Health effects on reproductive and developmental toxicities of haloacetic acids may be pay more attention to and may be interested in due to their high stability. In recent years numerous toxicological studies indicated that some HAAs could affect reproductive system and fertilizing capacity, inducing fetal anomaly and growth retardation in experimental animals. The recent studies on the reproductive and developmental effects of HAAs were discussed in this paper, the informations may be available for further study on reproductive and developmental effects of HAAs in drinking water.

  15. 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

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. Increased reproductive toxicity of landfill leachate after degradation was caused by nitrite.

    PubMed

    Dave, Göran; Nilsson, Eva

    2005-06-01

    Leachate from the landfill Lindbodarna was suspected to cause reproductive effects on fish in a Swedish lake, called Molnbyggen. The acute toxicity of this landfill leachate is caused by ammonia. In the present study the acute and chronic toxicity of the leachate from the landfill was tested with Ceriodaphnia dubia before and after treatment, either with (inoculated) or without addition of microorganisms from activated sludge, in both 2000 and 2001. On both occasions, the acute toxicity decreased after treatment, more rapidly with inoculum than without, and the cause of the decrease was mainly explained by decreasing concentrations of ammonia. However, the chronic toxicity decreased after treatment with inoculum but increased after treatment without inoculum. Therefore, we performed a series of acute and reproductive tests with ammonia, nitrite and nitrate on C. dubia, and the 24-h EC50s were 1.0, 2.7 and 59 mM, respectively, which are consistent with literature data. However, the chronic toxicity of these compounds gave quite a different picture with 8-day EC50s for reproduction of 3.0 mM for ammonia, 0.016 mM for nitrite and 1.5 mM for nitrate. Thus, the acute-chronic ratios for these compounds were 0.33 for ammonia, 170 for nitrite and 39 for nitrate. These findings show that reproduction is more sensitive than survival for both nitrite and nitrate, and that nitrite is the more hazardous of the two. This implies that the chronic and reproductive toxicity of nitrite and nitrate on zooplankton may in fact increase effects of eutrophication. In this study the toxicity of the fresh leachate was dominated by ammonia, but after treatment the contribution of nitrite increased, and especially the chronic toxicity of the treated landfill leachate was dominated by nitrite toxicity.

  1. Evaluation of reproduction as an endpoint in chronic toxicity tests with the amphipod Hyalella azteca

    SciTech Connect

    Brunson, E.L.; Dwyer, F.J.; Ingersoll, C.G.

    1995-12-31

    In 1994, USEPA published ``Methods for Measuring the Toxicity and Bioaccumulation of Sediment-associated Contaminants with Freshwater Invertebrates`` (EPA/600/R-94/024). Within that document a Hyalella azteca 10-d survival test for sediments is described. The 10-d survival test provides a measure of acute toxicity from moderately to highly contaminated sediments. In addition to survival, growth during the 10-d test can be measured and could be a more sensitive endpoint. However, the ecological significance of reduced growth is questionable. Reproduction may be a more sensitive endpoint than growth or survival and its ecological importance is not questionable. The objective of this research is to develop a Hyalella azteca sediment toxicity test with a reproductive endpoint. The reproductive test will closely resemble the 10-d test but will be longer in duration and may require isolation of amphipods from the sediment for reproduction. Presently, reproductive effects of different diets and water types have been evaluated. A preliminary test protocol has been developed and is being tested and refined. This presentation will provide the most current results of this ongoing research. This study will be used to develop standard methods for measuring chronic toxicity in sediments using Hyalella azteca.

  2. 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.

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

    PubMed

    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 (WAF) of weathered oil in conjunction with three levels of laboratory simulated UV (Reference = < 0.002 microW/cm(2)UVB; 3.0 microW/cm(2) UVA; Low = 0.30 microW/cm(2) UVB; 75.0 microW/cm(2) UVA; High = 2.0 microW/cm(2) UVB; 340.0 microW/cm(2) 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.

  4. 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.

  5. 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.

  6. 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.

  7. A review of reproductive and developmental toxicity of silver nanoparticles in laboratory animals.

    PubMed

    Ema, Makoto; Okuda, Hirokazu; Gamo, Masashi; Honda, Kazumasa

    2017-01-01

    We summarized significant effects reported in the literature on the reproductive and developmental toxicity of silver nanoparticles (AgNPs) in laboratory animals. AgNPs showed testicular/sperm toxicity in males and ovarian and embryonic toxicity in females. Maternal injection of AgNPs delayed physical development and impaired cognitive behavior in offspring. Ag was accumulated in the testes after administration of AgNPs. AgNPs were identified in the visceral yolk sac after administration during early gestation in mice. Radiolabeled AgNPs were detected in placenta, breast milk, and pre- and postnatal offspring after injection during late gestation in rats. Ag in the ionic form, and possibly also particles, was suggested to be bioavailable. Although this review provides initial information on the potential reproductive and developmental toxicity of AgNPs, data is still very limited. Further studies using state-of-the-art methodologies and the relevant routes and doses for human exposure are required.

  8. 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.

  9. Big Data in Chemical Toxicity Research: The Use of High-Throughput Screening Assays To Identify Potential Toxicants

    PubMed Central

    2015-01-01

    High-throughput screening (HTS) assays that measure the in vitro toxicity of environmental compounds have been widely applied as an alternative to in vivo animal tests of chemical toxicity. Current HTS studies provide the community with rich toxicology information that has the potential to be integrated into toxicity research. The available in vitro toxicity data is updated daily in structured formats (e.g., deposited into PubChem and other data-sharing web portals) or in an unstructured way (papers, laboratory reports, toxicity Web site updates, etc.). The information derived from the current toxicity data is so large and complex that it becomes difficult to process using available database management tools or traditional data processing applications. For this reason, it is necessary to develop a big data approach when conducting modern chemical toxicity research. In vitro data for a compound, obtained from meaningful bioassays, can be viewed as a response profile that gives detailed information about the compound’s ability to affect relevant biological proteins/receptors. This information is critical for the evaluation of complex bioactivities (e.g., animal toxicities) and grows rapidly as big data in toxicology communities. This review focuses mainly on the existing structured in vitro data (e.g., PubChem data sets) as response profiles for compounds of environmental interest (e.g., potential human/animal toxicants). Potential modeling and mining tools to use the current big data pool in chemical toxicity research are also described. PMID:25195622

  10. Big data in chemical toxicity research: the use of high-throughput screening assays to identify potential toxicants.

    PubMed

    Zhu, Hao; Zhang, Jun; Kim, Marlene T; Boison, Abena; Sedykh, Alexander; Moran, Kimberlee

    2014-10-20

    High-throughput screening (HTS) assays that measure the in vitro toxicity of environmental compounds have been widely applied as an alternative to in vivo animal tests of chemical toxicity. Current HTS studies provide the community with rich toxicology information that has the potential to be integrated into toxicity research. The available in vitro toxicity data is updated daily in structured formats (e.g., deposited into PubChem and other data-sharing web portals) or in an unstructured way (papers, laboratory reports, toxicity Web site updates, etc.). The information derived from the current toxicity data is so large and complex that it becomes difficult to process using available database management tools or traditional data processing applications. For this reason, it is necessary to develop a big data approach when conducting modern chemical toxicity research. In vitro data for a compound, obtained from meaningful bioassays, can be viewed as a response profile that gives detailed information about the compound's ability to affect relevant biological proteins/receptors. This information is critical for the evaluation of complex bioactivities (e.g., animal toxicities) and grows rapidly as big data in toxicology communities. This review focuses mainly on the existing structured in vitro data (e.g., PubChem data sets) as response profiles for compounds of environmental interest (e.g., potential human/animal toxicants). Potential modeling and mining tools to use the current big data pool in chemical toxicity research are also described.

  11. Factors influencing reproduction and genetic toxic effects on male gonads

    PubMed Central

    Lee, I. P.; Dixon, R. L.

    1978-01-01

    The objective of toxicological study of a target organ, such as the testis, is to elucidate the qualitative and quantitative toxic effects of a chemical on that organ. The ultimate objective is to assess the toxic effects of a chemical in laboratory animals and extrapolate the pertinent experimental data to man. To accomplish these objectives, one must consider the main factors which may influence and modulate the toxic effects of chemicals in the organ. In the male gonads, such modifying factors are the pharmacokinetic parameters governing the absorption, distribution, activation and detoxification of indirect carcinogens, covalent bindings to macromolecules, and DNA damage as well as DNA repair of damaged germ cells. All of these factors have been presently studied in our laboratory and are discussed in this paper with the exception of covalent bindings to macromolecules. The pharmacokinetic studies demonstrated that the functional blood–testis barrier (BTB) closely resembles the blood-brain barrier in transport characteristics: the permeability of nonelectrolytes and the acidic drugs with pKa values depend upon their molecular size and their partition coefficients, respectively. Thus, the functional BTB, restricts the permeability of many foreign compounds to male germ cells. Studies of mixed function oxidases and cytochrome P-450 system in male gonads demonstrated that the presence of AHH, EH, and GSH-ST implicate activation and detoxification of polycyclic hydrocarbons. Thus, active electrophiles may exert significant toxic effects locally within both interstitial and germ cell compartments. The presence of an efficient DNA repair system in premeiotic spermatogenic cells (and not in spermiogenic cells) can further modify both toxic and mutagenic events in the subsequent differentiation of germ cells to mature spermatozoa. PMID:17539139

  12. 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...

  13. 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.

  14. 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...

  15. 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...

  16. 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...

  17. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals

    PubMed Central

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed. PMID:28257483

  18. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    PubMed

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  19. 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. ...

  20. 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...

  1. Multiple reporter gene assays for the assessment and estimation of chemical toxicity.

    PubMed

    Takahashi, Junko; Iwahashi, Hitoshi

    2004-01-01

    To detect chemical toxicity, we are making new bioassay systems that use promoters selected from yeast DNA microarray experiments. We performed multiple reporter gene assays using the promoters of these genes; the promoter regions were inserted upstream of green fluorescence protein (GFP). In this report, six genes (HSP26, MET17, YLL057C, FIT2, CUP1 and OYE3) were selected and assays were carried out for 55 chemicals. The promoters of these genes showed different responses to chemicals within 4 h. This result indicates that this technique enables us to predict the toxicity of chemicals in the environment and to understand toxicities of newly synthesized chemicals.

  2. 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.

  3. Predictive value of cell assays for developmental toxicity and embryotoxicity of conazole fungicides.

    PubMed

    Dreisig, Karin; Taxvig, Camilla; Birkhøj Kjærstad, Mia; Nellemann, Christine; Hass, Ulla; Vinggaard, Anne Marie

    2013-01-01

    This paper evaluates in vivo predictability of a battery of in vitro tests covering developmental toxicity and embryotoxicity of five widely used conazole fungicides. The conazoles were investigated in the embryonic stem cell test, and data were compared to in vivo embryotoxicity data. The same conazoles were evaluated on the basis of data from a battery of cell assays for endocrine activity, including assays for AR, ER, AhR, and sex hormone synthesis, and data were compared to in vivo developmental toxicity data. Overall, the ranking of the five conazole fungicides based on in vitro data were in reasonably good agreement with available in vivo effects. Ketoconazole and epoxiconazole are the most potent embryotoxic compounds, whereas prochloraz belongs to the most potent developmental toxicants. In conclusion, a rough prediction of the ranking of these conazole fungicides for in vivo toxicity data was possible by a holistic evaluation of data from a panel of cell-based assays.

  4. 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.

  5. 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.

  6. 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...

  7. THE EFFECTS OF METHOXYCHLOR AND METHYLTESTOSTERONE ON REPRODUCTION IN A SHORT-TERM ASSAY USING THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

    EPA Science Inventory

    The effect of chemicals on reproduction of fishes is an area of great uncertainty. Because full life cycle testing of fish is cost prohibitive, we have developed a short-term assay to assess the effects of chemicals on reproduction of adult fathead minnows (Pimephales promelas). ...

  8. Feasibility study of the zebrafish assay as an alternative method to screen for developmental toxicity and embryotoxicity using a training set of 27 compounds.

    PubMed

    Selderslaghs, Ingrid W T; Blust, Ronny; Witters, Hilda E

    2012-04-01

    To anticipate to increased testing needs for reproductive toxicity and 3R approaches, we studied zebrafish embryo/larva as an alternative for animal testing for developmental toxicity and embryotoxicity and evaluated a training set of 27 compounds with a standardized protocol. The classification of compounds in the zebrafish embryo/larva assay, based on a prediction model using a TI (teratogenic index) cut-off value of 2, was compared to available animal and human data. When comparing the classification of compounds in the zebrafish embryo/larva assay to available animal classification, a sensitivity of 72% and specificity of 100% were obtained. The predictive values obtained in comparison to a limited set of human data were 50, 60% respectively for teratogens, non-teratogens. Overall, we demonstrated that the zebrafish embryo/larva assay, may be used as screening tool for prioritization of compounds and could contribute to reduction of animal experiments in the field of developmental toxicology.

  9. 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

  10. Optimizing the design of a reproduction toxicity test with the pond snail Lymnaea stagnalis.

    PubMed

    Charles, Sandrine; Ducrot, Virginie; Azam, Didier; Benstead, Rachel; Brettschneider, Denise; De Schamphelaere, Karel; Filipe Goncalves, Sandra; Green, John W; Holbech, Henrik; Hutchinson, Thomas H; Faber, Daniel; Laranjeiro, Filipe; Matthiessen, Peter; Norrgren, Leif; Oehlmann, Jörg; Reategui-Zirena, Evelyn; Seeland-Fremer, Anne; Teigeler, Matthias; Thome, Jean-Pierre; Tobor Kaplon, Marysia; Weltje, Lennart; Lagadic, Laurent

    2016-11-01

    This paper presents the results from two ring-tests addressing the feasibility, robustness and reproducibility of a reproduction toxicity test with the freshwater gastropod Lymnaea stagnalis (RENILYS strain). Sixteen laboratories (from inexperienced to expert laboratories in mollusc testing) from nine countries participated in these ring-tests. Survival and reproduction were evaluated in L. stagnalis exposed to cadmium, tributyltin, prochloraz and trenbolone according to an OECD draft Test Guideline. In total, 49 datasets were analysed to assess the practicability of the proposed experimental protocol, and to estimate the between-laboratory reproducibility of toxicity endpoint values. The statistical analysis of count data (number of clutches or eggs per individual-day) leading to ECx estimation was specifically developed and automated through a free web-interface. Based on a complementary statistical analysis, the optimal test duration was established and the most sensitive and cost-effective reproduction toxicity endpoint was identified, to be used as the core endpoint. This validation process and the resulting optimized protocol were used to consolidate the OECD Test Guideline for the evaluation of reproductive effects of chemicals in L. stagnalis.

  11. 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.

  12. 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.

  13. 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.

  14. Sensitivity of different generations and developmental stages in studies on reproductive toxicity.

    PubMed

    Schulz, F; Batke, M; Mangelsdorf, I; Pohlenz-Michel, C; Simetska, N; Lewin, G

    2014-04-21

    Numerous studies on reproductive toxicity are expected to be necessary under the EU program on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Therefore, it is important to analyse existing testing strategies including also the recently implemented extended one-generation reproduction toxicity study (EOGRTS, OECD guideline 443). For this purpose the responsiveness of the different generations and developmental stages in studies on reproductive toxicity is analysed and critical targets of reproductive toxicity are identified by using the Fraunhofer FeDTex database. The F1 generation is identified as most responsive generation in more than 50% of one-generation and multi-generation reproduction studies. Within the F1 generation the adult stage is mostly affected compared to the prenatal or postnatal stage. The target analysis in F1 has revealed alterations in body weight as highly sensitive for all developmental stages. Other important targets are the liver, kidney, testes, prostate, sperm parameters as well as developmental landmarks. The findings in the F2 generation have shown a higher responsiveness than F1 only in 3% of the studies. Although in 29 studies new effects are observed in F2 offspring compared to F1 irrespective of dose levels, overall no severe new effects have emerged that would change classification and labelling and justify an F1 mating. The presented data support the importance of F1 for risk assessment and demonstrate that the study design of the EOGRTS is a suitable alternative to two-generation studies. However, compared to a conventional one-generation study the EOGRTS may identify additional effects but will change risk assessment with respect to NOELs only in rare cases.

  15. Toxicity assessment of reference and natural freshwater sediments with the LuminoTox assay.

    PubMed

    Dellamatrice, P M; Monteiro, R T R; Blaise, C; Slabbert, J L; Gagné, F; Alleau, S

    2006-08-01

    We examined the possibility of adapting the LuminoTox, a recently-commercialized bioanalytical testing procedure initially developed for aqueous samples, to assess the toxic potential of sediments. This portable fluorescent biosensor uses photosynthetic enzyme complexes (PECs) to rapidly measure photosynthetic efficiency. LuminoTox testing of 14 CRM (Certified Reference Material) sediments was first undertaken with (1) a "solid phase assay" (Lum-SPA) in which PECs are in intimate contact with sediment slurries for a 15 min exposure period and (2) an elutriate assay (Lum-ELU) in which PECs are exposed for 15 min to sediment water elutriates. CRM sediment toxicity data were then compared with those generated with the Microtox Solid Phase Assay (Mic-SPA). A significant correlation (P < 0.05) was shown to exist between Lum-SPA and Mic-SPA, indicating that both tests display a similar toxicity response pattern for CRM sediments having differing contaminant profiles. The sediment elutriate Lum-ELU assay displayed toxicity responses (i.e. measurable IC20s) for eight of the 14 CRM sediments, suggesting that it is capable of determining the presence of sediment contaminants that are readily soluble in an aqueous elutriate. Lum-SPA and Mic-SPA bioassays were further conducted on 12 natural freshwater sediments and their toxicity responses were more weakly, yet significantly, correlated. Finally, Lum-SPA testing undertaken with increasing mixtures of kaolin clay confirmed that its toxicity responses, in a manner similar to those reported for the Mic-SPA assay, are also subject to the influence of grain size. While further studies will be required to more fully understand the relationship between Lum-SPA assay responses and the physicochemical makeup of sediments (e.g., grain size, combined presence of natural and anthropogenic contaminants), these preliminary results suggest that LuminoTox testing could be a useful screen to assess the toxic potential of solid media.

  16. Protective role of propolis against reproductive toxicity of triphenyltin in male rabbits.

    PubMed

    Yousef, Mokhtar I; Kamel, Kamel I; Hassan, Mervat S; El-Morsy, Ahmed M A

    2010-07-01

    Triphenyltin (TPT) is known to cause endocrine disruption, reproductive toxicity and a decrease in testosterone production. It is involved in the production of reactive oxygen species. Propolis has been reported to be an important antioxidant. Therefore, the present study aimed to elucidate the possible protective effects of propolis in alleviating the toxicity of triphenyltin chloride (TPTCl) on reproductive performance, testosterone levels, lipid peroxidation and enzyme activities in seminal plasma of male New Zealand white rabbits. Animals were orally administered the doses of propolis, TPTCl and propolis plus TPTCl every day for 12weeks. Results showed that semen quality was deteriorated following treatment with TPTCl. Also, testosterone levels, body weight (BW), relative weights of testes (RWT) and epididymis (RWE) were decreased. Thiobarbituric acid-reactive substances and lactate dehydrogenase were increased, while glutathione S-transferase, transaminases and phosphatases were decreased in seminal plasma of rabbits treated with TPTCl compared to control. Propolis alone significantly increased testosterone levels, BW, RTW, REW, semen characteristics and seminal plasma enzymes, and decreased the levels of free radicals and lactate dehydrogenase. Furthermore, the presence of propolis with TPTCl alleviates its toxic effects. From the present study, it can be concluded propolis can be effective in the protection of TPTCl-induced reproductive toxicity.

  17. 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...

  18. Environmental toxicants and effects on female reproductive function.

    PubMed

    Hutz, R J; Carvan, M J; Baldridge, M G; Conley, L K; Heiden, T King

    2006-01-01

    One of the most toxic substances known to humans, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), is also highly pervasive in the environment. It is created naturally in volcanic eruptions and forest fires, and anthropogenically in waste incineration, chlorination processes and certain plastics manufacture. From reports of large industrial and other accidents, or from experimental studies, dioxin exposure has been correlated in animal models and/or humans with chloracne of the skin, organ cancers, hepatotoxicity, gonadal and immune changes, pulmonary and other diseases such as diabetes, skewing of the sex ratio, and infertility. We have demonstrated that the aromatic hydrocarbon receptor (AHR) that binds dioxin in tissues is localized in zebrafish, rat and rhesus monkey (Macaca mulatta) ovaries and in rat and human luteinizing granulosa cells (GC) (among other tissues), that labeled dioxin is specifically localized to granulosa cells of the ovarian follicle as observed by autoradiography, and that incubations of GC or ovarian fragments with environmentally relevant concentrations (fM to nM) of dioxin inhibit estradiol secretion significantly. Our experiments show that in human, non-human primate, rat, trout, and zebrafish ovarian tissues, dioxin inhibits estrogen synthesis at some level of the steroid biosynthetic pathway, most likely by inhibiting transcription of mRNAs for or activity of side-chain cleavage (Cyp11a1 gene) and/or aromatase (Cyp19a1 gene) enzymes, or conceivably other steroidogenic enzymes/factors. Such an untoward effect on estrogen synthesis in females exposed to dioxin environmentally may predispose them to defects in aspects of their fertility.

  19. Male reproductive toxicity study of nitrazepam in rats.

    PubMed

    Sanbuissho, A; Terada, S; Suzuki, K; Masuda, N; Teranishi, M; Masuda, H

    1995-08-01

    The main focus of this study is the optimal administration period concerning toxic effects on male fertility in rats. To assess functional and morphological changes induced in the testis by nitrazepam, male rats were administered the drug at doses of 0, 20, 40 or 80 mg/kg during pre-mating periods of 2, 4 or 9 weeks and then the 2 weeks of mating. At the end of the administration period the animals were sacrificed and sperm number, motility, abnormalities and histopathological changes in the testis were examined. Decreases in testis weight, epididymis weight, number of sperm in the testis and sperm motility were observed in the 40 and 80 mg/kg sections of the 2, 4 and 9 week pre-mating treated groups. Mating with untreated females revealed no adverse effects on copulation rate in any group; however, a remarkable decrease in pregnancy rate was noted in the 80 mg/kg section of the 2, 4 and 9 week treated groups. On histological examination, various degrees of localized necrosis in the seminiferous epithelium and Leydig cell hyperplasia were observed in the testis. No clear changes were observed in the 20 mg/kg section of the 2 week pre-mating administration group, but at the 4 week time point, necrosis of spermatogenic cells began to appear. The primary morphological event was evident in spermatocytes with necrosis of the cytoplasm observed from 4 weeks after administration of nitrazepam, although sperm motility and sperm head counts were unaffected. From these findings, examination of sperm characteristics and histopathological changes in the testis are important parameters for evaluation of drugs inducing testicular damage. We conclude that a 4 week administration period is sufficient to detect effects of nitrazepam on male fertility.

  20. 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.

  1. A cellular viability assay to monitor drug toxicity.

    PubMed

    Hansen, Jakob; Bross, Peter

    2010-01-01

    A central part of the research in protein misfolding and its associated disorders is the development of treatment strategies based on ensuring cellular protein homeostasis. This often includes testing chemical substances or drugs for their ability to counteract protein misfolding processes and to promote correct folding. Such investigations also include assessment of how the tested chemical substances affect cellular viability, that is, their cytotoxic effect. Investigations of cytotoxicity often require testing several different concentrations and drug exposure times using cells in culture. It is therefore attractive to use a viability test that permits the analysis of many samples with little handling time. This protocol describes a simple and fast methodology to analyze viability of lymphoblastoid cells and to test putative cytotoxic effects associated with exposure to a chemical substance, here exemplified by celastrol. The natural substance celastrol has been used for many years in traditional Chinese medicine and has subsequently been shown to induce transcription of genes encoding molecular chaperones (heat shock proteins) that are involved in promoting folding of cellular proteins. The well-described colorimetric tetrazolium salt (MTT) assay, which monitors metabolic activity of cultured cells, was adapted to analyze the viability of cells exposed to celastrol. After having established a suitable cell seeding density, the dose-dependence and time-course of viability reduction of lymphoblastoid cells treated with celastrol were determined. It was found that 4- and 24-h exposure to 0.8 microM celastrol reduced the viability of lymphoblastoid cells, with the most severe effect observed at 24 h with MTT reductions approaching 30% of non-exposed cells. For a series of incubations for 24 h, it was found that concentrations as low as 0.2 microM were sufficient to affect the viability, and celastrol concentrations of 0.5 microM reduced the MTT reduction rate to

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Reproductive toxicity of methomyl insecticide in male rats and protective effect of folic acid.

    PubMed

    Shalaby, M A; El Zorba, H Y; Ziada, Reem M

    2010-11-01

    The acute toxicity (LD(50)) of insecticide methomyl and its effects on male reproduction in rats were carried out. Methomyl was given orally to male rats daily for 65 successive days at two doses (0.5 and 1.0 mg kg(-1) b.wt., corresponding to 1/40 and 1/20 LD(50)) alone and in combination with folic acid (1.1 mg kg(-1) b.wt., corresponding to acceptable daily intake, ADI). Fertility index, weight of sexual organs, semen picture, serum testosterone level and histopathology of testes were the parameters used to evaluate the reproductive efficiency of treated rats. The reversibility of methomyl effects was also studied after 65 days post-administration. The oral LD(50) of methomyl was 20.0 mg kg(-1) b.wt. in male rats. Methomyl significantly decreased the fertility index, weight of testes and accessory male sexual glands, serum testosterone level and sperm motility and count, but increased sperm cell abnormality. It induced testicular lesions characterized by moderate to severe degenerative changes of seminiferous tubules and incomplete arrest of spermatogenesis. These toxic effects were not persistent (reversible). Coadministration of folic acid with methomyl decreased its reproductive toxicity. A great attention should be taken during field application of methomyl to avoid its deleterious effects in farm animals and occupationally exposed humans.

  8. Application of toxicity identification procedures to the echinoderm fertilization assay to identify toxicity in a municipal effluent

    SciTech Connect

    Bailey, H.C.; Miller, J.L.; Miller, M.J.; Dhaliwal, B.S.

    1995-12-01

    Toxicity was detected in a municipal effluent with the echinoderm fertilization assay. Dendraster excentricus appeared more sensitive to the effluent than did Strongylocentrotus purpuratus. A Phase 1 toxicity identification evaluation (TIE) was conducted using procedures adapted to the echinoderm fertilization bioassay. The Phase 1 TIE implicated cationic metals as the cause of toxicity, and follow-up investigations suggested that copper was the primary cation responsible. As part of the TIE, bioassays were conducted on ammonia and several cations. No-observable-effect concentrations for D. excentricus were > 13.4 {micro}g/L (Ag), > 9.4 {micro}g/L (Cd), 3.8 to 13.1 {micro}g/L (Cu), > 0.7 {micro}g/L (Hg), and 10 mg/L (N, as total ammonia). The data also suggested that interspecific differences in sensitivity to copper and ammonia exist between Dendraster excentricus and Strongylocentrotus purpuratus.

  9. 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.

  10. 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

  11. Potential parameters of male reproductive toxicity: reproductive performance, histopathology and sperm evaluation in SD rats given nitrazepam.

    PubMed

    Kishi, K; Kanamori, S; Maruyama, T; Sasaki, K; Hara, K; Kawai, M; Ikeuchi, K

    1995-08-01

    The present study was designed to elucidate the correlation between findings from reproductive performance testing and those from histopathological examination of the testis and sperm analysis in rats given a benzodiazepine derivative, nitrazepam, for 2 and 4 weeks. The mechanisms of toxicological action of nitrazepam on the male reproductive organs were also investigated. Nitrazepam was given orally to Sprague-Dawley male rats (6-week-old) at a daily dose of 80 mg/kg for 2 weeks or at daily doses of 20, 40 or 80 mg/kg for 4 weeks. Treated males were mated to examine reproductive performance with untreated females after each dosing period, and after 4 and 9 week of recovery periods. Necropsy was performed for histopathological examination of the testis and epididymis and for sperm analysis after each dosing period and the final mating trial (total of 11 weeks recovery). In the findings from reproductive performance testing, significant decrease in the fertility index was observed in the 80 mg/kg group even after 2 weeks dosing and thereafter until 4 weeks recovery, though the mating index did not significantly differ from that of controls through the experiment. In the histopathological examination and sperm analysis, testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads in the seminiferous tubules were noted in the 80 mg/kg group after 2 weeks dosing and in the 40 and 80 mg/kg groups after 4 weeks dosing. Concentrations of plasma testosterone and content of testis testosterone in nitrazepam-treated groups were not significantly different from those of controls. Plasma FSH concentration was significantly elevated in the 80 mg/kg group through the experiment, although significant elevation of plasma LH was observed only after 2 weeks dosing. These results indicate that histopathological examination is the most reliable approach to detect male reproductive adverse effects induced by

  12. Scientific and Regulatory Policy Committee Points to Consider Review: Inclusion of Reproductive and Pathology End Points for Assessment of Reproductive and Developmental Toxicity in Pharmaceutical Drug Development.

    PubMed

    Halpern, Wendy G; Ameri, Mehrdad; Bowman, Christopher J; Elwell, Michael R; Mirsky, Michael L; Oliver, Julian; Regan, Karen S; Remick, Amera K; Sutherland, Vicki L; Thompson, Kary E; Tremblay, Claudine; Yoshida, Midori; Tomlinson, Lindsay

    2016-08-01

    Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.

  13. 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...

  14. 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...

  15. 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...

  16. Core structure and surface functionalization of carbon nanomaterials alter impacts to daphnid mortality, reproduction, and growth: acute assays do not predict chronic exposure impacts.

    PubMed

    Arndt, Devrah A; Moua, Maika; Chen, Jian; Klaper, Rebecca D

    2013-08-20

    There are currently over ninety products incorporating carbon nanomaterials (CNMs) on the market today for a variety of applications. Modifications in core structure and surface chemistry of manufactured nanomaterials are used to optimize nanomaterials for specific uses. However, there is a notable lack of information on how core structure and surface chemistry may alter toxicity in low-level, chronic exposures. This paper examines the effects of twelve CNMs that differ in their core structure and surface chemistry to Daphnia magna over a 21-day chronic exposure. Overall, nanomaterials with a carbon nanotube core were more toxic to daphnids than fullerenes, with the one exception of fullerenes with a gamma-cyclodextrin surface chemistry. Acute mortality was not a good predictor of chronic effects as none of the CNMs induced toxicity at tested concentrations after 48 h, yet chronic assays indicated significant differences in mortality, reproduction, and growth realized after 21 days. Our results indicate that (1) acute exposure assays do not accurately describe the impact of CNMs to biological systems, (2) chronic exposures provide valuable information that indicates the potential for different modes of action for nanomaterials of differing chemistries, and (3) core structure and surface chemistry both influence particle toxicity.

  17. 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...

  18. 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.

  19. Chronic exposure to environmentally relevant concentrations of PCB causes reproductive toxicity in mink

    SciTech Connect

    Brunstroem, B.; Oerberg, J.; Lund, B.O.; Athanasiadou, M.

    1995-12-31

    Female mink (Mustela vison) were exposed to the technical PCB preparation Clophen A50 (0.3 or 0.1 mg/animal/day) in the feed for 18 months, including two reproduction seasons. Isomer-specific PCB-analysis of the technical mixture was made and the concentrations of toxic equivalents (TEQs) in the feed were calculated. In addition, Clophen A50 was separated into two fractions, one containing the non and mono-ortho-chlorinated PCB congeners (planar fraction) and the other containing congeners with 2-4 chlorines in ortho-position (non-planar fraction). Animals in two separate groups were exposed daily to these individual fractions extracted from 0.3 mg Clophen A50. No effect on the reproduction outcome was observed during the first reproduction season. However, reduced birth weights were noted in the kits born to animals treated with 0.3 mg Clophen A50 per day. The reproductive performance was seriously affected in the second season. Only 39% of the females exposed to 0.3 mg Clophen A50 per day whelped, compared with 93% in the control group. All whelps in the group exposed to the high dose of Clophen A50 died within 1 day after birth. Kit survival and growth were reduced also in the group treated with the low dose of Clophen A50. Treatment with the non and mono-orthochlorinated PCB congeners strongly reduced kit survival and body weight gain. Only 8% of the kits survived until 2 weeks of age. It is concluded that the non and monoortho-chlorinated PCB congeners were responsible for the major part of the reproductive toxicity caused by Clophen A50. PCB residue concentrations in the mink, determined at the end of the experiment, were within the range of the levels that have been observed in wild mink in Sweden.

  20. Optimization of NRU assay in primary cultures of Eisenia fetida for metal toxicity assessment.

    PubMed

    Irizar, Amaia; Duarte, Daniel; Guilhermino, Lucia; Marigómez, Ionan; Soto, Manu

    2014-09-01

    Coelomocytes, immunocompetent cells of lumbricids, have received special attention for ecotoxicological studies due to their sensibility to pollutants. Their in vitro responses are commonly quantified after in vivo exposure to real or spiked soils. Alternatively, quantifications of in vitro responses after in vitro exposure are being studied. Within this framework, the present study aimed at optimizing the neutral red uptake (NRU) assay in primary culture of Eisenia fetida coelomocytes for its application in soil toxicity testing. Optimized assay conditions were: earthworm depuration for 24 h before retrieving coelomocytes by electric extrusion; 2 × 10(5) seeded cells/well (200 µl) for the NRU assay and incubation for 1 h with neutral red dye. Supplementation of the culture medium with serum was not compatible with the NRU assay, but coelomocytes could be maintained with high viability for 3 days in a serum-free medium without replenishment. Thus, primary cultures were used for 24 h in vitro toxicity testing after exposure to different concentrations of Cd, Cu, Ni and Pb (ranging from 0.1 to 100 μg/ml). Primary cultures were sensitive to metals, the viability declining in a dose-dependent manner. The toxicity rank was, from high to low, Pb > Ni > Cd > Cu. Therefore, it can be concluded that the NRU assay in coelomocytes in primary cultures provides a sensitive and prompt response after in vitro exposure to metals.

  1. A two generation reproductive toxicity study with curcumin, turmeric yellow, in Wistar rats.

    PubMed

    Ganiger, S; Malleshappa, H N; Krishnappa, H; Rajashekhar, Geetha; Ramakrishna Rao, V; Sullivan, Frank

    2007-01-01

    The reproductive toxicity of curcumin, turmeric yellow, in Wistar rats was studied in order to generate additional relevant toxicity information for the use of curcumin in humans by oral administration. The two generation reproduction study was designed and conducted in accordance with OECD Guideline No. 416 [OECD, 1983. Guidelines for Testing of Chemicals, Guideline No. 416. Two Generation Reproduction Toxicity Study, adopted on 26th May 1983] and in compliance with Good Laboratory Practices (OECD, 1997 Principles of Good Laboratory Practice for the Testing of Chemicals. OECD, C(97)186/Final). The curcumin, mixed in the experimental diet at the concentrations of 1500, 3000 and 10,000 ppm was fed to three groups of rats, i.e., low, mid and high dose groups, and studied for two successive generations. A concurrent control group received experimental diet without the curcumin mixture. There were no treatment related adverse toxicological effects in the parental animals. No gross or microscopic changes were observed in any of the organs. None of the reproductive parameters were affected and there were no effects on the offspring other than a small reduction in pre-weaning body weight gain of the F2 pups at the highest dose level. It was concluded that the no observed adverse effect level (NOAEL) for reproductive toxicity of curcumin, fed in the diet for two successive generations to rats in this study was 10,000 ppm, which is equivalent to 847 and 959 mg/kg bodyweight (bw) per day for male rats and 1043 and 1076 for females for F0 and F1 generations, respectively. This study was the final toxicology study on curcumin reviewed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at the 61st Meeting, 2003. The JECFA group considered that the small body weight reduction in the F2 pups of the highest dose group prevented this from being regarded as a no adverse effect level, and so allocated an ADI for curcumin of 0-3 mg/kg bw based on the intake of 250-320 mg

  2. 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.

  3. 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

  4. 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.

  5. Three-generation reproduction toxicity study of genetically modified rice with insect resistant genes.

    PubMed

    Hu, Yichun; Zhuo, Qin; Gong, Zhaolong; Piao, Jianhua; Yang, Xiaoguang

    2017-01-01

    In the present work, we evaluated the three generation reproductive toxicity of the genetically modified rice with insectresistant cry1Ac and sck genes. 120 Sprague-Dawley (SD) rats were divided into three groups which were fed with genetically modified rice diet (GM group), parental control rice diet (PR group) and AIN-93 control diet (both used as negative control) respectively. Bodyweight, food consumption, reproductive data, hematological parameters, serum chemistry, relative organ weights and histopathology for each generation were examined respectively. All the hematology and serum chemistry parameters, organ/body weight indicators were within the normal range or no change to the adverse direction was observed, although several differences in hematology and serum chemistry parameters (WBC, BUN, LDH of male rat, PLT, PCT, MPV of female rats), reproductive data (rate of morphologically abnormal sperm) were observed between GM rice group and two control groups. No macroscopic or histological adverse effects were found or considered as treatment-related, either. Overall, the three generation study of genetically modified rice with cry1Ac and sck genes at a high level showed no unintended adverse effects on rats's reproductive system.

  6. Reproductive and developmental toxicity of carbon-based nanomaterials: A literature review.

    PubMed

    Ema, Makoto; Hougaard, Karin Sørig; Kishimoto, Atsuo; Honda, Kazumasa

    2016-01-01

    We summarized the findings of reproductive and developmental toxicity studies on carbon-based nanomaterials (CNMs). Placental transfer of fullerenes in rats and single-walled (SW) and multi-walled (MW) CNTs in mice was shown after intravenous injection. SWCNTs appeared to be embryolethal and teratogenic in mice when given by intravenous injection and induced death and growth retardation in chicken embryos. In mice-administered MWCNTs, fetal malformations after intravenous and intraperitoneal injections and intratracheal instillation, fetal loss after intravenous injection, behavioral changes in offspring after intraperitoneal injection, and a delay in the delivery of the first litter after intratracheal instillation were reported. Oral gavage of MWCNTs had no developmental toxicity in mice and rats. MWCNTs produced morphological defects, developmental arrest, and death in zebrafish embryos. Intratracheal instillation of carbon black (CB) induced testicular toxicity in adult mice. Maternal airway exposure to CB in gestation had testicular toxicity and altered postnatal behavior, renal development, immune and genotoxic responses, and brain morphology in mouse offspring. Nanodiamonds and graphite nanoparticles inhibited vasculogenesis and/or angiogenesis in chicken embryos. Graphene oxide (GO) induced malformations in zebrafish embryos. Intravenous injection of reduced GO during late gestation caused maternal death and abortion in mice. Oral administration of GO during lactation caused growth retardation of offspring. Overall, the available data provide initial information on the potential reproductive and developmental toxicity of CNMs. However, confirmatory studies using well-characterized CNMs, state-of-the-art study protocol and appropriate route of exposure, are required to clarify the findings and provide information suitable for risk assessment.

  7. Toxicity of purified terephthalic acid manufacturing wastewater on reproductive system of male mice (Mus musculus).

    PubMed

    Zhang, Xu-Xiang; Sun, Shi-Lei; Zhang, Yan; Wu, Bing; Zhang, Zong-Yao; Liu, Bo; Yang, Liu-Yan; Cheng, Shu-Pei

    2010-04-15

    Reproductive toxicity of purified terephthalic acid (PTA) manufacturing wastewater on the male mice (Mus musculus) was investigated after 35-day intragastric perfusion treatment with the wastewater. Fluorescein diacetate and propidium iodide staining, and flow cytometry were used to assess the toxicity of PTA wastewater on spermatogenic cells. PTA wastewater induced significant variations in the relative percentages of immature haploid, diploid, tetraploid and S-phase spermatogonia. Percentage of viable spermatogenic cells was reduced from 93.1+/-2.3 in control group to 90.4+/-1.9 in the wastewater-treated group. Testicular histopathology revealed expansion of interstitial space and reduction in the number and size of Leydig cells induced by the wastewater, which was further certified by the decrease (10.6%) in relative testes weight and the increase (101.3%) in sperm shape abnormality in the wastewater-treated group. In this study, PTA wastewater was found to have reproductive toxicity on male mice, and public health problems may potentially arise from the discharge of the wastewater into the environment.

  8. One-generation reproductive toxicity study of epichlorohydrin in Sprague-Dawley rats.

    PubMed

    Shin, In-Sik; Park, Na-Hyeong; Lee, Jong-Chan; Kim, Kang-Hyeon; Moon, Changjong; Kim, Sung-Ho; Shin, Dong-Ho; Park, Seung-Chun; Kim, Hyeon-Young; Kim, Jong-Choon

    2010-07-01

    This study was conducted to evaluate the potential reproductive toxicity of epichlorohydrin in a one-generation reproduction toxicity study in compliance with OECD Test Guideline 415. Twenty-four male and female rats per group were given epichlorohydrin by gavage at 0, 3.3, 10, and 30 mg/kg/day. Males were dosed for 10 weeks prior to and during mating. Females were dosed from 2 weeks before mating to day 21 of lactation. At 30 mg/kg, an increase in the incidence of clinical signs (i.e., nasal discharge, soft feces, depression, and piloerection), gross necropsy findings (i.e., cystic pustule of the epididymidis and enlargement of the kidney) and the weights of heart, liver, and epididymidis, a decrease in male fertility, and an increased incidence of histopathological changes of the testis, epididymidis, and kidney were observed. At 10 mg/kg, decreased male fertility and increased kidney weight and incidence of histopathological changes of the epididymidis were found. There was a slight, but nonsignificant, reduction in the male fertility index at the dose of 3.3 mg/ kg. Under these experimental conditions, the lowest-observed-adverse-effect level of epichlorohydrin was 3.3 mg/kg/day for parent animals and their offspring. The absolute toxic dose for parent animals and their offspring was estimated to be 10 mg/kg/day.

  9. 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.

  10. 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.

  11. Reproduction of the estuarine and marine amphipod Corophium volutator (Pallas) in laboratory for toxicity testing.

    PubMed

    Peters, Carolin; Ahlf, Wolfgang

    2005-04-01

    The acute whole sediment bioassay with the estuarine and marine amphipod Corophium volutator (Pallas) is broadly used within Europe. Hitherto, the test is carried out with field-collected animals. In order to provide a more standardized and continuously available test organism reproduction and growth experiments were performed for a period of one year in laboratory under simulated summer conditions (light/dark 16:8 at 15, 19, and 23 degrees C). C. volutator was the first time reproduced successfully in laboratory for several generations and independent from its natural life cycle also in winter. The females produced two to three broods with a mean number of 96 offspring. A mean growth rate of 0.07 mm per day was determined at 15 degrees C. The reproduction and growth experiments provide consequently the essential base for the development of a chronic toxicity test with C. volutator.

  12. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals.

    PubMed

    Scala, R A; Bevan, C; Beyer, B K

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  13. 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.

  14. 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.

  15. 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

  16. A systematic evaluation of chemicals in hydraulic-fracturing fluids and wastewater for reproductive and developmental toxicity.

    PubMed

    Elliott, Elise G; Ettinger, Adrienne S; Leaderer, Brian P; Bracken, Michael B; Deziel, Nicole C

    2017-01-01

    Hydraulic-fracturing fluids and wastewater from unconventional oil and natural gas development contain hundreds of substances with the potential to contaminate drinking water. Challenges to conducting well-designed human exposure and health studies include limited information about likely etiologic agents. We systematically evaluated 1021 chemicals identified in hydraulic-fracturing fluids (n=925), wastewater (n=132), or both (n=36) for potential reproductive and developmental toxicity to triage those with potential for human health impact. We searched the REPROTOX database using Chemical Abstract Service registry numbers for chemicals with available data and evaluated the evidence for adverse reproductive and developmental effects. Next, we determined which chemicals linked to reproductive or developmental toxicity had water quality standards or guidelines. Toxicity information was lacking for 781 (76%) chemicals. Of the remaining 240 substances, evidence suggested reproductive toxicity for 103 (43%), developmental toxicity for 95 (40%), and both for 41 (17%). Of these 157 chemicals, 67 had or were proposed for a federal water quality standard or guideline. Our systematic screening approach identified a list of 67 hydraulic fracturing-related candidate analytes based on known or suspected toxicity. Incorporation of data on potency, physicochemical properties, and environmental concentrations could further prioritize these substances for future drinking water exposure assessments or reproductive and developmental health studies.

  17. 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.

  18. Health assessment of gasoline and fuel oxygenate vapors: Reproductive toxicity assessment

    PubMed Central

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

    2016-01-01

    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 20,000 mg/m3, 6 h/day, 7 days/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 off-spring 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 20,000 mg/m3 for all vapor condensates except for lower offspring NOAELs of 10,000 mg/m3 for G/TBA and 2000 mg/m3 for G/TAME. PMID:24813181

  19. Reproductive toxicity of di(2-ethylhexyl) phthalate in selenium-supplemented and selenium-deficient rats.

    PubMed

    Erkekoglu, Pinar; Zeybek, N Dilara; Giray, Belma; Asan, Esin; Arnaud, Josiane; Hincal, Filiz

    2011-10-01

    Phthalates are abundantly produced plasticizers, and di(ethylhexyl) phthalate (DEHP) is the most widely used derivative in various consumer products and medical devices. Animal studies show that DEHP and various other phthalates cause reproductive and developmental toxicity. Although the evidences are limited, it seems reasonable that DEHP may have a potential for similar adverse effects in humans. Such concerns are increasing, particularly for the developing reproductive system of male infants and children. By taking into account the essentiality of selenium (Se) in testicular structure and functions and the high prevalence of inadequate Se intake in various part of the world, this study was designed to investigate the testicular toxicity of DEHP in Se-deficient male rats and to examine the possible preventive effects of Se supplementation on phthalate toxicity. Se deficiency was generated by feeding 3-week-old Sprague-Dawley rats with a ≤0.05 Se mg/kg diet for 5 weeks. Supplementation groups were on a 1 mg Se/kg diet, and DEHP-treated groups received a 1,000 mg/kg dose by gavage during the last 10 days of the feeding period. Testicular histopathology, sperm count and motility, and sperm morphology were examined, and plasma levels of sex hormones were measured. Toxicity and antiandrogenic effects of DEHP were evidenced by disturbed testicular histology and spermatogenesis, diminished testosterone, leutinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and sperm motility. The effects of DEHP were much more pronounced in Se-deficient rats, whereas Se supplementation was found to be protective, reflecting its regulating role in cellular redox equilibrium.

  20. NTP CENTER FOR THE EVALUATION OF RISKS TO HUMAN REPRODUCTION: PHTHALATES EXPERT PANEL REPORT ON THE REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DI-N-OCTYL PHTHALATE

    EPA Science Inventory

    Kavlock et al.; "NTP Center for the Evaluation....

    Abstract

    The phthalates are a family of environmentally important compounds with diverse uses. Reproductive toxicity has been demonstrated for some members of this family. The NTP Center for the Evaluation of Risk...

  1. 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.

  2. 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.

  3. Study on the toxicity of phenolic and phenoxy herbicides using the submitochondrial particle assay.

    PubMed

    Argese, E; Bettiol, C; Marchetto, D; De Vettori, S; Zambon, A; Miana, P; Ghetti, P F

    2005-12-01

    A simple and rapid in vitro toxicological assay, utilizing submitochondrial particles (SMP), has been used to evaluate the toxic effects of fifteen herbicides belonging to the phenol and phenoxyalkanoic acid chemical classes. The SMP assay allows the quantitative evaluation of the toxicity of compounds with different mechanisms of action: uncouplers, inhibitors of the enzyme complexes involved in reverse electron transfer and in oxidative phosphorylation and chemicals that alter the membrane structure. The two groups of herbicides showed different levels of toxicity. For phenol derivatives, EC50 values ranged from 0.16 microM (ioxynil) to 6.7 microM (2,4-dinitrophenol), whereas for phenoxy herbicides EC50 values ranged from 21 microM (2,4,5-trichlorophenoxyacetic acid, 2,4,5-T) to 110 microM (4-chloro-2-methylphenoxyacetic acid, MCPA). On the average, the toxicity of phenolic compounds is greater than that of phenoxyalkanoic acids by two orders of magnitude. Quantitative structure-activity relationships (QSAR) were developed between EC50 values and various molecular descriptors. The results suggest the existence of different mechanisms of action for the two classes of compounds. The findings obtained for phenolic herbicides are consistent with a protonophoric uncoupling mechanism, whereas for phenoxy herbicides a non-specific mode of action at membrane level can be hypothesized.

  4. 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.

  5. The toxic effects of sodium fluoride on the reproductive system of male rats.

    PubMed

    Gupta, R S; Khan, T I; Agrawal, D; Kachhawa, J B S

    2007-10-01

    The present study was undertaken to evaluate the effect of fluoride toxicity on the reproductive system of male rats. Sexually mature male Wistar rats were exposed to 2, 4, and 6 ppm sodium fluoride in their drinking water for 6 months ad libitum. Sperm motility and density in cauda epididymis were assessed. Biochemical and histological analysis were performed in reproductive organs. Fluoride treatment brought about a significant decrease in the weight of testis, epididymis, and ventral prostate. The sperm motility and density were significantly reduced. There was a marked reduction in the number of primary spermatocyte, secondary spermatocyte, and spermatids. The Sertoli cell counts and their cross sectional surface areas were significantly decreased. The Leydig cell nuclear area and the number of mature Leydig cells were also significantly decreased. The protein content of the testis and epididymis were significantly reduced. Fructose in the seminal vesicles and cholesterol in testes were increased significantly. In conclusion, sodium fluoride administrated in drinking water of 2, 4, and 6 ppm concentration for 6 months to male rats adversely affected their fertility and reproductive system.

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

    PubMed

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

    2015-09-23

    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.

  7. 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

  8. 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

  9. A one-generation reproductive toxicity study of ethyl tertiary butyl ether in rats.

    PubMed

    Fujii, Sakiko; Yabe, Kaoru; Furukawa, Masatoshi; Matsuura, Masao; Aoyama, Hiroaki

    2010-11-01

    A one-generation reproductive toxicity study was conducted to evaluate the effects of ethyl tertiary butyl ether (ETBE), a bio-fuel, on reproduction of parental rats, as well as development and growth of their offspring at dose levels of 0, 100, 300 and 1000 mg/kg-d by gavage. No treatment-related changes were observed in either F0 parents or their F1 offspring in the 100 and 300 mg/kg groups in any parameters examined. Some parental animals in the 1000 mg/kg group exhibited transient salivation, possibly a reflex to a bitter taste of ETBE, immediately after dosing, although their body weights, food consumption, reproductive parameters, and gross pathological findings were not affected. Their absolute and relative liver weights increased significantly in the 1000 mg/kg group, suggesting enhanced activities of metabolic enzymes. Pup viability was slightly reduced during the early lactation period in the 1000 mg/kg group. These results lead to the conclusion that the no-observed-adverse-effect-level (NOAEL) of ETBE on both parental rats and their offspring is 300 mg/kg-d under the current study condition.

  10. 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.

  11. 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.

  12. 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.

  13. A two-generation inhalation reproductive toxicity study upon the exposure to manganese chloride.

    PubMed

    McGough, Doreen; Jardine, Lynne

    2017-01-01

    A number of published studies have suggested that high levels of exposure to manganese, especially those found in occupational settings, can adversely affect the reproductive system. The objective of this study was therefore to investigate if these findings can be replicated using the Sprague Dawley rat and, if so, to identify those parts of the reproductive system are more susceptible. Male and female rats were exposed to manganese dichloride (MnCl2) via inhalation at concentrations of 0 (air-control); 5, 10 and 20μg/L air over 10 weeks (F0) and over 11 weeks (F1) prior to mating, and then throughout mating, gestation and lactation until termination after the F1 and F2 generation had reached Day 21 of lactation respectively. Animals were monitored for clinical signs of toxicity and for effects on body weight, food consumption, effects on the entire reproductive system including maternal care. The offspring were monitored for survival and growth up to weaning. Blood samples were taken from all adult animals for bioanalytical of manganese analysis prior to dosing, prior to mating and prior to weaning/necropsy. There were no deaths related to treatment, though respiratory tract effects were observed in F0 animals in the mid and high dose animals. Body weight and food consumption were affected at high dose in both generation. There were no treatment-related effects on the oestrous cycles, mating performance, sexual maturity, fertility or duration of gestation or litter size, the sperm motility, count of morphology (sperm) or the ovary follicle scoring in either generation. The No Observed Effect Level (NOEL) for reproductive performance was considered to be the target dose level of 20μg/L. Based on these findings, manganese chloride could not be considered a reprotoxicant under these conditions of exposure. Therefore, soluble and insoluble forms of inorganic manganese compounds by extrapolation cannot be considered as reprotoxicants.

  14. Reproductive toxicity of seafood contaminants: Prospective comparisons of Swedish east and west coast fishermen's families

    PubMed Central

    Axmon, Anna; Rylander, Lars; Rignell-Hydbom, Anna

    2008-01-01

    Cohorts comprising fishermen's families on the east coast of Sweden have been found to have a high consumption of contaminated fish as well as high body burdens of persistent organochlorine pollutants (POPs). Their west coast correspondents are socio-economically similar, but with considerably lower POP exposure since the fish caught on the west coast is far less contaminated. The rationale for this was that the cohorts residing on the east coast of Sweden have been found to have a high consumption of contaminated fish as well as high body burdens of POPs, whereas their west coast correspondents are socio-economically similar, but with considerably lower POP exposure since the fish caught on the west coast is far less contaminated. Among the reproductive outcomes investigated are included both male and female parameters, as well as couple fertility and effects on the fetus. A range of exposure measures, including both questionnaire assessments of fish consumption and biomarkers, have been used. The most consistent findings of the studies are those related to the fetus, where a decreased birth weight was found across all measures of exposure, which is in agreement with studies from other populations. Some markers for male reproduction function, i.e. sperm motility, sperm chromatin integrity, and Y:X chromosome ratio, were associated with POP exposure, whereas others, such as sperm concentration and semen volume, were not. With respect to couple fertility and female reproductive parameters, no support was given for associations with POP exposure. Although some associations may have been affected by beneficial effects of essential nutrients in seafood, the overall findings are meaningful in the context of reproductive toxicity and support the usefulness of the epidemiological design. PMID:18507855

  15. 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.

  16. Role of ginger against the reproductive toxicity of aluminium chloride in albino male rats.

    PubMed

    Moselhy, W A; Helmy, N A; Abdel-Halim, B R; Nabil, T M; Abdel-Hamid, M I

    2012-04-01

    The aim of the current study was to evaluate reproductive disorders concomitant with aluminium chloride (AlCl(3) ) toxicity in Albino male rats. Attention was also directed to study the protective influence of ginger against this toxicity. Forty-five mature Albino Wistar male rats were equally divided into three groups; the first group was served as control group while those of the second group (AlCl(3) ) were daily treated with 34 mg/kg bw. AlCl(3) orally. The third group (AlCl(3)  + ginger) was treated daily with AlCl(3) as in group 2 in combination with ginger (40 mg/kg bw), which started 2 weeks prior to AlCl(3) . Five animals from each group were sacrificed on days 30, 45 and 60 of treatment. AlCl(3) administration significantly decreased serum testosterone levels, increased testicular homogenate malondialdehyde and deteriorated semen picture with increased testicular DNA fragmentation. Histopathological examination revealed degenerative changes of the seminiferous tubules with focal areas of necrosed spermatogenic cells, marked degeneration and desquamation of the lining epithelial cells of epididymis as well as multiple calcified material in prostate gland following 60 days of aluminium treatment. Ginger treatment started to improve significantly all studied parameters after 60 days as compared with AlCl(3) -treated group. In the current study, it was concluded that AlCl(3) had a destructive effect on all the studied reproductive parameters. Treatment with ginger has an ameliorating effect against AlCl(3) toxicity after 60 days post-treatment.

  17. Developmental and reproductive toxicity of PVP/PEI-coated silver nanoparticles to zebrafish.

    PubMed

    Orbea, Amaia; González-Soto, Nagore; Lacave, José María; Barrio, Irantzu; Cajaraville, Miren P

    2017-03-05

    Cellular and molecular mechanisms of toxicity of silver nanoparticles (NPs) and their toxicity to fish embryos after waterborne exposure have been widely investigated, but much less information is available regarding the effect of Ag NPs on physiological functions such as growth or reproduction. In this work, the effects of waterborne exposure of adult zebrafish (Danio rerio) to PVP/PEI coated Ag NPs (~5nm) on reproduction (fecundity) were investigated. Moreover, the development of the embryos after parental exposure was compared with the development of embryos after direct waterborne exposure to the NPs. For this, two experiments were run: 1) embryos from unexposed parents were treated for 5days with Ag NPs (10μg Ag L(-1)-10mg Ag L(-1)) and development was monitored, and 2) selected breeding zebrafish were exposed for 3weeks to 100ng Ag L(-1) (environmentally relevant concentration) or to 10μg Ag L(-1) of Ag NPs, fecundity was scored and development of resulting embryos was monitored up to 5 d. Waterborne exposure of embryos to Ag NPs resulted highly toxic (LC50 at 120h=50μg Ag L(-1)), causing 100% mortality during the first 24h of exposure at 0.1mg Ag L(-1). Exposure of adults, even at the environmentally relevant silver concentration, caused a significant reduction of fecundity by the second week of treatment and resulting embryos showed a higher prevalence of malformations than control embryos. Exposed adult females presented higher prevalence of vacuolization in the liver. These results show that Ag NPs at an environmentally relevant concentration are able to affect population level parameters in zebrafish.

  18. Bayesian approach to estimating reproductive inhibition potency in aquatic toxicity testing.

    PubMed

    Zhang, Jing; Bailer, A John; Oris, James T

    2012-04-01

    Effectively and accurately assessing the toxicity of chemicals and their impact on the environment continues to be an important concern in ecotoxicology. Single experiments conducted by a particular laboratory commonly serve as the basis of toxicity risk assessment. These laboratories often have a long history of conducting experiments using particular protocols. In the present study, a Bayesian analysis for estimating potency based on a single experiment was formulated, which then served as the basis for incorporating the experimental information from historical controls. A Bayesian hierarchical model was developed to estimate the relative inhibition concentrations (RIp) of a toxicant and flexible ways of using historical control information were suggested. The methods were illustrated using a data set produced by the test for reproduction in Ceriodaphnia dubia in which the number of young produced over three broods was recorded. In addition, simulation studies were included to compare the Bayesian methods with previously proposed estimators of potency. The Bayesian methods gave more precise RIp estimates with smaller variation and nominal coverage probability offsetting a small negative bias in the point estimate. Incorporating historical control information in the Bayesian hierarchical model effectively uses the useful information from past similar experiments when estimating the RIp, and results in potency estimates that are more precise compared to frequentist methods.

  19. Review on arsenic-induced toxicity in male reproductive system and its amelioration.

    PubMed

    Zubair, M; Ahmad, M; Qureshi, Z I

    2017-01-30

    Arsenic is an environmental toxicant which causes mutagenic, teratogenic and carcinogenic defects. It is used as herbicide, fungicide and rodenticide and results in contamination of air, soil and water. Arsenic is also produced through burning of coal industries. The sludge of factories contaminates the fodder and drinking source of water of human and livestock. Arsenic binds thiol groups in tissue proteins and impairs the function of the proteins. This metal affects the mitochondrial enzymes and interrupts the production of energy. Oxidative stress and the generation of reactive oxygen species could also be a consequence of arsenic exposure. High arsenic level may suppress the sensitivity of gonadotroph cells to GnRH as well as gonadotropin secretion by elevating plasma levels of glucocorticoids. These ultimately lead to the development of gonad toxicity in animals and cause the reduction in sperm number, sperm viability and motility. Massive degeneration of germ cells and alterations in the level of LH, FSH and testosterone are also reported. The objective of this review was to find out the effects of arsenic-induced toxicity on male reproductive system in animals and its amelioration.

  20. Evaluation of subchronic (13 week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene).

    PubMed

    Odio, M R; Azri-Meehan, S; Robison, S H; Kraus, A L

    1994-04-01

    Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene) in commercial sunscreen products has increased considerably in recent years. To support larger scale human exposure to this compound, additional toxicological information was needed in several key areas. The present studies evaluated subchronic toxicity, developmental toxicity, and in vitro genotoxic potential of Octocrylene. In the subchronic study, male and female New Zealand white (NZW) rabbits treated topically with concentrations of octocrylene up to 534 mg/kg/day for 13 weeks showed slight to moderate dose-dependent skin irritation that correlated positively with a mild depression in body weight gain. Lack of associated histopathologic or clinical hematology abnormalities suggested that the body weight effect probably reflected a nonspecific response to topical irritation. In percutaneous developmental toxicity studies, NZW does were treated topically with Octocrylene at levels up to 267 mg/kg/day on Days 6 through 18 of gestation. Body weight gain, food consumption, and all maternal, reproductive, and offspring parameters evaluated were comparable between Octocrylene-treated and control animals. In the oral developmental toxicity assay, female CD-1 mice received oral doses of Octocrylene up to 1000 mg/kg/day on Days 8-12 of gestation. No evidence of maternal or developmental toxicity was seen at any dose tested. Genotoxicity was evaluated in vitro using the Chinese hamster ovary cell assay to assess clastogenicity and the mouse lymphoma cell assay to assess forward gene mutations. Octocrylene did not induce any significant increase in genotoxicity. This evaluation of toxicological potential supports the use of Octocrylene as a human photoprotectant.

  1. 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.

  2. 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.

  3. 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.

  4. Toxicity of selected plant volatiles in microbial and mammalian short-term assays.

    PubMed

    Stammati, A; Bonsi, P; Zucco, F; Moezelaar, R; Alakomi, H L; von Wright, A

    1999-08-01

    In this study, several short-term microbial and mammalian in vitro assays were used to evaluate cytotoxicity and genotoxicity of four plant volatiles showing antifungal activity: cinnamaldehyde, carvacrol, thymol and S(+)-carvone. All inhibited viability and proliferation of Hep-2 cells in a dose-dependent manner. IC50 ranged from 0.3 mM (cinnamaldehyde) to 0.7 mM (thymol) in viability tests and from 0.2 mM (carvacrol) to 0.9 mM (carvone) in the proliferation test. The morphological analysis suggested an involvement of apoptosis in the cases of carvone, carvacrol and cinnamaldehyde. At nontoxic doses, carvacrol and thymol increased the number of revertants in the Ames test by 1.5-1.7 times, regardless of metabolic activation. In the SOS-chromotest, none of the four plant volatiles caused DNA damage at non-toxic doses. In the DNA repair test, a marked dose-dependent differential toxicity was observed with carvone and, to a lesser extent, with cinnamaldehyde, while with thymol and carvacrol, this effect was less pronounced. In conclusion, the considered in vitro cytotoxicity assays have shown to be sensitive enough to highlight a variety of toxic effects at the cellular level, which can be rather different between chemically closely related compounds, such as isomers.

  5. 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.

  6. 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...

  7. Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats.

    PubMed

    Luo, Qihui; Chen, Zhengli; Cheng, Anchun; Wang, Mingshu; Fang, Jing; Peng, Xi; Tang, Li

    2015-03-01

    Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6-15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6-20 pregnant days were significantly different (P < 0.01, P < 0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P < 0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg·d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg·d) there is no teratogenic side effects.

  8. 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.

  9. Acute toxicity assessment of explosive-contaminated soil extracting solution by luminescent bacteria assays.

    PubMed

    Xu, Wenjie; Jiang, Zhenming; Zhao, Quanlin; Zhang, Zhenzhong; Su, Hongping; Gao, Xuewen; Ye, Zhengfang

    2016-11-01

    Explosive-contaminated soil is harmful to people's health and the local ecosystem. The acute toxicity of its extracting solution was tested by bacterial luminescence assay using three kinds of luminescent bacteria to characterize the toxicity of the soil. An orthogonal test L 16 (4(5)) was designed to optimize the soil extracting conditions. The optimum extracting conditions were obtained when the ultrasonic extraction time, ultrasonic extraction temperature, and the extraction repeat times were 6 h, 40 °C, and three, respectively. Fourier transform infrared spectroscopy (FTIR) results showed that the main components of the contaminated soil's extracting solution were 2,4-dinitrotoluene-3-sulfonate (2,4-DNT-3-SO3(-)); 2,4-dinitrotoluene-5-sulfonate (2,4-DNT-5-SO3(-)); and 2,6-dinitrotoluene (2,6-DNT). Compared with Photobacterium phosphoreum and Vibrio fischeri, Vibrio qinghaiensis sp. Nov. is more suitable for assessing the soil extracting solution's acute toxicity. Soil washing can remove most of the contaminants toxic to luminescent bacterium Vibrio qinghaiensis sp. Nov., suggesting that it may be a potential effective remediation method for explosive-contaminated soil.

  10. 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.

  11. Estrogenicity and acute toxicity of selected anilines using a recombinant yeast assay.

    PubMed

    Hamblen, Elizabeth L; Cronin, Mark T D; Schultz, T Wayne

    2003-08-01

    Suspected estrogen modulators include industrial organic chemicals (i.e., xenoestrogens), and have been shown to consist of alkylphenols, bisphenols, biphenylols, and some hydroxy-substituted polycyclic aromatic hydrocarbons. The most prominent structural feature identified to be important for estrogenic activity is a polar group capable of donating hydrogen bonds (i.e., hydroxyl) on an aromatic system. The present study was undertaken to explore the estrogenic activity and acute toxicity of chemicals containing a weaker hydrogen bond donor group on aromatic systems, i.e., the amino substituent. There is a great deal of chemical similarity between aromatic amines (anilines) and aromatic alcohols (phenols). The chemicals chosen for the current study contained an amino-substituted benzene ring with hydrophobic constituents varying in size and shape. Thus, 37 substituted aromatic amines were assayed for estrogenic activity EC50 and acute toxicity LC50 using the Saccharomyces cerevisiae recombinant yeast assay. While the EC50 of 17-beta-estradiol occurs at the 10(-10) range, the aniline with the greatest activity had an EC50 of 10(-6) M. Thus, anilines, in general, are capable only of very weak estrogenic activity in this assay. A comparison of estrogenic potency between the present group of anilines and a set of previously tested analogous phenols indicated that anilines are consistently less estrogenic than phenols. A comparison of hazard indices (EC50/LC50) of these chemicals revealed that, for the vast majority of anilines, the EC50 and LC50 were in the same order of magnitude. More specifically, estrogenic activity of para-substituted alkylanilines increases with alkyl group size up to 5 carbons in length, after which the acute toxicity of the larger alkyl-substituents precluded the ability of the compound to induce the estrogenic response.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

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

    PubMed

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

    2016-09-22

    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.

  2. 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

  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

    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.

  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 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

  5. 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

  6. Toxicity of four veterinary pharmaceuticals on the survival and reproduction of Folsomia candida in tropical soils.

    PubMed

    Zortéa, Talyta; Segat, Julia C; Maccari, Ana Paula; Sousa, José Paulo; Da Silva, Aleksandro S; Baretta, Dilmar

    2017-04-01

    This study aimed to evaluate the effect of veterinary pharmaceuticals (VPs) used to control endo- and ectoparasites in ruminants, on the survival and reproduction of the collembolan species Folsomia candida. Standard ecotoxicological tests were conducted in Tropical Artificial Soil and the treatments consisted of increasing dosages of four commercial products with different active ingredients: ivermectin, fipronil, fluazuron and closantel. Ecotoxicological effects were related to the class and mode of action of the different compounds. Fipronil and ivermectin were the most toxic compounds causing a significant reduction in the number of juveniles at the lowest doses tested (LOECreprod values of 0.3 and 0.2 mg kg(-1) of dry soil, respectively) and similar low EC50 values (fipronil: 0.19 mg kg(-1) dry soil, CL95% 0.16-0.22; ivermectin: 0.43 mg kg(-1) dry soil, CL95% 0.09-0.77), although the effects observed in the former compound were possibly related to a low adult survival (LC50 of 0.62 mg kg(-1) dry soil; CL95%: 0.25-1.06). For the latter compound no significant lethal effects were observed. Fluazuron caused an intermediate toxicity (EC50 of 3.07 mg kg(-1) dry soil, CL95%: 2.26-3.87), and also here a decrease in adult survival could explain the effects observed at reproduction. Closantel, despite showing a significant reduction on the number of juveniles produced, no dose-response relationship nor effects higher than 50% were observed. Overall, all tested compounds, especially ivermectin, when present in soil even at sub-lethal concentrations, can impair the reproduction of collembolans and possibly other arthropods. However, the actual risk to arthropod communities should be further investigated performing tests under a more realistic exposure (e.g., by testing the dung itself as the contaminated matrix) and by deriving ecotoxicologically relevant exposure concentration in soil derived from the presence of cattle dung.

  7. 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...

  8. 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 ...

  9. Overview of developmental and reproductive toxicity research in China: history, funding mechanisms, and frontiers of the research.

    PubMed

    Wu, Chunqi

    2010-02-01

    Reproductive and developmental toxicology (DART) is the discipline that deals with adverse effects on male and female resulting from exposures to harmful chemical and physical agents. DART research in China boasted a long history, but presently has fallen behind the western world in education and research. The funding mechanisms for DART research in China were similar to that for other toxicological disciplines, and the funding has come from research grants and fellowships provided by national, ministerial, and provincial institutions. Finally, the frontiers of DART research in China could be summarized as follows: (1) use of model animals such as the zebrafish and roundworm, and use of cutting-edge techniques such as stem cell culture, as well as transgenic, metabonomic, and virtual screening to study the mechanisms of developmental toxicity for some important toxicants in China; (2) use of model animals and other lower-level sentinel organisms to evaluate and monitor the developmental toxicogical risk of environmental chemicals or pollutants; (3) epidemiological studies of some important reproductive hazards; (4) in-depth studying of the reproductive and developmental toxicity of some important environmental chemicals; and (5) evaluation and study of the reproductive and developmental toxicity of traditional Chinese medicines.

  10. Demonstration of toxicity to fish and to mammalian cells by Pfiesteria species: comparison of assay methods and strains.

    PubMed

    Burkholder, Joann M; Gordon, Andrew S; Moeller, Peter D; Law, J Mac; Coyne, Kathryn J; Lewitus, Alan J; Ramsdell, John S; Marshall, Harold G; Deamer, Nora J; Cary, S Craig; Kempton, Jason W; Morton, Steven L; Rublee, Parke A

    2005-03-01

    Toxicity and its detection in the dinoflagellate fish predators Pfiesteria piscicida and Pfiesteria shumwayae depend on the strain and the use of reliable assays. Two assays, standardized fish bioassays (SFBs) with juvenile fish and fish microassays (FMAs) with larval fish, were compared for their utility to detect toxic Pfiesteria. The comparison included strains with confirmed toxicity, negative controls (noninducible Pfiesteria strains and a related nontoxic cryptoperidiniopsoid dinoflagellate), and P. shumwayae strain CCMP2089, which previously had been reported as nontoxic. SFBs, standardized by using toxic Pfiesteria (coupled with tests confirming Pfiesteria toxin) and conditions conducive to toxicity expression, reliably detected actively toxic Pfiesteria, but FMAs did not. Pfiesteria toxin was found in fish- and algae-fed clonal Pfiesteria cultures, including CCMP2089, but not in controls. In contrast, noninducible Pfiesteria and cryptoperidiniopsoids caused no juvenile fish mortality in SFBs even at high densities, and low larval fish mortality by physical attack in FMAs. Filtrate from toxic strains of Pfiesteria spp. in bacteria-free media was cytotoxic. Toxicity was enhanced by bacteria and other prey, especially live fish. Purified Pfiesteria toxin extract adversely affected mammalian cells as well as fish, and it caused fish death at environmentally relevant cell densities. These data show the importance of testing multiple strains when assessing the potential for toxicity at the genus or species level, using appropriate culturing techniques and assays.

  11. Demonstration of toxicity to fish and to mammalian cells by Pfiesteria species: Comparison of assay methods and strains

    PubMed Central

    Burkholder, JoAnn M.; Gordon, Andrew S.; Moeller, Peter D.; Law, J. Mac; Coyne, Kathryn J.; Lewitus, Alan J.; Ramsdell, John S.; Marshall, Harold G.; Deamer, Nora J.; Cary, S. Craig; Kempton, Jason W.; Morton, Steven L.; Rublee, Parke A.

    2005-01-01

    Toxicity and its detection in the dinoflagellate fish predators Pfiesteria piscicida and Pfiesteria shumwayae depend on the strain and the use of reliable assays. Two assays, standardized fish bioassays (SFBs) with juvenile fish and fish microassays (FMAs) with larval fish, were compared for their utility to detect toxic Pfiesteria. The comparison included strains with confirmed toxicity, negative controls (noninducible Pfiesteria strains and a related nontoxic cryptoperidiniopsoid dinoflagellate), and P. shumwayae strain CCMP2089, which previously had been reported as nontoxic. SFBs, standardized by using toxic Pfiesteria (coupled with tests confirming Pfiesteria toxin) and conditions conducive to toxicity expression, reliably detected actively toxic Pfiesteria, but FMAs did not. Pfiesteria toxin was found in fish- and algae-fed clonal Pfiesteria cultures, including CCMP2089, but not in controls. In contrast, noninducible Pfiesteria and cryptoperidiniopsoids caused no juvenile fish mortality in SFBs even at high densities, and low larval fish mortality by physical attack in FMAs. Filtrate from toxic strains of Pfiesteria spp. in bacteria-free media was cytotoxic. Toxicity was enhanced by bacteria and other prey, especially live fish. Purified Pfiesteria toxin extract adversely affected mammalian cells as well as fish, and it caused fish death at environmentally relevant cell densities. These data show the importance of testing multiple strains when assessing the potential for toxicity at the genus or species level, using appropriate culturing techniques and assays. PMID:15728353

  12. 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 ...

  13. DEVELOPMENT OF AN IN VITRO ASSAY THAT MAY IDENTIFY WHICH ORGANOPHOSPHORUS PESTICIDES ARE MORE TOXIC TO THE YOUNG.

    EPA Science Inventory

    Some, but not all, organophosphorus pesticides are more acutely toxic to the young as compared to adults. We have developed an in vitro assay which measures the detoxification potential (via carboxylesterase and A-esterases) of tissues. Previous results using this in vitro assay ...

  14. [Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (1). Fertility study in rats].

    PubMed

    Nishimura, T; Chihara, N; Oku, H; Mori, H; Shinomiya, K; Ozeki, Y; Fujita, T

    1997-12-01

    A fertility study of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to males from the 64th day before mating until necropsy, and to females from 15th day before mating until day 7 of gestation, at a dose level of 0 (control), 25, 50 or 100 mg/kg/day. On day 20 of gestation, all dams were sacrificed and their fetuses were examined. In the 100 mg/kg/day group, hypoactivity, clonic convulsion, bradypnea/apnea and redish lacrimation were observed after administration in both sexes, and 3 males and 2 females died. Reddish lacrimation was occasionally seen in males at late stage of the treatment period in 50 mg/kg/day group. In the 100 mg/kg/day group, body weight gain suppressed in females from the premating through the gestation period, and food consumption decreased in females during the premating period, and mean thymus weight decreased in males. ONO-1101 did not affect estrous cycle, copulatory or fertility in both sexes or external, skeletal or visceral features of the fetuses. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for general toxicity in parents, and 100 mg/kg/day for the reproductive performance in parents and for the development of fetuses.

  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. Perturbations in Polar Lipids, Starvation Survival and Reproduction Following Exposure to Unsaturated Fatty Acids or Environmental Toxicants in Daphnia magna

    PubMed Central

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

    2015-01-01

    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 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

  17. 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.

  18. Predicting the relative toxicity of metal ions using ion characteristics: Microtox{reg_sign} bioluminescence assay

    SciTech Connect

    McCloskey, J.T.; Newman, M.C.; Clark, S.B.

    1996-10-01

    Quantitative structure-activity relationships have been used to predict the relative toxicity of organic compounds. Although not as common, ion characteristics have also proven useful for predicting the relative toxicity of metal ions. The purpose of this study was to determine if the relative toxicity of metal ions using the Microtox{reg_sign} bioassay was predictable using ion characteristics. Median effect concentrations (EC50s) were determined for 20 metals in a NaNO{sub 3} medium, which reflected freshwater speciation conditions, using the Microtox bacterial assay. The log of EC50 values was modeled using several ion characteristics, and Akaike`s Information Criterion was calculated to determine which ion characteristics provided the best fit. Whether modeling total ion or free ion EC50 values, the one variable which best modeled EC50s was the softness index, while a combination of {chi}{sub m}{sup 2}r ({chi}{sub m} = electronegativity, r = Pauling ionic radius) and {vert_bar}log K{sub OH}{vert_bar} was the best two-variable model. Other variables, including {Delta}E{sub 0} and {chi}{sub m}{sup 2}r (one-variable models) and (AN/{Delta}IP, {Delta}E{sub 0}) and ({chi}{sub m}{sup 2}r, Z{sup 2}/r) (two-variable models), also gave adequate fits. Modeling with speciated (free ion) versus unspeciated (total ion) EC50 values did not improve fits. Modeling mono-, di-, and trivalent metal ions separately improved the models. The authors conclude that ion characteristics can be used to predict the relative toxicity of metal ions whether in freshwater (NaNO{sub 3} medium) or saltwater (NaCl medium) speciation conditions and that this approach can be applied to metal ions varying widely in both valence and binding tendencies.

  19. 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.

  20. 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

  1. 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

  2. Bioluminescent Vibrio fischeri Assays in the Assessment of Seasonal and Spatial Patterns in Toxicity of Contaminated River Sediments

    PubMed Central

    Jarque, Sergio; Masner, Petr; Klánová, Jana; Prokeš, Roman; Bláha, Ludek

    2016-01-01

    Several bacteria-based assays, notably Vibrio fischeri luminescence assays, are often used as environmental monitoring tool for toxicity in sediments that may serve as both sinks and secondary source of contamination in aquatic ecosystems. In this study, we used 30-s kinetic bioassays based on V. fischeri to evaluate the toxicity associated to sediments from five localities with different contamination inputs (Morava River and its tributary Drevnice River in the south-eastern part of the Czech Republic). Toxicity assessed as half maximal inhibitory concentration (IC50) over the course of a year-long sampling was compared in bottom sediments and freshly trapped particulate material. Standard approach based on testing of aqueous elutriates was compared with toxicity of whole sediments (contact suspension toxicity). Bottom sediments showed lower toxicity compared to freshly trapped suspended materials in all cases. On the other hand, standardized elutriates induced generally weaker effects than suspended sediments likely due to losses during the extraction process. Toxicity generally increased during winter reaching maximum peaks in early spring months in all five sites. Total organic carbon (TOC) was found to be highly correlated with toxic effects. Toxicity from sites with direct industrial and agricultural water inputs also correlated with concentrations of metals, polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs). Single time point sampling followed by the extraction and testing of elutriates, do not truly reflect the spatial and temporal variability in natural sediments and may lead to underestimation of ecotoxic risks. PMID:27872614

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model.

    PubMed

    Cereda, Cintia Maria Saia; Guilherme, Viviane Aparecida; Alkschbirs, Melissa Inger; de Brito Junior, Rui Barbosa; Tofoli, Giovana Radomille; Franz-Montan, Michelle; de Araujo, Daniele Ribeiro; de Paula, Eneida

    2017-03-01

    The aim of this study was to evaluate the in vitro cytotoxicity and the in vivo analgesic effect and local toxicity of the local anesthetic butamben (BTB) encapsulated in conventional or elastic liposomes incorporated in gel formulations. The results showed that both gel formulations of liposomal BTB reduced the cytotoxicity (p < 0.001; one-way ANOVA/Tukey's test) and increased the topical analgesic effect (p < 0.05; one-way ANOVA/Tukey's test) of butamben, compared to plain BTB gel. The gel formulations presented good rheological properties, and stability assays detected no differences in physicochemical stability up to 30 d after preparation. Moreover, histological assessment revealed no morphological changes in rat skin after application of any of the gel formulations tested.

  9. Identifying contact-mediated, localized toxic effects of MWCNT aggregates on epithelial monolayers: a single-cell monitoring toxicity assay.

    PubMed

    Rotoli, Bianca M; Gatti, Rita; Movia, Dania; Bianchi, Massimiliano G; Di Cristo, Luisana; Fenoglio, Ivana; Sonvico, Fabio; Bergamaschi, Enrico; Prina-Mello, Adriele; Bussolati, Ovidio

    2015-03-01

    Aggregates of multiwalled carbon nanotubes (MWCNT) impair the barrier properties of human airway cell monolayers. To resolve the mechanism of the barrier alteration, monolayers of Calu-3 human airway epithelial cells were exposed to aggregated MWCNT. At the cell-population level, trans-epithelial electrical resistance (TEER) was used as an indicator of barrier competence, caspase activity was assessed with standard biochemical assays, and cell viability was investigated by biochemical techniques and high-throughput screening (HTS) technique based on automated epifluorescence microscopy. At cell level, the response to MWCNT was investigated with confocal microscopy, by evaluating cell death (calcein/propidium iodide (PI)), proliferation (Ki-67), and apoptosis (caspase activity). At the cell-population level, exposure to aggregated MWCNT caused a decrease in TEER, which was not associated with a decrease in cell viability or onset of apoptosis even after an 8-d exposure. In contrast, confocal imaging demonstrated contact with MWCNT aggregates triggered cell death after 24 h of exposure. In the presence of a natural surfactant, both TEER decrease and contact-mediated toxicity were mitigated. With confocal imaging, increased proliferation and apoptosis were detected in Calu-3 cells next to the aggregates. Contact-mediated cytotoxicity was recorded in two additional cell lines (BEAS-2B and A549) derived from human airways. Similar results were confirmed by adopting two additional MWCNT preparations with different physico-chemical features. This indicates MWCNT caused localized damage to airway epithelial monolayers in vitro and altered the apoptotic and proliferative rate of epithelial cells in close proximity to the aggregates. These findings provide evidence on the pathway by which MWCNT aggregates impair airway barrier function, and support the use of imaging techniques as a possible regulatory-decision supporting tool to identify effects of aggregated nanomaterials

  10. 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...

  11. 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.

  12. 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.

  13. 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. PMID:27818735

  14. 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.

  15. Xenopus laevis is a potential alternative model animal species to study reproductive toxicity of phytoestrogens.

    PubMed

    Cong, Lin; Qin, Zhan-Fen; Jing, Xiang-Ning; Yang, Lei; Zhou, Jing-Ming; Xu, Xiao-Bai

    2006-05-10

    This study investigated effects of phytoestrogen quercetin on the gonadal development in Xenopus laevis. X. laevis at Nieuwkoop and Faber stage 46/47 were exposed to 50, 100 and 200 microg/L quercetin till 1 month postmetamorphosis. Gonads from frogs at 1 and 3 months postmetamorphosis were examined in gross morphology and histology. The highest dose of quercetin as well as estradiol (E2) significantly increased the percentages of phenotypic females. Exposure to quercetin at all doses induced abnormal testes with certain ovarian characteristics to some degree in gross morphology, including ovotestes. The abnormality rate exceeded 10% in each quercetin treatment. Histologic examination revealed that some abnormal testes exhibited intersexuality with testicular structure and ovarian structure or oocytes interspersed in testicular structure at 1 month postmetamorphosis. At 3 months postmetamorphosis, testicular abnormalities were more obvious, such as necrosis or apoptosis of spermatogonia, occurrence of developed or undeveloped oocytes, delay of the development of seminiferous tubes without or less late stage spermatocytes. The results have shown that quercetin cannot only feminize but also impair testicular development of X. laevis, i.e. X. laevis is sensitive to phytoestrogen. It is suggested that X. laevis might be an alternative model species to study reproductive toxicity of phytoestrogens.

  16. One-year chronic oral toxicity with combined reproduction toxicity study of a novel probiotic, Bacillus coagulans, as a food ingredient.

    PubMed

    Endres, J R; Qureshi, I; Farber, T; Hauswirth, J; Hirka, G; Pasics, I; Schauss, A G

    2011-05-01

    Some strains of Bacillus coagulans can survive extremes of heat, stomach acid and bile acids, to which commonly consumed probiotics are susceptible. A toxicological safety assessment was published in 2009 on a proprietary preparation of B. coagulans - GanedenBC(30)™ - a novel probiotic. It was concluded that GanedenBC(30)™ is safe for chronic human consumption based upon scientific procedures, supported by a safe history of use (Endres et al., 2009). A one-year chronic oral toxicity study combined with a one-generation reproduction study was conducted to further investigate safety of long-term consumption. The one-year study of GanedenBC(30)™ administered to male and female HsdBrlHan: Wistar rats in their diet showed no signs of toxicity at the highest dose tested. The conclusion from the reproduction toxicity study is that administration of GanedenBC(30)™ in the diet caused no signs of toxicity in the parental generation (male or female) nor the F1 offspring. Using the lowest NOEL of 1948 mg/kg concluded at the end of the 1-year feeding study, a 100-fold safety factor, a test article concentration of 6.88×10(10) CFU (colony forming units) per gram, and an average 70 kg human, it is determined that GanedenBC(30)™ is safe for chronic consumption at up to 9.38×10(10) CFUs per day.

  17. Daidzein: bioavailability, potential for reproductive toxicity, and breast cancer chemoprevention in female rats.

    PubMed

    Lamartiniere, Coral A; Wang, Jun; Smith-Johnson, Michelle; Eltoum, Isam-Eldin

    2002-02-01

    Soy products containing phytoestrogens have received much attention as dietary components to promote better health. Daidzein, an isoflavone and phytoestrogen component of soy, was investigated for its potential to alter fertility and cause developmental toxicity to the reproductive tract in female rats, for chemoprevention to the mammary gland, and to study its bioavailability. Diets containing 0 mg, 250 mg (low dose), and 1000 mg (high dose) daidzein/kg feed were fed to virgin female rats, starting 2 weeks prior to breeding and continued until the offspring were 50 days postpartum. The serum daidzein concentrations in adult female rats fed the low and high daidzein-containing diets were determined to be 6- and 13-fold higher than serum daidzein concentrations of Asians eating a traditional diet high in soy. Both daidzein doses had no significant effect on fertility, numbers of male and female offspring, and anogenital distances. The high, but not the low, daidzein dose resulted in reduced body weight, a fact that may be explained by reduced feed consumption. Circulating progesterone, but not estrogen, levels were statistically reduced with the high, but not low daidzein-containing diet. Both daidzein doses resulted in slight, but not significant, decreases in ovarian and uterine weights, and mammary gland size. Histomorphological analysis of the reproductive tracts of female offspring 50 days of age exposed perinatally to daidzein did not reveal any pathology in the vaginal, uterine, ovarian, and mammary tissues. Perinatal exposure of female offspring to 250 mg daidzein/kg diet did not alter mammary gland development or ontogeny of chemically induced mammary tumors in rats treated with dimethylbenz(a)anthracene on day 50. With the low dietary daidzein dose, total equol (major metabolite) and daidzein concentrations in the blood of pregnant females, 7-day-old, 21-day-old, and 50-day-old female offspring were 529 and 303 nM, 163 and 982 nM, 1188 and 1359 nM, and

  18. 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.

  19. 40 CFR 799.9355 - TSCA reproduction/developmental toxicity screening test.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 32 2011-07-01 2011-07-01 false TSCA reproduction/developmental... AND MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9355 TSCA reproduction... reproduction and/or development, either at an early stage of assessing the toxicological properties...

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false TSCA reproduction/developmental... AND MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9355 TSCA reproduction... reproduction and/or development, either at an early stage of assessing the toxicological properties...

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 33 2012-07-01 2012-07-01 false TSCA reproduction/developmental... AND MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9355 TSCA reproduction... reproduction and/or development, either at an early stage of assessing the toxicological properties...

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

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA reproduction/developmental... AND MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9355 TSCA reproduction... reproduction and/or development, either at an early stage of assessing the toxicological properties...

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false TSCA reproduction/developmental... AND MIXTURE TESTING REQUIREMENTS Health Effects Test Guidelines § 799.9355 TSCA reproduction... reproduction and/or development, either at an early stage of assessing the toxicological properties...

  4. 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

  5. Paired image- and FACS-based toxicity assays for high content screening of spheroid-type tumor cell cultures.

    PubMed

    Trumpi, Kari; Egan, David A; Vellinga, Thomas T; Borel Rinkes, Inne H M; Kranenburg, Onno

    2015-01-01

    Novel spheroid-type tumor cell cultures directly isolated from patients' tumors preserve tumor characteristics better than traditionally grown cell lines. However, such cultures are not generally used for high-throughput toxicity drug screens. In addition, the assays that are commonly used to assess drug-induced toxicity in such screens usually measure a proxy for cell viability such as mitochondrial activity or ATP-content per culture well, rather than actual cell death. This generates considerable assay-dependent differences in the measured toxicity values. To address this problem we developed a robust method that documents drug-induced toxicity on a per-cell, rather than on a per-well basis. The method involves automated drug dispensing followed by paired image- and FACS-based analysis of cell death and cell cycle changes. We show that the two methods generate toxicity data in 96-well format which are highly concordant. By contrast, the concordance of these methods with frequently used well-based assays was generally poor. The reported method can be implemented on standard automated microscopes and provides a low-cost approach for accurate and reproducible high-throughput toxicity screens in spheroid type cell cultures. Furthermore, the high versatility of both the imaging and FACS platforms allows straightforward adaptation of the high-throughput experimental setup to include fluorescence-based measurement of additional cell biological parameters.

  6. 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...

  7. Reproductive Toxicity of Zishen Yutai Pill in Rats: The Fertility and Early Embryonic Development Study (Segment I)

    PubMed Central

    Zhou, Li; Huang, Qiuling; Wang, Rong; Zhou, Jie; Ma, Aicui; Chong, Liming; Wu, Yubing; Wang, Yong; Xu, Li; Chen, Ying; Jia, Yuling; Gui, Bo

    2016-01-01

    Purpose. This study was aimed to investigate the reproductive toxicity of Zishen Yutai Pill (ZYP) on fertility and early embryonic development in rats. Methods. SD rats were randomly divided into 5 groups: vehicle control group (distilled water, i.g.), positive control group (80 mg/kg of cyclophosphamide, i.p.), and three ZYP-treated groups (3, 6, and 12 g/kg/d, i.e., 12x, 24x, and 48x clinical doses, i.g.). The high dose was set as the maximum gavage dosage. Results. Cyclophosphamide showed diverse hazards, such as decreased weight of male reproductive organs and sperm density (P < 0.05). However, there were no obvious effects of ZYP on physical signs, animal behavior, and survival rate, as well as on weight and food intake during the premating and gestation periods. Importantly, there were no significant adverse effects of ZYP on indexes of copulation, fecundity and fertility indexes, weights and coefficients of male reproductive organs, epididymal sperm number and motility, estrous cycle, preimplantation loss rate, and implantation rate. Besides, the numbers of live and resorbed fetuses per litter were not significantly altered. Conclusions. ZYP had no reproductive toxicities on fertility and early embryonic development in rats at 48x equivalent clinical doses. PMID:28058057

  8. Protection of male reproductive toxicity in rats exposed to di-n-butyl phthalate during embryonic development by testosterone.

    PubMed

    Giribabu, Nelli; Reddy, Pamanji Sreenivasula

    2017-03-01

    Di-n-butyl phthalate (DBP) widely spread industrial chemical that made drastic alteration in male reproductive system. The present study elucidates the protective role of testosterone on reproductive toxicity in prenatal DBP exposed adult male rats. Pregnant rats were injected with corn oil or 100 and 500mg/kg body weight of DBP on gestation day (GD) 1, 7 and 14. F1 male rats were weaned, injected with either testosterone or vehicle. On postnatal day (PND) 100 F1 adult male rats were cohabited with untreated female rats. Then rats were sacrificed and analyzed for other reproductive end points. Prenatal DBP exposed male rat testes, seminal vesicle weight, sperm count, motility, viability and HOS tail coiled sperm were significantly decreased with increased sperm morphological abnormalities. The levels of testicular 3β, 17βHSD, serum testosterone were significantly decreased with increased FSH, LH levels in experimental rats. The fertility studies revealed that increased pre, post-implantation losses and resorptions in normal females cohabited with experimental rats. Higher testicular LPO with lower SOD, CAT and GPx activity levels in experimental rats. Administration of testosterone to prenatal DBP treated male rats showed significant protection in above all parameters. In conclusions, testosterone deteriorates prenatal DBP induced reproductive and fertility toxicity by decreased oxidative stress and increased testicular antioxidant enzymes.

  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. A two-generational reproductive toxicity study of zinc in rats.

    PubMed

    Khan, Abu T; Graham, Thomas C; Ogden, L; Ali, S; Salwa; Thompson, Sherylee J; Shireen, Kaniz F; Mahboob, Mohd

    2007-05-01

    A two-generation reproductive toxicity study of zinc chloride (ZnCl(2)) was conducted in rats. F(o) male and female rats were administered 0.00 (control), 7.50 (low), 15.00 (mid) and 30.00 (high) mg/kg/day of ZnCl(2). Selected F(1) male and female rats were exposed to the same doses received by their parents (F(o)). Exposure of F(0) parental rats to ZnCl(2) showed significant reduction in fertility, viability (days 0 and 4), and the body weight of F(1) pups from the high-dose group but caused no effects on litter size, weaning index, and sex ratio. Similarly, the continued exposure of F(1) parental rats to ZnCl(2) also reduced fertility, liter size, viability (day 0), and the body weight of F(2) pups within the high-dose group but caused no effects on weaning index and sex ratio. Exposure of ZnCl(2) to F(0) and F(1) parental males resulted in a significant reduction in their body weights, and the F(0) and F(1) parental females did not show any significant difference in their body weights compared to their control groups. However, the postpartum dam weights of both F(0) and F(1) female rats were significantly reduced compared to their controls. Exposure of ZnCl(2) to F(o) and F(1) generation parental rats did not produce any significant change of their clinical signs as well as their clinical pathology parameters, except the alkaline phosphotase (ALK) level, which showed an upward trend in both sexes of both generations. Exposure of ZnCl(2) to F(0) rats resulted in a reduction of brain, liver, kidney, spleen and seminal vesicles weights of males and in the spleen and uterus of females. Similarly, exposure of F(1) rats to ZnCl(2) also resulted in reduction of brain, liver, kidney, adrenal, spleen, prostate and seminal vesicles weights of males and in spleen and uterus of females. ZnCl(2) exposure resulted in grossly observed gastro-intestianla (GI) tract, lymphoreticular/hematopoietic, and reproductive tract lesions in parental rats in both generations. Reduced body

  11. Gestational Zearalenone Exposure Causes Reproductive and Developmental Toxicity in Pregnant Rats and Female Offspring

    PubMed Central

    Gao, Xin; Sun, Lvhui; Zhang, Niya; Li, Chong; Zhang, Jiacai; Xiao, Zhuohui; Qi, Desheng

    2017-01-01

    Zearalenone (ZEN) is an oestrogenic mycotoxin commonly found in food and feed products and can affect reproduction and development in both humans and animals. This study aimed to determine the toxic effects of ZEN on maternal SD rats and the F1 female offspring. Sixty-four pregnant rats were divided into 4 groups and exposed to feed contaminated with ZEN (0, 5, 10, and 20 mg/kg feed) on gestational days (GDs) 0–21. Compared with the controls, the groups exposed to 10 and 20 mg/kg ZEN showed significantly decreased feed intake and body weight of pregnant rats and/or female offspring. Meanwhile, 20 mg/kg ZEN significantly decreased the birth weight and viability of F1 newborn rats. Moreover, 10 and 20 mg/kg ZEN diets increased follicle-stimulating hormone concentrations but decreased oestradiol in both maternal and F1 adult rats. In the F1 generation, ZEN caused no pathological changes in ovaries and uterus in weaned rats, but significant follicular atresia and a thinning uterine layer were found in F1 female adult rats in the 20 mg/kg ZEN group. These impairments concurred with the inhibited mRNA and protein levels of oestrogen receptor-alpha (Esr1) and 3β-hydroxysteroid dehydrogenase (HSD) in the adult uterus and/or ovaries. Furthermore, 10 and/or 20 mg/kg ZEN exposure significantly reduced Esr1, gonadotropin-releasing hormone receptor (GnRHr), and ATP binding cassette transporters b1 and c1 (ABCb1 and ABCc1) in the placenta and foetal and weaned F1 brains, and also produced a dose-dependent increase in 3β-HSD in the placenta. Additionally, 20 mg/kg ZEN significantly upregulated ABCc5 expression in the placenta and ovaries of weaned rats. These results suggested that prenatal ZEN exposure in rats affected maternal and foetal development and may lead to long-term reproductive impairment in F1 adult females. PMID:28067781

  12. Reproductive Toxicity and Life History Study of Silver Nanoparticle Effect, Uptake and Transport in Arabidopsis thaliana

    PubMed Central

    Geisler-Lee, Jane; Brooks, Marjorie; Gerfen, Jacob R.; Wang, Qiang; Fotis, Christin; Sparer, Anthony; Ma, Xingmao; Berg, R. Howard; Geisler, Matt

    2014-01-01

    Concerns about nanotechnology have prompted studies on how the release of these engineered nanoparticles impact our environment. Herein, the impact of 20 nm silver nanoparticles (AgNPs) on the life history traits of Arabidopsis thaliana was studied in both above- and below-ground parts, at macroscopic and microscopic scales. Both gross phenotypes (in contrast to microscopic phenotypes) and routes of transport and accumulation were investigated from roots to shoots. Wild type Arabidopsis growing in soil, regularly irrigated with 75 μg/L of AgNPs, did not show any obvious morphological change. However, their vegetative development was prolonged by two to three days and their reproductive growth shortened by three to four days. In addition, the germination rates of offspring decreased drastically over three generations. These findings confirmed that AgNPs induce abiotic stress and cause reproductive toxicity in Arabidopsis. To trace transport of AgNPs, this study also included an Arabidopsis reporter line genetically transformed with a green fluorescent protein and grown in an optical transparent medium with 75 μg/L AgNPs. AgNPs followed three routes: (1) At seven days after planting (DAP) at S1.0 (stages defined by Boyes et al. 2001 [41]), AgNPs attached to the surface of primary roots and then entered their root tips; (2) At 14 DAP at S1.04, as primary roots grew longer, AgNPs gradually moved into roots and entered new lateral root primordia and root hairs; (3) At 17 DAP at S1.06 when the Arabidopsis root system had developed multiple lateral roots, AgNPs were present in vascular tissue and throughout the whole plant from root to shoot. In some cases, if cotyledons of the Arabidopsis seedlings were immersed in melted transparent medium, then AgNPs were taken up by and accumulated in stomatal guard cells. These findings in Arabidopsis are the first to document specific routes and rates of AgNP uptake in vivo and in situ.

  13. 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...

  14. [Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (2). Teratogenicity study in rats].

    PubMed

    Nishimura, T; Chihara, N; Shirakawa, R; Sugai, S; Sakamoto, T; Nakagawa, Y; Tanaka, M; Shimouchi, K; Ozeki, Y; Fujita, T

    1997-12-01

    A teratogenicity study of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day to pregnant rats from day 7 to 17 of gestation, and effects of ONO-1101 on dams, fetuses and their offspring, were examined. In the 100 mg/kg/day group, hypoactivity, bradypnea, reddish lacrimation, clonic convulsion and loss of righting reflex were observed and 2 animals died. Food consumption in the 100 mg/kg/day group decreased during the treatment period. No drug-related changes were observed in dams for their body weights, necropsy findings or organ weights. Decrease in placental weight was seen in the 100 mg/kg/day group, but no effect was found in fetal weight. ONO-1101 had no effects on delivery and lactation. On day 4 after birth, viability of offspring were decrease in the 50 or 100 mg/kg/day group, and body weight of males were decreased in the 100 mg/kg/day group, but no change caused by the treatment was observed in growth of offspring thereafter. On skeletal examination in offsprings culled on day 4 after birth, increase in the incidence of unossificated talus were seen in the 50 or 100 mg/kg/day group. But no drug-related anomalies were observed in external, skeletal or visceral findings in fetuses. It was not also found any influence of ONO-1101 on external differentiations, functional, behavioral or learning abilities or reproductive performance in offspring. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for dams, and 25 mg/kg/day for their offspring.

  15. 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.

  16. Two-generation reproductive toxicity study of implanted depleted uranium (DU) in CD rats.

    PubMed

    Arfsten, D P; Still, K R; Wilfong, E R; Johnson, E W; McInturf, S M; Eggers, J S; Schaeffer, D J; Bekkedal, M Y-V

    2009-01-01

    Depleted uranium (DU) munitions and armor plating have been used in several conflicts over the last 17 yr, including the Persian Gulf War and the Iraq War. Because of its effectiveness and availability, DU will continue to be used in military applications into the foreseeable future. There is much controversy over the use of DU in weapons and equipment because of its potential radiological and toxic hazards, and there is concern over the chronic adverse health effects of embedded DU shrapnel in war veterans and bystanders. This study evaluated the effects of long-term implantation of DU on the reproductive success of F0 generation adults and development and survival of subsequent F1 and F2 generations in a two-generation reproductive toxicity study. F0 generation Sprague-Dawley rats, 8 wk of age, were surgically implanted with 0, 4, 8, 12, or 20 DU pellets (1 x 2 mm). Inert implant control animals were implanted with 12 or 20 tantallum (Ta) pellets. The F0 generation was then mated at 120 d post DU implantation. In the F0 generation, when measured on postimplantation d 27 and 117, uranium was present in the urine of DU-implanted animals in a dose-dependent manner. F0 reproductive success was similar across treatment groups and the maternal retrieval test revealed no changes in maternal behavior. DU implantation exerted no effect on the survival, health, or well-being of the F0 generation. Necropsy results of F0 animals were negative with the exception of a marked inflammatory response surrounding the implanted DU pellets. For the F1 generation, measures of F1 development through postnatal day (PND) 20 were unremarkable and no gross abnormalities were observed in F1 offspring. No uranium was detected in whole-body homogenates of PND 4 or PND 20 pups. Necropsy findings of F1 PND 20 pups were negative and no instances of ribcage malformation were observed in F1 PND 20 pups. Body weight and body weight gain of F1 rats through PND 120 were similar across treatment

  17. Rapid assays for lectin toxicity and binding changes that reflect altered glycosylation in mammalian cells.

    PubMed

    Stanley, Pamela; Sundaram, Subha

    2014-06-03

    Glycosylation engineering is used to generate glycoproteins, glycolipids, or proteoglycans with a more defined complement of glycans on their glycoconjugates. For example, a mammalian cell glycosylation mutant lacking a specific glycosyltransferase generates glycoproteins, and/or glycolipids, and/or proteoglycans with truncated glycans missing the sugar transferred by that glycosyltransferase, as well as those sugars that would be added subsequently. In some cases, an alternative glycosyltransferase may then use the truncated glycans as acceptors, thereby generating a new or different glycan subset in the mutant cell. Another type of glycosylation mutant arises from gain-of-function mutations that, for example, activate a silent glycosyltransferase gene. In this case, glycoconjugates will have glycans with additional sugar(s) that are more elaborate than the glycans of wild type cells. Mutations in other genes that affect glycosylation, such as nucleotide sugar synthases or transporters, will alter the glycan complement in more general ways that usually affect several types of glycoconjugates. There are now many strategies for generating a precise mutation in a glycosylation gene in a mammalian cell. Large-volume cultures of mammalian cells may also generate spontaneous mutants in glycosylation pathways. This article will focus on how to rapidly characterize mammalian cells with an altered glycosylation activity. The key reagents for the protocols described are plant lectins that bind mammalian glycans with varying avidities, depending on the specific structure of those glycans. Cells with altered glycosylation generally become resistant or hypersensitive to lectin toxicity, and have reduced or increased lectin or antibody binding. Here we describe rapid assays to compare the cytotoxicity of lectins in a lectin resistance test, and the binding of lectins or antibodies by flow cytometry in a glycan-binding assay. Based on these tests, glycosylation changes expressed

  18. 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...

  19. 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.

  20. 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...

  1. Early-life exposure to dimethoate-induced reproductive toxicity: evaluation of effects on pituitary-testicular axis of mice.

    PubMed

    Verma, Ruchna; Mohanty, Banalata

    2009-12-01

    In utero and lactational exposure to organophosphate dimethoate exerted toxic impact on the reproductive system of male mice. Pregnant mice were exposed to 4, 8, and 16 mg/kg of the pesticide, the sublethal doses (2.5, 5, and 10% of Lethal Dose(50) [LD(50)]), via gavaging from gestation day (GD) 6 to postnatal day (PND) 21. The effects on the male reproductive system were evaluated at two stages: at prepubertal age (PND 22) and at the postpubertal age of PND 63. Gonadal inhibition was reflected in the significant reduction of weight and distinct histopathological alteration of testis and epididymis as well as in decreased sperm counts, which could be linked to hormonal imbalance caused by dimethoate interference of reproductive axis. Disruption of pituitary-testicular axis was shown in the weak immunointensity of luteinizing hormone (LH) cells, reduction in their size and number, and lowered plasma LH and testosterone levels as observed in the neonates exposed to two higher tested doses. In addition, the direct toxic impact of the pesticide on the testicular Leydig cells and inhibition of steroidogenesis could be suggested. Drastic reduction in the testosterone level (approximately 70%) was suggestive of this effect. The adverse effects were persisted in the young adult mice. Developmental toxicity was evident in the highest dose-exposed (10% LD(50)) group where GD length and stillbirths were significantly increased along with a decrease of body weight and anogenital distance of the fetus. Maternal exposure of pesticide during gestation and lactation periods thus adversely affected the pituitary-testicular axis of mice neonates, which further caused reproductive dysfunctioning of young adult mice.

  2. 90-Day Inhalation Toxicity Study of Swedish Biofuel Alcohol-to-Jet (ATJ) Synthetic Kerosene with Aromatics (SPA) in Rats with Neurotoxicity Testing and Genotoxicity Assay

    DTIC Science & Technology

    2015-09-01

    concentration in the 700 or 2000 mg/m3 exposure groups. No indications of changes in reproductive health were found when vaginal cytology and sperm...deemed biologically significant. As an indicator of reproductive health, vaginal cytology was assessed during week 9 of exposure and sperm count...endpoints assessed were neurotoxicity, reproductive toxicity, and genotoxicity. 4 Distribution Statement A. Approved for public release

  3. Contrasting effects of chloride on growth, reproduction, and toxicant sensitivity in two genetically distinct strains of Hyalella azteca.

    PubMed

    Soucek, David J; Mount, David R; Dickinson, Amy; Hockett, J Russell; McEwen, Abigail R

    2015-10-01

    The strain of Hyalella azteca (Saussure: Amphipoda) commonly used for aquatic toxicity testing in the United States has been shown to perform poorly in some standardized reconstituted waters frequently used for other test species. In 10-d and 42-d experiments, the growth and reproduction of the US laboratory strain of H. azteca was shown to vary strongly with chloride concentration in the test water, with declining performance observed below 15 mg/L to 20 mg/L. In contrast to the chloride-dependent performance of the US laboratory strain of H. azteca, growth of a genetically distinct strain of H. azteca obtained from an Environment Canada laboratory in Burlington, Ontario, Canada, was not influenced by chloride concentration. In acute toxicity tests with the US laboratory strain of H. azteca, the acute toxicity of sodium nitrate increased with decreasing chloride in a pattern similar not only to that observed for control growth, but also to previous acute toxicity testing with sodium sulfate. Subsequent testing with the Burlington strain showed no significant relationship between chloride concentration and the acute toxicity of sodium nitrate or sodium sulfate. These findings suggest that the chloride-dependent toxicity shown for the US laboratory strain may be an unusual feature of that strain and perhaps not broadly representative of aquatic organisms as a whole.

  4. UV and arsenate toxicity: a specific and sensitive yeast bioluminescence assay.

    PubMed

    Bakhrat, Anya; Eltzov, Evgeni; Finkelstein, Yishay; Marks, Robert S; Raveh, Dina

    2011-06-01

    We describe a Saccharomyces cerevisiae bioluminescence assay for UV and arsenate in which bacterial luciferase genes are regulated by the promoter of the yeast gene, UFO1. UFO1 encodes the F-box subunit of the Skp1–Cdc53–F-box protein ubiquitin ligase complex and is induced by DNA damage and by arsenate. We engineered the UFO1 promoter into an existing yeast bioreporter that employs human genes for detection of steroid hormone-disrupting compounds in water bodies. Our analysis indicates that use of an endogenous yeast promoter in different mutant backgrounds allows discrimination between different environmental signals. The UFO1-engineered yeast give a robust bioluminescence response to UVB and can be used for evaluating UV protective sunscreens. They are also effective in detecting extremely low concentrations of arsenate, particularly in pdr5Δ mutants that lack a mechanism to extrude toxic chemicals; however, they do not respond to cadmium or mercury. Combined use of endogenous yeast promoter elements and mutants of stress response pathways may facilitate development of high-specificity yeast bioreporters able to discriminate between closely related chemicals present together in the environment.

  5. In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

    PubMed

    Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

    2016-06-01

    Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture.

  6. Fish short-term reproduction assay (FSTRA) with atrazine and the Japanese medaka (Oryzias latipes).

    PubMed

    Hosmer, Alan J; Schneider, Suzanne Z; Anderson, Julie C; Knopper, Loren D; Brain, Richard A

    2017-02-15

    Breeding groups of Japanese medaka (Oryzias latipes) were exposed to atrazine at measured concentrations of 0.6, 5.5, and 53 µg/L for 35 d. Evaluated endpoints included survival, fecundity, fertility, growth (weight and length), behavior, secondary sex characteristics (anal fin papillae), gonad histopathology, and hepatic vitellogenin. No statistically significant effects of atrazine exposure on survival and growth of medaka were noted during the test, and mean survival was ≥97.5% in all treatment groups on Day 35. No significant effects of atrazine exposure on reproduction were observed. The number of mean cumulative eggs produced in the negative control, 0.6, 5.5, and 53 µg/L treatment groups was 7158, 6691, 6883, and 6856 eggs, respectively. The mean number of eggs per female reproductive day was 40.9, 38.2, 40.2, and 39.2 eggs per day, respectively. There were also no dose-dependent effects on mean anal fin papillae counts among male fish or expression of vtg-II in males or females. In addition, atrazine exposure was not related to the development stage of test fish, with testes stages ranging from 2 to 3 in all groups and ovaries ranging from stage 2 to 2.5. Overall, exposure to atrazine up to 53 µg/L for 35 d did not result in significant, treatment-related effects on measured endpoints related to survival, growth, or reproduction in Japanese medaka. This article is protected by copyright. All rights reserved.

  7. 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...

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

    PubMed

    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.

  9. Digital gene expression analysis of reproductive toxicity of benzo[a]pyrene in male scallop chlamys farreri.

    PubMed

    Deng, Xuxu; Pan, Luqing; Miao, Jingjing; Cai, Yuefeng; Hu, Fengxiao

    2014-12-01

    Benzo[a]pyrene (BaP) is a representative polycyclic aromatic hydrocarbon (PAH) and is studied widely for its strong toxicity and wide distribution. Although BaP pollution in marine environment is increasing, molecular mechanisms underlying reproductive toxicity of BaP in marine mollusks have been seldom systematically studied, especially in males. In this study, genes that regulated reproductive responses of Chlamys farreri under BaP stress were analyzed through digital gene expression (DGE) sequencing with testis tissues. A total of 12,485,055 and 14,454,127 clean reads were generated from control and BaP exposure DGE libraries, respectively. After comparing two libraries, 1051 differentially expressed genes were detected, with 223 up-regulated and 828 down-regulated genes. Gene ontology (GO) annotation and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed on all genes to understand their biological functions and processes. The results showed that numerous enriched, differentially expressed genes related to aromatic compound catabolic processes, spermatid development, microtubule-based movement, energy production and immune response. Quantitative real-time PCR was performed to verify the expressed genes of DGE. The study generated data to show the overall reproductive transcription responses of male C. farreri under BaP stress, and it also can serve as the reference for future study of organic pollutions in aquatic mollusks.

  10. Cell viability and PSA secretion assays in LNCaP cells: a tiered in vitro approach to screen chemicals with a prostate-mediated effect on male reproduction within the ReProTect project.

    PubMed

    Lorenzetti, Stefano; Marcoccia, Daniele; Narciso, Laura; Mantovani, Alberto

    2010-08-01

    Prostate function is critical for male fertility; nevertheless, prostate was so far overlooked in reproductive toxicity assays. Within the EU project ReProTect, the human prostate cell line LNCaP was utilized to identify molecules targeting prostate function by the integrated assessment of cell viability (MTS assay) and prostate-specific antigen (PSA) secretion as specific marker; a training set - five (anti)androgenic chemicals - and a ReProTect feasibility set - ten chemicals - were used. Several compounds reduced PSA only at cytotoxic concentrations. Androgens (DHT, MT) markedly increased PSA as did the herbicide glufosinate ammonium, not known as androgen agonist. Anti-androgens (2OH-flutamide, linuron, vinclozolin, di-n-butyl phthalate) also increased PSA, but the effect of magnitude was much lower than for androgens. The ER-binder bisphenol A reduced PSA, while increasing cell viability. At this stage, the approach can identify chemicals able to interfere with prostate function: further refinements may allow to include prostate effects in reproductive toxicity in vitro testing.

  11. Reverse transcription recombinase polymerase amplification assay for the rapid detection of type 2 porcine reproductive and respiratory syndrome virus.

    PubMed

    Wang, Jian-Chang; Yuan, Wan-Zhe; Han, Qing-An; Wang, Jin-Feng; Liu, Li-Bing

    2017-05-01

    Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in pigs, and has tremendous negative economic impact on the swine industry worldwide. PRRSV is classified into the two distinct genotypes: type 1 and type 2, and most of the described PRRSV isolates in China are type 2. Rapid and sensitive detection of PRRSV is of great importance for the disease control and regional eradication programs. Recombinase polymerase amplification (RPA) has emerged as a novel isothermal amplification technology for the molecular diagnosis of infectious diseases. In this study, a fluorescence reverse transcription RPA (RT-RPA) assay was developed to detect the type 2 PRRSV using primers and exo probe specific for the viral nucleocapsid gene. The reaction was performed at 40°C within 20min. The RT-RPA assay could detect both the classical (C-PRRSV) and highly pathogenic PRRSV (HP-PRRSV), but there was no cross-reaction to other pathogens. Using the in vitro transcribed PRRSV RNA as template, the analytical sensitivity of RT-RPA was 690 copies. The assay performance was evaluated by testing 60 field samples and compared to real-time RT-PCR. The detection rate of RT-RPA was 86.6% (52/60), while the detection rate of real-time RT-PCR was 83.3% (50/60). This simple, rapid and reliable method could be potentially applied for rapid detection of PRRSV in point-of-care and rural areas.

  12. 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.

  13. Final report on the reproductive toxicity of acrylamide (ACRL) (CAS No. 79-06-1) in CD-1 (trade name) swiss mice

    SciTech Connect

    Not Available

    1993-01-01

    Acrylamide (ACRL), known to cause reproductive toxicity, neurotoxicity, and induce dominant lethal mutations, was tested in a modified Reproductive Assessment by Continuous Breeding (RACB) Protocol in Swiss CD-1 mice. Exposure to ACRL in water at dose levels of 30 ppm (9.2 mg/kg) resulted in slight reproductive toxicity (decreased pups/litter and spermatid head counts) and increased postimplantation loss (dominant lethal effect) in the absence of demonstrable neurotoxicity for the F0 animals. F1 animals dosed with 30 ppm ACRL were more severely affected than the F0 animals exhibiting a more profound effect on fertility in the presence of slight neurotoxicity (decreased grip strength in males).

  14. 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.

  15. The Reproductive Toxicity of CdSe/ZnS Quantum Dots on the in vivo Ovarian Function and in vitro Fertilization

    PubMed Central

    Xu, Gaixia; Lin, Guimiao; Lin, Suxia; Wu, Na; Deng, Yueyue; Feng, Gang; Chen, Qiang; Qu, Junle; Chen, Danni; Chen, Siping; Niu, Hanben; Mei, Shujiang; Yong, Ken-Tye; Wang, Xiaomei

    2016-01-01

    Despite the usefulness of quantum dots (QDs) in biomedicine and optoelectronics, their toxicity risks remain a major obstacle for clinical usages. Hence, we studied the reproductive toxicity of CdSe/ZnS QDs on two aspects, (i) in vivo ovarian functions and (ii) in vitro fertilization process. The body weight, estrous cycles, biodistribution of QDs, and oocyte maturation are evaluated on female mice treated with QDs. The mRNA level of the follicle-stimulating hormone receptor (FSHr) and luteinizing hormone receptor (LHr) in ovaries are assayed. Then, the matured cumulus-oocyte-complexes are harvested to co-culture with in vitro capacitated sperms, and the in vitro fertilization is performed. The result revealed that QDs are found in the ovaries, but no changes are detected on the behavior and estrous cycle on the female mice. The mRNA downregulations of FSHr and LHr are observed and the number of matured oocytes has shown a significant decrease when the QDs dosage was above 1.0 pmol/day. Additionally, we found the presence of QDs has reduced the in vitro fertilization success rate. This study highly suggests that the exposure of CdSe/ZnS QDs to female mice can cause adverse effects to the ovary functions and such QDs may have limited applications in clinical usage. PMID:27876896

  16. 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

  17. Alleviation of reproductive toxicity of gossypol using selenium supplementation in rams.

    PubMed

    El-Mokadem, M Y; Taha, T A; Samak, M A; Yassen, A M

    2012-09-01

    The objective of this study was to evaluate the reproductive toxicity of gossypol and the possible counteracting effect of selenium supplementation in rams. Twenty-five mature crossbred (Barki × Rahamni) rams were randomly divided into 5 equal groups. The first group served as a control (no gossypol in diet). The second and third groups received diets containing free gossypol of 9 and 14 mg·kg(-1) BW·d(-1)(low level and high level of gossypol), respectively. The fourth and fifth groups received the same diets given to the second and third groups, respectively, with an oral administration of 1 mg selenium (as sodium selenite) daily for each animal. Results showed reductions in ejaculate volume (P = 0.028), percentage of dead sperm (P = 0.003), total functional sperm fraction (P < 0.001), and blood serum concentration of testosterone (P < 0.001) in the presence of both levels of gossypol inclusion. Furthermore, high level of gossypol reduced forward motility (P < 0.001) and semen initial fructose concentration (P = 0.002) and increased abnormal-head sperm (P = 0.003) and blood serum concentration of triiodothyronine (P = 0.006). Regardless of selenium supplementation, increasing level of free gossypol in diet resulted in a significant decrease in the percentage of forward motility (P = 0.037) and significant increases in the mean values of sperm concentration (P < 0.001), total sperm output (P = 0.002), percentage of total abnormal sperm (P = 0.058), and abnormal-head sperm (P = 0.016). On the other hand, regardless of levels of gossypol inclusion, selenium supplementation resulted in significant increases in libido (P < 0.001), mean values of ejaculate volume (P < 0.001), percentage of forward motility (P = 0.019), total sperm output (P < 0.001), total functional sperm fraction (P < 0.001), semen initial fructose concentration (P = 0.031), and blood serum concentrations of both testosterone and triiodothyronine (P < 0.001). In conclusion, free gossypol in diet

  18. 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

  19. Specific in vitro toxicity of crude and refined petroleum products: 3. Estrogenic responses in mammalian assays.

    PubMed

    Vrabie, Cozmina M; Candido, Angelica; van den Berg, Hans; Murk, Albertinka J; van Duursen, Majorie B M; Jonker, Michiel T O

    2011-04-01

    Current petroleum risk assessment considers only narcosis as the mode of action, but several studies have demonstrated that oils contain compounds with dioxin-like, estrogenic or antiestrogenic, and androgenic or antiandrogenic activities. The present study is the third in a series investigating the specific toxic effects of 11 crude oils and refined products. By employing recombinant mammalian cells stably transfected with the human estrogen receptor alpha (ERα) or beta (ERβ), and expressing the luciferase protein (ERα-U2OS-Luc and ERβ-U2OS-Luc assay), the estrogenicity or antiestrogenicity of oils was studied. All oils, except for two refined oils and one crude oil, induced estrogenic responses. The calculated estrogenic potencies of the oils were six to nine orders of magnitude lower than the potency of 17β-estradiol (E2). Upon coexposure to a fixed concentration of E2 and increasing concentrations of oils, additive, antagonistic, and synergistic effects were revealed. One nautical fuel oil was tested in the human breast carcinoma cell line MCF-7, in which it induced cell proliferation up to 70% relative to the maximal induction by E2. At its minimum effect concentration of 25 mg/L, the oil was also capable of inducing mRNA expression of the estrogen-dependent protein pS2 by a factor of two. The present results indicate that oils naturally contain potentially endocrine-disrupting compounds that are able to influence the estrogenicity of other compounds and may cause biological responses beyond receptor binding.

  20. 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.

  1. 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...

  2. 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...

  3. 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...

  4. 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...

  5. 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.

  6. Comparison of the sensitivities of common in vitro and in vivo assays of estrogenic activity: application of chemical toxicity distributions.

    PubMed

    Dobbins, Laura L; Brain, Richard A; Brooks, Bryan W

    2008-12-01

    A number of contaminants in municipal effluent discharges are estrogen agonists to fish. Whereas several in vitro and in vivo techniques have been developed to assess the estrogenic activity of these compounds or ambient environmental samples, previous comparisons of the relative sensitivities of these approaches remain inconclusive. We employed a probabilistic hazard assessment approach using chemical toxicity distributions (CTDs) to perform a novel evaluation of relative sensitivities of six common in vitro and in vivo assays. We predicted that there was an 8.3% (human breast ademocarcinoma cell line, MCF-7, assay), 6.3% (yeast estrogen screen assay), or 1.9% (fish hepatocyte vitellogenin, VTG, assay) probability of detecting a compound in aquatic systems that will elicit an estrogenic response at concentrations at or below 0.1 microg/L, suggesting that the MCF-7 assay was the most sensitive in vitro assay evaluated in this study. The probabilities of eliciting the estrogenic response of VTG induction at a concentration less than 0.1 microg/L in rainbow trout, fathead minnow, and Japanese medaka were determined at 29.9, 26.2, and 18.8%, respectively. Thus, rainbow trout VTG induction was the most sensitive in vivo assay assessed. Subsequently, CTDs may provide a useful technique for hazard assessment of chemical classes for which exposure data are limited and for chemicals with common toxicological mechanisms and modes of action.

  7. 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.

  8. 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.

  9. 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

  10. Effect of soil contaminant extraction method in determining toxicity using the Microtox{reg_sign} assay

    SciTech Connect

    Harkey, G.A.; Young, T.M.

    2000-02-01

    This project examined the influence of different extraction methods on the measured toxicity of contaminated soils collected from manufactured gas plant (MGP) sites differing in soil composition and contaminant concentration. Aged soils from a number of MGP sites were extracted using a saline solution, supercritical fluid extraction (SFE), and Soxhlet extraction. Toxicity was assessed using two forms of Microtox tests: acute aqueous tests on saline and SFE soil extracts and solid-phase tests (SPTs) on soil particles. Microtox SPTs were performed on soils before and after SFE to determine resulting toxicity reduction. Three hypotheses were tested: (1) Toxicity of soil extracts is related to contaminant concentrations of the extracts, (2) measured toxicity significantly decreases with less vigorous methods of extraction, and (3) supercritical fluid extractability correlates with measured toxicity. The EC50s for SPTs performed before and after SFE were not different for some soils but were significantly greater after extraction for other soils tested. The most significant toxicity reductions were observed for soils exhibiting the highest toxicity in both preextraction SPTs and acute aqueous tests. Acute Microtox tests performed on SFE extracts showed significantly lower EC50s than those reported from saline-based extraction procedures. Toxicity of the soils measured by Microtox SPTs was strongly correlated with both SFE efficiency and measures of contaminant aging. Data from this project provide evidence of sequestration and reduced availability of polycyclic aromatic hydrocarbons (PAHs) from soils extracted via physiologically based procedures compared to vigorous physical extraction protocols.

  11. Testing Silver Nanoparticle Toxicity Using the Ammonia Oxidizing Bacteria Nitrosomonas Europaea and a High-throughput Assay

    NASA Astrophysics Data System (ADS)

    Semprini, L.; Bartow, S.; Radniecki, T.

    2012-04-01

    Understanding the toxicity of nanoparticles on ecologically significant wastewater microbiota, specifically ammonia oxidizing bacteria (AOB), is critical due to the exponential increase in commercialization of nanoparticles as well as the sensitivity of AOB to inhibitors. A high-throughput activity assay was developed to rapidly screen for nanoparticle toxicity on AOB, using a multi-well plate method and AOB Nitrosomonas Europaea. This method demonstrated good agreement with previously established batch bottle assays utilizing both silver ions (Ag+) and nanoparticles (Ag-NPs) as nitrification inhibitors. The method was used to study the inhibition of Ag+ and Ag-NPs (20 nm) on the nitrification by N. Europaea cells grown in fill-and-draw reactors compared exponentially grown batch cells. Results indicate longer hydraulic residence times increased some protection against inhibition as measured by the production of nitrite over a three hour assay. The cells were more sensitive to Ag+ than Ag-NP, which is consistent with our past observations. Studies are currently being conducted to determine the effects that the presence of humic acid and cations on the inhibition and toxicity. Our initial results show that the presence of Mg++ provides protect from Ag-NP inhibition, which partly results from the aggregation of the Ag-NP and a decrease in the rate of oxidation of the Ag-NP to Ag+. The presence of humic acid also provides for some protection from Ag-NP inhibition.

  12. 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

  13. 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.

  14. 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.

  15. The reproductive toxicity of organic compounds extracted from drinking water sources on Sprague Dawley rats: an in vitro study.

    PubMed

    Wu, Jiang; Hu, Guanjiu; Wang, Xiaoyi; Li, Dongmei; Yu, Hongxia; Han, Xiaodong

    2010-06-01

    The safety of drinking water always causes worldwide concern. Water pollution increases with urban development and industrialization in developing countries. During recent decades, increasing numbers of environmental organic compounds have been found in aquatic environments. These organic compounds are capable of bioaccumulating to much higher concentrations in food webs and cause health effects on human beings. Reproductive impairment is one of the commonest consequences of environmental pollution. Our goal was to investigate the reproductive toxicity of organic compounds extracted from surface water samples collected in drinking water sources. This study focused on the surface water in lower Yangtze River and Taihu Lake, which act as drinking water sources of Jiangsu province, one of the most rapidly developing regions in China. We used solid-phase extraction (SPE) to condense organic compounds by 286 times from natural surface water samples and established in vitro system to evaluate their effects on reproductive system. We found that organic compounds destroyed the plasma membrane integrity of Sertoli cells and Spermatogenic cells to a certain degree and significantly depressed viability of Sertoli cells and Spermatogenic cells as well. Accordingly, the proportion of apoptotic Sertoli cells and dead Spermatogenic cells enhanced markedly. Although viability of organic-compound-treated Leydig cells did not come down remarkably, testosterone production of Leydig cells decreased evidently. These results suggest that accumulated comprehensive effects of organic compounds in surface water of drinking water sources may induce spermatogenesis malfunction and reduction of testosterone production in the long term.

  16. [Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (1)--Fertility study in male rats by intravenous administration].

    PubMed

    Okada, F; Sagami, F; Tirone, P; Morisetti, A; Bussi, S; Baguley, J K

    1999-11-01

    The influence of gadobenate dimeglumine formulation (E7155) on general reproductive performance and fertility in male rats of the Sprague-Dawley strain was assessed in this study. E7155 was administered by intravenous injection at a dosage of 0.3, 1.0, or 2.0 mmol/kg/day to groups of 22 male rats for 13 weeks. Control animals received 0.9% sterile physiological saline throughout the same period. After four weeks of treatment, each male was paired with an untreated female of the same strain. Each male was paired again after 10 weeks of treatment with another untreated female of the same strain. All females were killed on Day 14 of gestation for examination of pregnancy status. No significant toxicological signs associated with systemic exposure to E7155 were observed. There were no effects of treatment with E7155 on body weight gain, food consumption, macroscopic findings, reproductive organ weights and sperm count or sperm motility in male rats. Mating performance after pairing at Weeks 4 and 10 of treatment as well as litter size and number of survival embryos on Day 14 of gestation were not affected by paternal treatment with E7155. From these results, the No Observed Adverse Effect Level (NOAEL) of E7155 was 2.0 mmol/kg/day for general and reproductive toxicity parameters in male rats treated with E7155 and for development in their embryos.

  17. Reproductive toxicity of bisphenol A and cadmium in Potamopyrgus antipodarum and modulation of bisphenol A effects by different test temperature.

    PubMed

    Sieratowicz, Agnes; Stange, Daniela; Schulte-Oehlmann, Ulrike; Oehlmann, Jörg

    2011-10-01

    An OECD initiative for the development of mollusc-based toxicity tests for endocrine disrupters and other chemicals has recommended three test species with respective test designs for further standardisation. Preparing a subsequent pre-validation study we performed a reproduction test with Potamopyrgus antipodarum, determining the concentration range of the selected test substances, bisphenol A (BPA) and cadmium (Cd). At 16 °C, the recommended test temperature, the number of embryos in the brood pouch was increased by BPA and decreased by Cd (NOEC: 20 μg BPA/L and 1 μg Cd/L). Coinstantaneous BPA tests at 7 °C and 25 °C demonstrated a temperature dependency of the response, resulting in lower NOECs (5 μg/L respectively). As expected, reproduction in control groups significantly varied depending on temperature. Additional observations of the brood stock showed seasonal fluctuations in reproduction under constant laboratory conditions. The recommended temperature range and test conditions have to be further investigated.

  18. 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...

  19. 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.

  20. 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...

  1. 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...

  2. 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...

  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.

  4. 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 ...

  5. 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...

  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 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...

  8. REPRODUCTIVE TOXICITY OF CHLORPYRIFOS, DIELDRIN, AND METHYL MERCURY MIXTURES TO THE AMPHIPOD, HYALELLA AZTECA

    EPA Science Inventory

    Toxicological interactions were assessed on the reproduction of the amphipod Hyalella azteca throughout a chronic exposure to methyl mercury (0.9, 4.7, 23.3 nM), chlorpyrifos (0.01, 0.05, 0.24), dieldrin (0.5, 2.3, 11.4 nM) and their binary mixtures. H. azteca were exposed to the...

  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. 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...

  11. Developmental toxicity, uptake and distribution of sodium chromate assayed by frog embryo teratogenesis assay-Xenopus(FETAX).

    PubMed

    Bosisio, Stefano; Fortaner, Salvador; Bellinetto, Sonia; Farina, Massimo; Del Torchio, Riccardo; Prati, Mariangela; Gornati, Rosalba; Bernardini, Giovanni; Sabbioni, Enrico

    2009-09-01

    The embryotoxicity and teratogenicity of Cr(VI) on the survival and morphology of the anuran Xenopus laevis have been assessed by frog embryo teratogenesis assay-Xenopus (FETAX). The lethal median (LC(50)) and teratogenic median (TC(50)) concentration values of Cr(VI) were 890 microM and 260 microM, respectively. The calculated teratogenic index (TI) value was 3.42, suggesting that hexavalent chromium has a teratogenic potential. Malformations of embryos included lifting of the body, coiling of the tail and body oedema. Furthermore, the chromium salt caused significant growth retardation at 25 microM exposure concentrations. The use of radiolabelled (51)Cr(VI) allowed the determination of the time course uptake of Cr in Xenopus exposed to concentrations ranging from 0.025 to 500 microM. The evaluation of its distribution into the body (head-abdomen-tail) was evaluated at different exposure times. Chromium is taken up at 24 h by Xenopus embryos for all concentrations tested. At 48 h post fertilization (stage of larva) the amount of Cr accumulated by the two-day-old larva ranged from 0.42 to 580 pg mg(-1) wet weight at 0.025 and 500 microM respectively. These amounts were lower than those at 24 h (2.77 to 11016 pg mg(-1) wet weight embryo) reaching values of the same order of magnitude at 120 h (five-days-old larva). Since at 48 h Xenopus development leads to a swimming embryo, the observed uptake at 24 h could be the result of the binding of Cr to jelly coat compounds surrounding the embryo body as confirmed by gel filtration experiments on (51)Cr-jelly coat. The interaction of Cr with jelly coat is in agreement with the role of jelly coat in protecting the embryo against pathogen and chemical toxins to ensure fertilization. This work further supports the hypothesis that Cr contamination of surface waters could contribute to explain the reported worldwide depletion of frog population.

  12. Acute toxicity evaluation of explosive wastewater by bacterial bioluminescence assays using a freshwater luminescent bacterium, Vibrio qinghaiensis sp. Nov.

    PubMed

    Ye, Zhengfang; Zhao, Quanlin; Zhang, Mohe; Gao, Yuchen

    2011-02-28

    The compositions of explosive wastewater generated from TNT (2,4,6-trinitrotoluene) purification stage were characterized by using UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), high performance liquid chromatograph (HPLC) and gas chromatograph/mass spectroscopy (GC/MS). The acute toxicity was evaluated by bacterium bioluminescence assay using a freshwater luminescent bacterium (Vibrio qinghaiensis sp. Nov.) and a marine luminescent bacterium (Photobacterium phosphoreum). The results showed that the wastewater's biodegradability was poor due to the high amount of chemical oxygen demand (COD). The main organic components were dinitrotoluene sulfonates (DNTS) with small amount of TNT, dinitrotoluene (DNT), mononitrotoluene (MNT) and other derivatives of nitrobenzene. It was highly toxic to luminescent bacteria P. phosphoreum and V. qinghaiensis sp. Nov. After reaction time of 15 min, the relative concentration of toxic pollutants (expressed as reciprocal of dilution ratio of wastewater) at 50% of luminescence inhibition ratio was 5.32×10(-4) for P. phosphoreu, while that was 4.34×10(-4) for V. qinghaiensis. V. qinghaiensis is more sensitive and suitable for evaluating the wastewater's acute toxicity than P. phosphoreum. After adsorption by resin, the acute toxicity can be greatly reduced, which is helpful for further treatment by biological methods.

  13. Foraging, feeding, and reproduction on silica substrate: Increased waterborne zinc toxicity to the estuarine epibenthic amphipod Melita plumulosa.

    PubMed

    Mann, Reinier M; Hyne, Ross V; Ascheri, Laure M E

    2011-07-01

    Artificial substrates consisting of fine milled silica with or without α-cellulose were evaluated for their capacity to support survival, growth, and fecundity in the amphipod Melita plumulosa. There were no significant differences in the survival and fecundity of adult amphipods maintained for up to 13 d on natural sediment, silica-only, or silica/α-cellulose substrate when fed two algal foods, Sera micron and Rotiselco-ALG. However, growth among juveniles maintained on the silica/α-cellulose mixture was significantly inhibited over 14 d compared with natural sediment. Addition of a microencapsulated shrimp feed, Frippak, to the algal foods improved juvenile growth over 28 d but still did not match the nutritive value of natural sediment. Fine silica without cellulose was subsequently used in acute and reproductive toxicity tests with waterborne zinc. With food, a 10-d median lethal concentration (LC50) of 140 µg Zn/L and a 10-d no-effect concentration (NEC) of 80 µg Zn/L were obtained for juvenile survival on silica. In contrast, a 10-d LC50 of 200 µg Zn/L and a 10-d NEC of 180 µg Zn/L were obtained for juveniles in water-only exposures. Similarly, exposure of adult females to Zn without food on silica compared with water-only exposures gave 10-d LC50s of 380 and 490 µg Zn/L and 10-d NECs of 130 and 370 µg Zn/L, respectively. The reproduction toxicity test indicated significant adult mortality at 92 µg Zn/L and significantly reduced fecundity at 22 µg Zn/L. We surmised that the toxicity of waterborne zinc to M. plumulosa increased when maintained on nutrient-depleted silica compared with water-only exposure because of increased energy expended through foraging, in concert with the likely increased exposure to Zn via the digestive tract and the gills.

  14. Crataegus monogyna fruit aqueous extract as a protective agent against doxorubicin-induced reproductive toxicity in male rats

    PubMed Central

    Shalizar Jalali, Ali; Hasanzadeh, Shapour

    2013-01-01

    Objective: Doxorubicin (DOX) is a broad spectrum chemotherapeutic agent used in the treatment of several malignancies. The use of DOX in clinical chemotherapy has been restricted due to its diverse toxicities, including reproductive toxicity. Crataegus monogyna (C. monogyna) is one of the oldest medicinal plants that have been shown to be cytoprotective because of scavenging free radicals. The present study was undertaken to determine whether C. monogyna fruits aqueous extract could serve as a protective agent against reproductive toxicity during DOX treatment in a rat model through antioxidant-mediated mechanisms. Materials and Methods: Male Wistar rats were allocated to four groups. Two groups of rats were treated with DOX at a dose of 4 mg/kg intraperitoneally on days 1, 7, 14, 21, and 28 (accumulated dose of 20 mg/kg). One of the groups received C. monogyna fruits aqueous extract at a dose of 20 mg/kg per day orally for 28 days along with DOX. A vehicle-treated control group and a C. monogyna control group were also included. Results: The DOX-treated group showed significant decreases in the body and organ weights and spermatogenic activities as well as many histological alterations. DOX treatment also caused a significant decrease in sperm count and motility with an increase in dead and abnormal sperms. Moreover, significant decrease in serum levels of testosterone and increased serum concentrations of FSH, LH, LDH, CPK, and SGOT were observed in DOX-treated rats. Notably, Crataegus co-administration caused a partial recovery in above-mentioned parameters. Conclusion: These findings indicated that doxorubicin can adversely damage the testicular tissue, while Crataegus co-administration could effectively prevent these adverse effects by effective inhibiting oxidative processes and restoration of antioxidant defense system. PMID:25050270

  15. 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.

  16. 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 ...

  17. 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.

  18. Solid-Phase Contact Assay That Uses a lux-Marked Nitrosomonas europaea Reporter Strain To Estimate Toxicity of Bioavailable Linear Alkylbenzene Sulfonate in Soil

    PubMed Central

    Brandt, Kristian K.; Pedersen, Anders; Sørensen, Jan

    2002-01-01

    Information about in situ toxicity of the bioavailable pools of adsorptive soil pollutants is a prerequisite for proper ecological risk assessment in contaminated soils. Such toxicity data may be obtained by assays allowing for direct exposure of introduced test microorganisms to the toxicants, as they appear in solid solution equilibria in the natural soil. We describe a novel sensitive solid-phase contact assay for in situ toxicity testing of soil pollutants based on a recombinant bioluminescent reporter strain of Nitrosomonas europaea. A slurry of the reporter strain and soil sample was shaken for 1 h, after which bioluminescence was measured either directly (soil slurry protocol) or in the supernatant obtained after centrifugation (soil extract protocol). The assay was validated for both protocols by using linear alkylbenzene sulfonate (LAS) as a toxic and adsorptive model compound in the soil samples. Interestingly, LAS showed the same toxicity to the reporter strain with either soil incubation (both protocols) or pure culture, suggesting that adsorbed LAS pools contributed to the observed toxicity. The solid-phase contact assay that used the reporter strain of lux-marked N. europaea was slightly more sensitive for the detection of LAS toxicity in soil than activity-based assays targeting indigenous nitrifiers and much more sensitive than assays targeting indigenous heterotrophic microbes. We conclude that the new solid-phase contact assay, which is based on direct interaction of the test microorganisms with bioavailable pools of the toxicants in soil, provides a most sensitive and relevant method for evaluating the in situ toxicity and assessing the risks of soil contaminants. PMID:12089034

  19. Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development – the LIFE Study

    PubMed Central

    Louis, Germaine M. Buck; Schisterman, Enrique F.; Sweeney, Anne M.; Wilcosky, Timothy C.; Gore-Langton, Robert E.; Lynch, Courtney D.; Barr, Dana Boyd; Schrader, Steven M.; Kim, Sungduk; Chen, Zhen; Sundaram, Rajeshwari

    2014-01-01

    Summary Buck Louis GM, Schisterman EF, Sweeney AM, Wilcosky TC, Gore-Langton RE, Lynch CD, Boyd Barr D, Schrader SM, Kim S, Chen Z, Sundaram R, on behalf of the LIFE Study. Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development – the LIFE Study. Paediatric and Perinatal Epidemiology 2011; 25: 413–424. The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy;obtaining environmental data across sensitive windows of reproduction and development;home-based biospecimen collection; anddevelopment of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e. fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424 423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ~85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility

  20. 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.

  1. Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants.

    PubMed

    Nyffeler, Johanna; Karreman, Christiaan; Leisner, Heidrun; Kim, Yong Jun; Lee, Gabsang; Waldmann, Tanja; Leist, Marcel

    2017-01-01

    Migration of neural crest cells (NCCs) is one of the pivotal processes of human fetal development. Malformations arise if NCC migration and differentiation are impaired genetically or by toxicants. In the currently available test systems for migration inhibition of NCC (MINC), the manual generation of a cell-free space results in extreme operator dependencies, and limits throughput. Here a new test format was established. The assay avoids scratching by plating cells around a commercially available circular stopper. Removal of the stopper barrier after cell attachment initiates migration. This microwell-based circular migration zone NCC function assay (cMINC) was further optimized for toxicological testing of human pluripotent stem cell (hPSC)-derived NCCs. The challenge of obtaining data on viability and migration by automated image processing was addressed by developing a freeware. Data on cell proliferation were obtained by labelling replicating cells, and by careful assessment of cell viability for each experimental sample. The role of cell proliferation as an experimental confounder was tested experimentally by performing the cMINC in the presence of the proliferation-inhibiting drug cytosine arabinoside (AraC), and by a careful evaluation of mitotic events over time. Data from these studies led to an adaptation of the test protocol, so that toxicant exposure was limited to 24 h. Under these conditions, a prediction model was developed that allows classification of toxicants as either inactive, leading to unspecific cytotoxicity, or specifically inhibiting NC migration at non-cytotoxic concentrations.

  2. An integrated omic analysis of hepatic alteration in medaka fish chronically exposed to cyanotoxins with possible mechanisms of reproductive toxicity.

    PubMed

    Qiao, Qin; Le Manach, Séverine; Huet, Hélène; Duvernois-Berthet, Evelyne; Chaouch, Soraya; Duval, Charlotte; Sotton, Benoit; Ponger, Loïc; Marie, Arul; Mathéron, Lucrèce; Lennon, Sarah; Bolbach, Gérard; Djediat, Chakib; Bernard, Cécile; Edery, Marc; Marie, Benjamin

    2016-12-01

    Cyanobacterial blooms threaten human health as well as the population of other living organisms in the aquatic environment, particularly due to the production of natural toxic components, the cyanotoxin. So far, the most studied cyanotoxins are microcystins (MCs). In this study, the hepatic alterations at histological, proteome and transcriptome levels were evaluated in female and male medaka fish chronically exposed to 1 and 5 μg L(-1) microcystin-LR (MC-LR) and to the extract of MC-producing Microcystis aeruginosa PCC 7820 (5 μg L(-1) of equivalent MC-LR) by balneation for 28 days, aiming at enhancing our understanding of the potential reproductive toxicity of cyanotoxins in aquatic vertebrate models. Indeed, both MC and Microcystis extract adversely affect reproductive parameters including fecundity and egg hatchability. The liver of toxin treated female fish present glycogen storage loss and cellular damages. The quantitative proteomics analysis revealed that the quantities of 225 hepatic proteins are dysregulated. In particular, a notable decrease in protein quantities of vitellogenin and choriogenin was observed, which could explain the decrease in reproductive output. Liver transcriptome analysis through Illumina RNA-seq reveals that over 100-400 genes are differentially expressed under 5 μg L(-1) MC-LR and Microcystis extract treatments, respectively. Ingenuity pathway analysis of the omic data attests that various metabolic pathways, such as energy production, protein biosynthesis and lipid metabolism, are disturbed by both MC-LR and the Microcystis extract, which could provoke the observed reproductive impairment. The transcriptomics analysis also constitutes the first report of the impairment of circadian rhythm-related gene induced by MCs. This study contributes to a better understanding of the potential consequences of chronic exposure of fish to environmental concentrations of cyanotoxins, suggesting that Microcystis extract could impact a

  3. Reproductive Toxicity of a Mixture of Regulated Drinking-Water Disinfection By-Products in a Multigenerational Rat Bioassay

    PubMed Central

    Klinefelter, Gary R.; Goldman, Jerome M.; DeAngelo, Anthony B.; Best, Deborah S.; McDonald, Anthony; Strader, Lillian F.; Murr, Ashley S.; Suarez, Juan D.; George, Michael H.; Hunter, E. Sidney; Simmons, Jane Ellen

    2015-01-01

    Background Trihalomethanes (THMs) and haloacetic 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 in a multigenerational reproductive toxicity bioassay. Methods Sprague-Dawley rats were exposed (parental, F1, and F2 generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the F2 generation to a realistically proportioned mixture of THMs and HAAs at 0, 500×, 1,000×, or 2,000× of the U.S. Environmental Protection Agency’s maximum contaminant levels (MCLs). Results Maternal water consumption was reduced at ≥ 1,000×; body weights were reduced at 2,000×. Prenatal and postnatal survival were unaffected. F1 pup weights were unaffected at birth but reduced at 2,000× on PND6 and at ≥ 1,000× on PND21. Postweaning F1 body weights were reduced at 2,000×, and water consumption was reduced at ≥ 500×. Males at 2,000× had a small but significantly increased incidence of retained nipples and compromised sperm motility. Onset of puberty was delayed at 1,000× and 2,000×. F1 estrous cycles and fertility were unaffected, and F2 litters showed no effects on pup weight or survival. Histologically, P0 (parental) dams had nephropathy and adrenal cortical pathology at 2,000×. Conclusions A mixture of regulated DBPs at up to 2,000× the MCLs had no adverse effects on fertility, pregnancy maintenance, prenatal survival, postnatal survival, or birth weights. Delayed puberty at ≥ 1,000× may have been secondary to reduced water consumption. Male nipple retention and compromised sperm motility at 2,000× may have been secondary to reduced body weights. Citation Narotsky MG, Klinefelter GR, Goldman JM, DeAngelo AB, Best DS, McDonald A, Strader LF, Murr AS, Suarez JD, George MH, Hunter ES III, Simmons JE. 2015. Reproductive toxicity of a mixture of regulated

  4. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity.

    PubMed

    Ghanayem, Burhan I; Bai, Re; Kissling, Grace E; Travlos, Greg; Hoffler, Undi

    2010-01-01

    The prevalence of human obesity and related chronic disorders such as diabetes, cardiovascular diseases, and cancer is rapidly increasing. Human studies have shown a direct relationship between obesity and infertility. The objective of the current work was to examine the effect of diet-induced obesity on male fertility and the effect of obesity on susceptibility to chemical-induced reproductive toxicity. From 5 to 30 wk of age, genetically intact male C57Bl/6J mice were fed a normal diet or one in which 60% of the kilocalories were from lard. Obese mice exhibited significant differences in the mRNA of several genes within the testes in comparison to lean males. Pparg was increased 2.2-fold, whereas Crem, Sh2b1, Dhh, Igf1, and Lepr were decreased 6.7, 1.4, 3.2, 1.6, and 7.2-fold, respectively. The fertility of male mice was compared through mating with control females. Acrylamide (AA)-induced reproductive toxicity was assessed in obese or lean males treated with water or 25 mg AA kg(-1) day(-1) via gavage for 5 days and then mated to control females. Percent body fat and weight were significantly increased in mice fed a high-fat vs. a normal diet. Obesity resulted in significant reduction in plugs and pregnancies of control females partnered with obese vs. lean males. Serum leptin and insulin levels were each approximately 5-fold higher in obese vs. age-matched lean mice. Sperm from obese males exhibited decreased motility and reduced hyperactivated progression vs. lean mice. Treatment with AA exacerbated male infertility of obese and lean mice; however, this effect was more pronounced in obese mice. Further, females partnered with AA-treated obese mice exhibited a further decrease in the percentage of live fetuses, whereas the percentage of resorptions increased. This work demonstrated that diet-induced obesity in mice caused a significant reduction in male fertility and exacerbated AA-induced reproductive toxicity and germ cell mutagenicity.

  5. Resazurin reduction assay, a useful tool for assessment of heavy metal toxicity in acidic conditions.

    PubMed

    Zare, Mohammadreza; Amin, Mohammad Mehdi; Nikaeen, Mahnaz; Bina, Bijan; Pourzamani, Hamidreza; Fatehizadeh, Ali; Taheri, Ensieh

    2015-05-01

    Almost all bioassays have been designed only for pH levels around 7; however, some toxicant characteristics may be different at lower pH values. In this study, a modified resazurin reduction method was used to evaluate the toxicity of heavy metals and metal plating wastewater on acid-tolerant (AT) and conventional bacteria at the natural and acidic pH conditions. According to our optimized protocol, resazurin was rapidly reduced by both conventional and AT active microorganisms. Considering the 30-min median effective concentration (30 min EC₅₀) values, conventional bacteria were comparatively more resistant than the acid-tolerant bacteria (ATB) in the case of exposure to Cd, Pb, Cr, and Zn, but the reverse case was found for Hg. After an exposure of 30 min, Cr and Hg showed the highest toxicity to ATB (30 min EC₅₀ values were 0.34 and 17.02 μmol/L, respectively), while Zn and Pb had a considerably lower toxicity. The modified resazurin reduction method successfully assessed the impact of metal plating wastewaters on the activities of conventional and AT bacteria. According to the findings where the wastewaters contain heavy metals, wastewater treatment facilities, which are dependent on ATB activity, should use bioassays at acidic pH values for better understanding of the effects of toxicants.

  6. 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.

  7. 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.

  8. The MTT assay as tool to evaluate and compare excipient toxicity in vitro on respiratory epithelial cells.

    PubMed

    Scherliess, Regina

    2011-06-15

    There are not many excipients already approved in drug products for the use in the respiratory tract. In this study, a rapid in vitro screening procedure to assess and compare acute toxicity of soluble excipient substances on respiratory epithelial cells utilising the Calu-3 cell line is presented. The test substances are either dissolved in HBSS+HEPES buffer or are directly applied to the cellular surface. After 4h incubation, the substances are removed and the cell viability is assessed using an MTT assay. The tested excipients include polysorbate 20 and 80, lactose and povidone 30 as well as glycerol and propylene glycol as examples of excipients already being used in formulations for application in the respiratory tract. These substances are sorted according to their toxic effect and new excipients not yet used in the respiratory tract like HPMC can be classified in this scheme. With this, besides information from systemic toxicity tests, a first valuation of the acute toxic effect of the substance on respiratory epithelial cells is gained. This can aid in the choice of new excipients being necessary for modern respiratory formulations comprising new active compounds as biomolecules or new delivery strategies such as sustained or prolonged delivery.

  9. 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

  10. Growth-Based Bacterial Viability Assay for Interference-Free and High-Throughput Toxicity Screening of Nanomaterials.

    PubMed

    Qiu, Tian A; Nguyen, Thu Ha Thi; Hudson-Smith, Natalie V; Clement, Peter L; Forester, Dona-Carla; Frew, Hilena; Hang, Mimi N; Murphy, Catherine J; Hamers, Robert J; Feng, Z Vivian; Haynes, Christy L

    2017-02-07

    Current high-throughput approaches evaluating toxicity of chemical agents toward bacteria typically rely on optical assays, such as luminescence and absorbance, to probe the viability of the bacteria. However, when applied to toxicity induced by nanomaterials, scattering and absorbance from the nanomaterials act as interferences that complicate quantitative analysis. Herein, we describe a bacterial viability assay that is free of optical interference from nanomaterials and can be performed in a high-throughput format on 96-well plates. In this assay, bacteria were exposed to various materials and then diluted by a large factor into fresh growth medium. The large dilution ensured minimal optical interference from the nanomaterial when reading optical density, and the residue left from the exposure mixture after dilution was confirmed not to impact the bacterial growth profile. The fractions of viable cells after exposure were allowed to grow in fresh medium to generate measurable growth curves. Bacterial viability was then quantitatively correlated to the delay of bacterial growth compared to a reference regarded as 100% viable cells; data analysis was inspired by that in quantitative polymerase chain reactions, where the delay in the amplification curve is correlated to the starting amount of the template nucleic acid. Fast and robust data analysis was achieved by developing computer algorithms carried out using R. This method was tested on four bacterial strains, including both Gram-negative and Gram-positive bacteria, showing great potential for application to all culturable bacterial strains. With the increasing diversity of engineered nanomaterials being considered for large-scale use, this high-throughput screening method will facilitate rapid screening of nanomaterial toxicity and thus inform the risk assessment of nanoparticles in a timely fashion.

  11. 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.

  12. Possible ameliorative effects of kolaviron against reproductive toxicity in sub-lethally whole body gamma-irradiated rats.

    PubMed

    Adaramoye, Oluwatosin A; Adedara, Isaac A; Farombi, E Olatunde

    2012-05-01

    Ionizing radiation is one of the environmental factors that may contribute to reproductive dysfunction by a mechanism involving oxidative stress. We investigated the possible ameliorative effects of kolaviron (KV) (a biflavonoid from the seeds of Garcinia kola) on sperm characteristics, testicular lipid peroxidation (LPO) and antioxidant status after a whole body γ-irradiation in Wistar rats. Vitamin C (VC) served as standard antioxidant in this study. The study consists of four groups of 6 rats each. Group I received corn oil, whereas group II received a single dose of γ-radiation (5 Gy). The animals in groups III and IV were pretreated with KV (250 mg/kg) and VC (250 mg/kg) by oral gavage five times in a week, respectively, for 6 weeks prior to and 8 weeks after exposure to γ-radiation. Gamma-irradiation resulted in a significant (p<0.05) decrease in body weight and relative testes weight. Also, γ-irradiation significantly (p<0.05) decreased the activities of superoxide dismutase, catalase and glutathione S-transferase as well as glutathione level, but markedly elevated malondialdehyde levels in the serum and testes. Irradiated rats showed testicular degeneration with concomitant decrease in sperm motility and viability. Although sperm abnormalities significantly increased, it has no effect on the epididymal sperm count. KV and VC significantly (p<0.05) decreased the body weight loss and increased relative testes weights of the rats. Furthermore, supplementation of KV and VC ameliorated radiation-induced toxicity by increasing the activities of antioxidant enzymes, decreased LPO and abrogated testicular degeneration. Taken together, γ-irradiation caused reproductive dysfunction by depleting the antioxidant defence system in the rats, while administration of KV or VC ameliorated the radiation-induced testicular toxicity.

  13. Evaluation of the reproductive and developmental toxicity of aluminium ammonium sulfate in a two-generation study in rats.

    PubMed

    Hirata-Koizumi, Mutsuko; Fujii, Sakiko; Ono, Atsushi; Hirose, Akihiko; Imai, Toshio; Ogawa, Kumiko; Ema, Makoto; Nishikawa, Akiyoshi

    2011-09-01

    Aluminium ammonium sulfate (AAS) was tested for reproductive/developmental toxicity in a two-generation study. Male and female rats were continuously given AAS in drinking water at 0, 50, 500 or 5000 ppm. Water consumption was decreased in all AAS-treated groups, and the body weight of parental animals transiently decreased in the 5000 ppm group. In either generation, no compound-related changes were found in estrous cyclicity, sperm parameters, copulation, fertility and gestation index, number of implantations and live birth pups, sex ratios of pups or viability during the preweaning period. Male and female F1 pups in the 5000 ppm group showed a lower body weight on postnatal day 21, while there were no differences in the birth weight of F1 and F2 pups between the control and AAS-treated groups. Preweaning body weight gain in F2 males and females indicated a similar decreasing tendency at 5000 ppm. In F1 and F2 weanlings, the weight of the liver, spleen and thymus decreased at 5000 ppm, but no histopathological changes were found in these organs. In F1 females in the 5000 ppm group, vaginal opening was delayed slightly. There were no compound-related changes in male preputial separation or in other developmental landmarks. In behavioral tests conducted for F1 animals at 4-6 weeks of age, no compound-related changes were found in spontaneous locomotor activity and performance in a water-filled multiple T-maze. In conclusion, the NOAEL of AAS for two-generation reproductive/developmental toxicity was considered to be 500 ppm in rats. Considering the aluminium content in the basal diet, the total ingested dose of aluminium from drinking water and food in this 500 ppm group was calculated to be 5.35 mgAl/kgbw/day.

  14. Selenium provides protection to the liver but not the reproductive organs in an atrazine-model of experimental toxicity.

    PubMed

    Adesiyan, Adebukola C; Oyejola, Titilola O; Abarikwu, Sunny O; Oyeyemi, Matthew O; Farombi, Ebenezer O

    2011-03-01

    The present study evaluated the possible protective effects of selenium against atrazine-induced toxicity in the liver and reproductive system of rats. Atrazine administered to rats orally at a dose of 120 mg/kg caused an inhibition in the activity of glutathione-S-transferase and an increase in malondialdehyde formation in the liver, testis and epididymis. Superoxide dismutase decreased in the liver and testis but was increased in the epididymis. Furthermore, hepatic glutathione and lactate dehydrogenase activity increased while epididymal catalase, ascorbate content, hepatic aspartate aminotransferase and glutathione peroxidase activities in all the tissues decreased in the atrazine-treated animals. Hepatic, testicular and epididymal alanine aminotransferase activities were not affected by atrazine (p>0.05). Decreased epididymal and testicular sperm number, sperm motility, daily sperm production and increased number of dead and abnormal sperm were observed in atrazine-treated rats. Treatment of rats orally with selenium at a dose of 0.25 mg/kg did not prevent atrazine-induced changes in sperm characteristics and had no protective effects against atrazine-induced biochemical alterations in the testis and epididymis except testicular lactate dehydrogenase. Catalase activity and ascorbate contents were unchanged in these groups of animals. However, selenium effectively protected against atrazine-induced changes in biochemical indices in the liver. In rats treated with selenium alone, glutathione peroxidase in all the tissues, hepatic glutathione and superoxide dismutase, testicular lactate dehydrogenase activity and ascorbate content increased, while hepatic catalase activities decreased (p<0.05). Our data suggest that selenium effectively attenuated the toxic effects of atrazine-induced liver changes but not in the reproductive organs and sperms of rats. Selenium might therefore be useful in ameliorating oxidative stress in the liver.

  15. Alfa-lipoic acid protects testosterone secretion pathway and sperm quality against 4-tert-octylphenol induced reproductive toxicity.

    PubMed

    Othman, Azza I; El-Missiry, Mohamed A; Koriem, Khaled M; El-Sayed, Aml A

    2012-07-01

    The protective effect of α-lipoic acid (LA) (50 mg/kg bw) against 4-tert-octylphenol (OP) (50 mg/kg bw) induced reproductive toxicity in male rats was studied. LA was injected 1h prior to OP administration three times a week. OP caused significant increase in oxidative stress in hypothalamus and epididymal sperm, disturbed hormonal levels in serum, decreased sperm quality, increased DNA fragmentation and loss of 35 and 95 kDa proteins in sperm, as well as elevated proliferating index in testis. LA protected against oxidative stress through promoting the levels of glutathione and glutathione-S-transferase in hypothalamus and sperm. In addition, LA prevented the decrease in testosterone, dehydroepiandrosterone sulfate, 3β-hydroxysteroid dehydrogenase, and inhibited the elevations in sex-hormone-binding globulin levels and showed normal sperm quality. LA modulated proliferation of germ cell, protected against DNA fragmentation and maintained membrane protein organization in the sperm. In conclusion, LA normalized oxidative stress and protected testosterone synthesis pathway across hypothalamus-testicular axis and sperm quality indicating its defensive influence against OP-induced oxidative reproductive dysfunction in male rats.

  16. 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.

  17. Joint Toxicity of Arsenic, Copper and Glyphosate on Behavior, Reproduction and Heat Shock Protein Response in Caenorhabditis elegans.

    PubMed

    Wang, Yunbiao; Ezemaduka, Anastasia N; Li, Zhuheng; Chen, Zhanyan; Song, Chuantao

    2017-04-01

    The soil nematode Caenorhabditis elegans was used in 24-h acute exposures to arsenic (As), copper (Cu) and glyphosate (GPS) and to mixtures of As/Cu and As/GPS to investigate the effects of mixture exposures in the worms. A synergistic type of interaction was observed for acute toxicity with the As/Cu and As/GPS mixtures. Sublethal 24-h exposures of 1/1000, 1/100 and 1/10 of the LC50 concentrations for As, Cu and GPS individually and for As/Cu and As/GPS mixtures were conducted to observe responses in locomotory behavior (head thrashing), reproduction, and heat shock protein expression. Head thrash frequency and reproduction exhibited concentration dependent decreases in both individual and combined exposures to the tested chemical stressors, and showed synergistic interactions even at micromolar concentrations. Furthermore, the HSP70 protein level was significantly increased following exposure to individual and combined chemical stressors in wild-type C. elegans. Our findings establish for the first time the effects of exposure to As/GPS and As/Cu mixtures in C. elegans.

  18. Mechanisms of toxicity of di(2-ethylhexyl) phthalate on the reproductive health of male zebrafish.

    PubMed

    Uren-Webster, Tamsyn M; Lewis, Ceri; Filby, Amy L; Paull, Gregory C; Santos, Eduarda M

    2010-09-01

    Phthalates are ubiquitous in the aquatic environment and are known to adversely affect male reproductive health in mammals through interactions with multiple receptor systems. However, little is known about the risks they pose to fish. This project investigated the effects of di(2-ethylhexyl) phthalate (DEHP), the most commonly used phthalate, on the reproductive health of male zebrafish (Danio rerio). Males were treated with 0.5, 50 and 5000 mg DEHP kg(-1) (body weight) for a period of 10 days via intraperitoneal injection. The effects of the exposure were assessed by analysing fertilisation success, testis histology, sperm DNA integrity and transcript profiles of the liver and testis. A significant increase in the hepatosomatic index and levels of hepatic vitellogenin transcript were observed following exposure to 5000 mg DEHP kg(-1). Exposure to 5000 mg DEHP kg(-1) also resulted in a reduction in fertilisation success of oocytes spawned by untreated females. However, survival and development of the resulting embryos were unaffected by all treatments, and no evidence of DEHP-induced sperm DNA damage was observed. Exposure to 50 and 5000 mg DEHP kg(-1) caused alterations in the proportion of germ cells at specific stages of spermatogenesis in the testis, including a reduction in the proportion of spermatozoa and an increase in the proportion of spermatocytes, suggesting that DEHP may inhibit the progression of meiosis. In parallel, exposure to 5000 mg DEHP kg(-1) increased the levels of two peroxisome proliferator-activated receptor (PPAR) responsive genes (acyl-coenzyme A oxidase 1 (acox1) and enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase (ehhadh). These data demonstrated that exposure to high concentrations of DEHP disrupts spermatogenesis in adult zebrafish with a consequent decrease in their ability to fertilise oocytes spawned by untreated females. Furthermore, our data suggest that the adverse effects caused by exposure to DEHP are

  19. 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...

  20. Zebrafish Assays as Developmental Toxicity Indicators in The Design of TAML Oxidation Catalysts

    PubMed Central

    Truong, Lisa; DeNardo, Matthew A.; Kundu, Soumen

    2014-01-01

    TAML activators promise a novel water treatment approach by efficiently catalysing peroxide-based degradation of chemicals of high concern at environmental concentrations. Green design ethics demands an exploration of TAML toxicity. Exposure to high concentrations of certain activators caused adverse effects in zebrafish. At typical TAML operational concentrations, development was not perturbed. PMID:24748850

  1. INTERLABORATORY STUDY OF PRECISION: HYALELLA AZTECA AND CHIRONOMUS TENTANS FRESHWATER SEDIMENT TOXICITY ASSAYS

    EPA Science Inventory

    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 se...

  2. 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 ...

  3. Determination of the relative toxicity of enantiomers with cell-based assays

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is an important need to determine the relative biological effects of toxin enantiomers found in poisonous plants. Current estimations of plant toxicities are based on total toxin levels without considering stereochemistry. However, if the predominant enantiomer found in a plant is of a less ...

  4. 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...

  5. 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 ...

  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. Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans.

    PubMed

    Abraham, Vivek C; Towne, Danli L; Waring, Jeffrey F; Warrior, Usha; Burns, David J

    2008-07-01

    Prioritization of compounds based on human hepatotoxicity potential is currently a key unmet need in drug discovery, as it can become a major problem for several lead compounds in later stages of the drug discovery pipeline. The authors report the validation and implementation of a high-content multiparametric cytotoxicity assay based on simultaneous measurement of 8 key cell health indicators associated with nuclear morphology, plasma membrane integrity, mitochondrial function, and cell proliferation. Compounds are prioritized by (a) computing an in vitro safety margin using the minimum cytotoxic concentration (IC(20)) across all 8 indicators and cell-based efficacy data and (b) using the minimal cytotoxic concentration alone to take into account concentration of drug in tissues. Feasibility data using selected compounds, including quinolone antibiotics, thiazolidinediones, and statins, suggest the viability of this approach. To increase overall throughput of compound prioritization, the authors have identified the higher throughput, plate reader-based CyQUANT assay that is similar to the high-content screening (HCS) assay in sensitivity of measuring inhibition of cell proliferation. It is expected that the phenotypic output from the multiparametric HCS assay in combination with other highly sensitive approaches, such as microarray-based expression analysis of toxic signatures, will contribute to a better understanding and predictivity of human hepatotoxicity potential.

  8. 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).

  9. 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...

  10. Effects of six priority controlled phthalate esters with long-term low-dose integrated exposure on male reproductive toxicity in rats.

    PubMed

    Gao, Hai-Tao; Xu, Run; Cao, Wei-Xin; Qian, Liang-Liang; Wang, Min; Lu, Lingeng; Xu, Qian; Yu, Shu-Qin

    2017-03-01

    Human beings are inevitably exposed to ubiquitous phthalate esters (PEs) surroundings. The purposes of this study were to investigate the effects of long-term low-dose exposure to the mixture of six priority controlled phthalate esters (MIXPs): dimethyl phthalate (DMP), diethyl phthalate (DEP), di(n-butyl) phthalate (DBP), butyl benzyl phthalate (BBP), di(2-ethyhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP), on male rat reproductive system and further to explore the underlying mechanisms of the reproductive toxicity. The male rats were orally exposed to either sodium carboxymethyl cellulose as controls or MIXPs at three different low-doses by gavage for 15 weeks. Testosterone and luteinizing hormone (LH) in serum were analyzed, and pathological examinations were performed for toxicity evaluation. Steroidogenic proteins (StAR, P450scc, CYP17A1 and 17β-HSD), cell cycle and apoptosis-related proteins (p53, Chk1, Cdc2, CDK6, Bcl-2 and Bax) were measured for mechanisms exploration. MIXPs with long-term low-dose exposure could cause male reproductive toxicity to the rats, including the decrease of both serum and testicular testosterone, and the constructional damage of testis. These effects were related to down-regulated steroidogenic proteins, arresting cell cycle progression and promoting apoptosis in rat testicular cells. The results indicate that MIXPs with long-term low-dose exposure may pose male reproductive toxicity in human.

  11. Development of an in situ toxicity assay system using recombinant baculoviruses.

    PubMed

    Grant, D F; Greene, J F; Pinot, F; Borhan, B; Moghaddam, M F; Hammock, B D; McCutchen, B; Ohkawa, H; Luo, G; Guenthner, T M

    1996-02-23

    A new method for experimentally analyzing the role of enzymes involved in metabolizing mutagenic, carcinogenic, or cytotoxic chemicals is described. Spodoptera fugiperda (SF-21) cells infected with recombinant baculoviruses are used for high level expression of one or more cloned enzymes. The ability of these enzymes to prevent or enhance the toxicity of drugs and xenobiotics is then measured in situ. Initial parameters for the system were developed and optimized using baculoviruses engineered for expression of the mouse soluble epoxide hydrolase (msEH, EC 3.3.2.3) or the rat cytochrome P4501A1. SF-21 cells expressing msEH were resistant to trans-stilbene oxide toxicity as well as several other toxic epoxides including: cis-stilbene oxide, 1,2,7,8-diepoxyoctane, allylbenzene oxide, and estragole oxide. The msEH markedly reduced DNA and protein adduct formation in SF-21 cells exposed to [3H]allylbenzene oxide or [3H]estragole oxide. On the other hand, 9,10-epoxyoctadecanoic acid and methyl 9,10-epoxyoctadecanoate were toxic only to cells expressing sEH, suggesting that the corresponding fatty acid diols were cytotoxic. This was confirmed by showing that chemically synthesized diols of these fatty acid epoxides were toxic to control SF-21 cells at the same concentration as were the epoxides to cells expressing sEH. A recombinant baculovirus containing a chimeric cDNA formed between the rat P4501A1 and the yeast NADPH-P450 reductase was also constructed and expressed in this system. A model compound, naphthalene, was toxic to SF-21 infected with the rat P4501A1/reductase chimeric co-infecting SF-21 cells with either a human or a rat microsomal EH virus along with P4501A1/reductase virus. These results demonstrate the usefulness of this new system for experimentally analyzing the role of enzymes hypothesized to metabolize endogenous and exogenous chemicals of human health concern.

  12. Rapid detection of highly pathogenic porcine reproductive and respiratory syndrome virus by a fluorescent probe-based isothermal recombinase polymerase amplification assay.

    PubMed

    Yang, Yang; Qin, Xiaodong; Sun, Yingjun; Chen, Ting; Zhang, Zhidong

    2016-12-01

    A novel fluorescent probe-based real-time reverse transcription recombinase polymerase amplification (real-time RT-RPA) assay was developed for rapid detection of highly pathogenic type 2 porcine reproductive and respiratory syndrome virus (HP-PRRSV). The sensitivity analysis showed that the detection limit of RPA was 70 copies of HP-PRRSV RNA/reaction. The real-time RT-RPA highly specific amplified HP-PRRSV with no cross-reaction with classic PRRSV, classic swine fever virus, pseudorabies virus, and foot-and-mouth disease virus. Assessment with 125 clinical samples showed that the developed real-time RT-RPA assay was well correlated with real-time RT-qPCR assays for detection of HP-PRRSV. These results suggest that the developed real-time RT-RPA assay is suitable for rapid detection of HP-PRRSV.

  13. Polarized Light Scattering as a Rapid and Sensitive Assay for Metal Toxicity to Bacteria

    DTIC Science & Technology

    2001-07-01

    Escherichia coli bacteria with no toxin exposure to the corresponding, but reduced, changes that occur when there is exposure to a small concentration of certain toxicants. The changes are due to growth of a specially prepared population of these bacteria. The changes in the pattern normally reflect a change in average bacterial size due to growth, whereas the reduction of the change in pattern occurs when there is rapid cessation of bacterial growth. The method was tested with varying concentration

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

    PubMed Central

    Brener, Oleksandr; Dunkelmann, Tina; Gremer, Lothar; van Groen, Thomas; Mirecka, Ewa A.; Kadish, Inga; Willuweit, Antje; Kutzsche, Janine; Jürgens, Dagmar; Rudolph, Stephan; Tusche, Markus; Bongen, Patrick; Pietruszka, Jörg; Oesterhelt, Filipp; Langen, Karl-Josef; Demuth, Hans-Ulrich; Janssen, Arnold; Hoyer, Wolfgang; Funke, Susanne A.; Nagel-Steger, Luitgard; Willbold, Dieter

    2015-01-01

    Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease. PMID:26394756

  19. Can Artemia Hatching Assay Be a (Sensitive) Alternative Tool to Acute Toxicity Test?

    PubMed

    Rotini, A; Manfra, L; Canepa, S; Tornambè, A; Migliore, L

    2015-12-01

    Artemia sp. is extensively used in ecotoxicity testing, despite criticisms inherent to both acute and long-term tests. Alternative endpoints and procedures should be considered to support the use of this biological model. The hatching process comprises several developmental steps and the cyst hatchability seems acceptable as endpoint criterion. In this study, we assessed the reliability of the hatching assay on A. franciscana by comparing with acute and long-term mortality tests, using two chemicals: Diethylene Glycol (DEG), Sodium Dodecyl Sulphate (SDS). Both DEG and SDS tests demonstrated a dose dependent hatching inhibition. The hatching test resulted more sensitive than acute mortality test and less sensitive than the long-term one. Results demonstrate the reliability and high sensitivity of this hatching assay on a short time lag and support its useful application in first-tier risk assessment procedures.

  20. Toxic Effect of Cadmium Assay in Contaminated Soil Earthworm Cell Using Modified Sensor.

    PubMed

    Ly, Suw Young; Kyung, Lee; Kim, Chae Hwa; Seo, Roma; Lee, Soo Youn; Kim, Lina; Chae, Su Min; Choi, Sung Wook; Kim, Ji Yoon

    2015-06-01

    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.

  1. 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

  2. Reproductive toxicity of the industrial solvent 2-ethoxyethanol in rats and interactive effects of ethanol.

    PubMed

    Nelson, B K; Brightwell, W S; Setzer, J V; O'Donohue, T L

    1984-08-01

    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.

  3. 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.

  4. A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats.

    PubMed

    Otabe, A; Fujieda, T; Masuyama, T

    2011-11-01

    Rats received diets containing 0, 2000, 10,000, or 50,000 ppm advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) for 2 generations. F(0) animals (30/sex/group) were treated from 10 weeks before pairing. Males continued until week 16; females through gestation and lactation. Once weaned, F(1) animals (25/sex/group) continued receiving the same diet until F(2) pups were weaned. Mean advantame intakes from each of the diets were 164, 833, and 4410 mg/kg bw/day among F(0) males, and 204, 1036, and 5431 mg/kg bw/day among F(1) males. F(0) and F(1) females had comparable intakes up to lactation, when intakes increased (up to 8447 mg/kg bw/day from 50,000 ppm diet). No treatment-related effects on mortality, body weights, reproduction, litter observations, or postnatal offspring development were noted. Atypical coloration of the feces and cage liners seen with test diets was attributed to excretion of test material/metabolites in the feces and urine. Slightly higher food consumption was seen in F(0) and F(1) animals, especially males, receiving 50,000 ppm. However, these differences were considered to be a secondary response to the high levels of non-nutritive material in the diet. The no-observed-adverse-effect level for reproductive and developmental toxicity was considered to be 50,000 ppm, the highest dietary concentration tested.

  5. Oral (Gavage) Combined Developmental and Perinatal/Postnatal Reproduction Toxicity Study of Ammonium Salt of Perfluorinated Hexanoic Acid in Mice.

    PubMed

    Iwai, Hiroyuki; Hoberman, Alan M

    2014-05-01

    The reproductive toxicity potential of Ammonium Salt of Perfluorinated Hexanoic Acid (PFHxA Ammonium Salt) in pregnant Crl: CD1(ICR) mice was investigated. Twenty females/group were administered the test substance or vehicle once daily from gestation day 6 through 18. Phase 1 doses: 0, 100, 350, and 500 mg/kg/d; phase 2: 0, 7, 35, and 175 mg/kg/d. Parameters evaluated include mortality, viability, body weights, clinical signs, abortions, premature deliveries, pregnancy and fertility, litter observations, maternal behavior, and sexual maturity in the F1 generation. The level of PFHxA Ammonium Salt was measured in the liver of F0 and F1 mice. At doses of 350 and 500 mg/kg/d maternal mortalities, excess salivation and changes in body weight gains occurred. Pup body weights were reduced on postpartum day (PPD) 0 in all the dosage groups, but persisted only in the 350 and 500 mg/kg/d groups. Additional effects at 300 and 500 mg/kg/d included stillbirths, reductions in viability indices, and delays in physical development. Levels of PFHxA Ammonium Salt in the livers of the 100 mg/kg/d dams were all below the lower limit of quantization (0.02 µg/mL); in the 350 mg/kg/d group, 3 of the 8 samples had quantifiable analytical results. In phase 2 no PFHxA Ammonium Salt was found in the liver. Adverse effects occurred only in the 175 mg/kg/d group and consisted of increased stillborn pups, pups dying on PPD 1, and reduced pup weights on PPD 1. Based on these data, the maternal and reproductive no observable adverse effect level of PFHxA Ammonium Salt is 100 mg/kg/d.

  6. 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.

  7. 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

  8. Oral propylparaben administration to juvenile male Wistar rats did not induce toxicity in reproductive organs.

    PubMed

    Gazin, Vincent; Marsden, Edward; Marguerite, Fabien

    2013-12-01

    Parabens are in widespread use as preservatives in drugs. In the late 1990 s, concerns were raised about their capacity to disrupt endocrine function based on in vitro data and in vivo uterotrophic tests. Studies in juvenile male rats provided conflicting results on pospubertal sperm production. In an exploratory pharmacokinetic study, Wistar male rats received a single dose of propylparaben (PP) at 3, 10, 100, or 1000 mg/kg, orally on postnatal day (PND) 31. Plasma PP concentrations were quantifiable up 8h after dosing with a mean T max value of 15 min. Distribution was 4.8 l/kg, the plasma elimination half-life was 47 min, and clearance was 4.20 (l/h)/kg at 10mg/kg. A sulfoconjugated metabolite was detected. In the juvenile toxicology study, PP was orally administered by gavage to 20 Wistar male rats at doses of 3, 10, 100, or 1000 mg/kg/day in 1% hydroxyethylcellulose for 8 weeks starting on PND21. A first subgroup of 10 males/dose was necropsied immediately after the 8-week exposure period; a second subgroup of 10 males/dose was necropsied after a 26-week washout period. Blood samples were taken from additional satellite animals after dosing on PND21 and PND77 for toxicokinetic analysis. There was no evidence of an effect of PP on the weight of the male reproductive organs, epididymal sperm parameters, hormone levels, or histopathology. The dose of 1000 mg/kg/day was the no-observed adverse effect level, corresponding to a maximum plasma concentration of 12,030 ng/ml and exposure to 47 760 ng · h/ml (AUC0-8 h) at the end of the treatment.

  9. Framework for identifying chemicals with structural features associated with the potential to act as developmental or reproductive toxicants.

    PubMed

    Wu, Shengde; Fisher, Joan; Naciff, Jorge; Laufersweiler, Michael; Lester, Cathy; Daston, George; Blackburn, Karen

    2013-12-16

    Developmental and reproductive toxicity (DART) end points are important hazard end points that need to be addressed in the risk assessment of chemicals to determine whether or not they are the critical effects in the overall risk assessment. These hazard end points are difficult to predict using current in silico tools because of the diversity of mechanisms of action that elicit DART effects and the potential for narrow windows of vulnerability. DART end points have been projected to consume the majority of animals used for compliance with REACH; thus, additional nonanimal predictive tools are urgently needed. This article presents an empirically based decision tree for determining whether or not a chemical has receptor-binding properties and structural features that are consistent with chemical structures known to have toxicity for DART end points. The decision tree is based on a detailed review of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have DART end-point data and are grouped into defined receptor binding and chemical domains. When tested against a group of chemicals not included in the training set, the decision tree is shown to identify a high percentage of chemicals with known DART effects. It is proposed that this decision tree could be used both as a component of a screening system to identify chemicals of potential concern and as a component of weight-of-evidence decisions based on structure-activity relationships (SAR) to fill data gaps without generating additional test data. In addition, the chemical groupings generated could be used as a starting point for the development of hypotheses for in vitro testing to elucidate mode of action and ultimately in the development of refined SAR principles for DART that incorporate mode of action (adverse outcome pathways).

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. [Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (3). Teratogenicity study in rabbits].

    PubMed

    Nishimura, T; Chihara, N; Sakamoto, T; Nakagawa, Y; Aze, Y; Tanaka, M; Shimouchi, K; Ozeki, Y; Fujita, T

    1997-12-01

    A teratogenicity study of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in KAR:NZW rabbits. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day to pregnant rabbit from day 6 to 18 of gestation to examine the effects on dams and fetuses. Death occurred on 3 animals in the 100 mg/kg/day group and one animal in the 50 mg/kg/day group during the treatment period. Hypoactivity, bradypnea/apnea and clonic convulsion after administration was observed in animal dosed 100 mg/kg/day. No maternal effects were seen on body weight, food consumption, necropsy findings or organ weights. External, skeletal and visceral findings revealed no adverse effects of ONO-1101 on fetuses. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 25 mg/kg/day for dams and 100 mg/kg for fetuses.

  15. Reproductive and neurobehavioural toxicity study of tartrazine administered to mice in the diet.

    PubMed

    Tanaka, Toyohito

    2006-02-01

    Tartrazine was given in the diet to provide levels of 0% (control), 0.05%, 0.15%, and 0.45% (approximately 83, 259, 773 mg/kg/day, respectively) from five weeks of age of the F0 generation to nine weeks of age of the F1 generation in mice, and selected reproductive and neurobehavioural parameters were measured. In movement activity of exploratory behaviour in the F0 generation, number of vertical activity was significantly increased in the middle-dose group in males. There were no adverse effects of tartrazine on either litter size, litter weight and sex ratio at birth. The average body weight of male offspring was significantly increased in the high-dose group and that of female offspring was significantly increased in the middle-dose group at birth. In behavioural developmental parameters, surface righting at PND 4 was significantly accelerated in the high-dose group in male offspring, and those effects were significantly dose-related in a trend test (P<0.01). Cliff avoidance at PND 7 was significantly accelerated in the middle-dose group in male offspring. Negative geotaxis at PND 4 was significantly delayed in the high-dose group in female offspring. Other variables measured showed no significant adverse effects in either sex in the lactation period. In movement activity of exploratory behaviour in the F1 generation, number of movement showed a significant tendency to be affected in the treatment groups in male offspring in a trend test (P<0.05). The dose level of tartrazine in the present study produced a few adverse effects in neurobehavioural parameters during the lactation period in mice. Nevertheless, the high-dose level were in excess of the ADI of tartrazine (0-7.5 mg/kgbw), and the actual dietary intake of tartrazine is presumed to be much lower. It would therefore appear that the levels of actual dietary intake of tartrazine is unlikely to produce any adverse effects in humans.

  16. Systematic Evaluation of Nanomaterial Toxicity: Utility of Standardized Materials and Rapid Assays

    SciTech Connect

    Harper, Stacey; Carriere, Jason L.; Miller, John M.; Hutchison, James E.; Maddux, Bettye L.; Tanguay, Robert

    2011-06-28

    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.

  17. A highly efficient nonchemical method for isolating live nematodes (Caenorhabditis elegans) from soil during toxicity assays.

    PubMed

    Kim, Shin Woong; Moon, Jongmin; An, Youn-Joo

    2015-01-01

    The success of soil toxicity tests using Caenorhabditis elegans may depend in large part on recovering the organisms from the soil. However, it can be difficult to learn the International Organization for Standardization/ASTM International recovery process that uses the colloidal silica flotation method. The present study determined that a soil-agar isolation method provides a highly efficient and less technically demanding alternative to the colloidal silica flotation method. Test soil containing C. elegans was arranged on an agar plate in a donut shape, a linear shape, or a C curve; and microbial food was placed outside the soil to encourage the nematodes to leave the soil. The effects of ventilation and the presence of food on nematode recovery were tested to determine the optimal conditions for recovery. A linear arrangement of soil on an agar plate that was sprinkled with microbial food produced nearly 83% and 90% recovery of live nematodes over a 3-h and a 24-h period, respectively, without subjecting the nematodes to chemical stress. The method was tested using copper (II) chloride dihydrate, and the resulting recovery rate was comparable to that obtained using colloidal silica flotation. The soil-agar isolation method portrayed in the present study enables live nematodes to be isolated with minimal additional physicochemical stress, making it a valuable option for use in subsequent sublethal tests where live nematodes are required.

  18. 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.

  19. 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.

  20. 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.

  1. Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials.

    PubMed

    Jiang, Xiumei; Wang, Liming; Ji, Yinglu; Tang, Jinglong; Tian, Xin; Cao, Mingjing; Li, Jingxuan; Bi, Shuying; Wu, Xiaochun; Chen, Chunying; Yin, Jun-Jie

    2017-03-01

    As a widely used nanomaterial in daily life, silver nanomaterials may cause great concern to female reproductive system as they are found to penetrate the blood-placental barrier and gain access to the ovary. However, it is largely unknown about how silver nanomaterials influence ovarian physiology and functions such as hormone production. This study performs in vitro toxicology study of silver nanomaterials, focusing especially on cytotoxicity and steroidogenesis and explores their underlying mechanisms. This study exposes primary rat granulosa cells to gold nanorod core/silver shell nanostructures (Au@Ag NRs), and compares outcomes with cells exposed to gold nanorods. The Au@Ag NRs generate more reactive oxygen species and reduce mitochondrial membrane potential and less production of adenosine triphosphate. Au@Ag NRs promote steroidogenesis, including progesterone and estradiol, in a time- and dose-dependent manner. Chemical reactivity and transformation of Au@Ag NRs are then studied by electron spin resonance spectroscopy and X-ray absorption near edge structure, which analyze the generation of free radical and intracellular silver species. Results suggest that both particle-specific activity and intracellular silver ion release of Au@Ag NR contribute to the toxic response of granulosa cells.

  2. Contact toxicity of metals in sewage sludge: Evaluation of alternatives to sodium chloride in the Microtox[reg sign] assay

    SciTech Connect

    Carlson-Ekvall, C.E.A.; Morrison, G.M. . Dept. of Sanitary Engineering)

    1995-01-01

    The presence of chloride ions in the Microtox[reg sign] test can cause problems when testing metal toxicity, both due to extraction of metals from solid samples and formation of chloro complexes of metals in the liquid phase. To investigate alternatives to NaCl in the Microtox test, the toxicity of Cu, Cd, Pb, and Zn to Photobacterium phosphoreum was tested in 28 osmotic surrogates for NaCl. It was found that Na[sup +] must be present to keep the blank luminescence stable for 30 min. The results point to NaClO[sub 4] as the most satisfactory surrogate solution as it has an inert behavior and does not form complexes with any metal of environmental interest. Raw, digested, and reference sewage sludges were tested in the osmotic surrogates. The EC50 values for sludges were lower in solutions of NaNO[sub 3], Na[sub 2]SO[sub 4], and NaClO[sub 4], and higher in sucrose, mannitol, and KCl, compared to NaCl. NaClO[sub 4] can be recommended as an osmotic surrogate for sewage sludge testing. Another problem with the Microtox assay is the lack of pH control in the cuvette. Copper toxicity tests were carried out in Tris buffer and KH[sub 2]PO[sub 4] at two different concentrations and at pH 7 and 8. The results show that 1 mM phosphate buffer, pH 7.0, can be recommended for solid samples. However, owing to formation of KClO[sub 4] a buffer containing potassium is not recommended in combination with NaClO[sub 4].

  3. 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...

  4. 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

  5. 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.

  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. Extended evaluation on the ES-D3 cell differentiation assay combined with the BeWo transport model, to predict relative developmental toxicity of triazole compounds.

    PubMed

    Li, Hequn; Flick, Burkhard; Rietjens, Ivonne M C M; Louisse, Jochem; Schneider, Steffen; van Ravenzwaay, Bennard

    2016-05-01

    The mouse embryonic stem D3 (ES-D3) cell differentiation assay is based on the morphometric measurement of cardiomyocyte differentiation and is a promising tool to detect developmental toxicity of compounds. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, is useful to determine relative placental transport velocities of compounds. We have previously demonstrated the usefulness of the ES-D3 cell differentiation assay in combination with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies of a set of reference azole compounds. To further evaluate this combined in vitro toxicokinetic and toxicodynamic approach, we combined ES-D3 cell differentiation data of six novel triazoles with relative transport rates obtained from the BeWo model and compared the obtained ranking to the developmental toxicity ranking as derived from in vivo data. The data show that the combined in vitro approach provided a correct prediction for in vivo developmental toxicity, whereas the ES-D3 cell differentiation assay as stand-alone did not. In conclusion, we have validated the combined in vitro approach for developmental toxicity, which we have previously developed with a set of reference azoles, for a set of six novel triazoles. We suggest that this combined model, which takes both toxicodynamic and toxicokinetic aspects into account, should be further validated for other chemical classes of developmental toxicants.

  10. Cell reproductive patterns in the green alga Pseudokirchneriella subcapitata (=Selenastrum capricornutum) and their variations under exposure to the typical toxicants potassium dichromate and 3,5-DCP

    PubMed Central

    Yamagishi, Takahiro; Yamaguchi, Haruyo; Suzuki, Shigekatsu; Horie, Yoshifumi; Tatarazako, Norihisa

    2017-01-01

    Pseudokirchneriella subcapitata is a sickle-shaped freshwater green microalga that is normally found in unicellular form. Currently, it is the best known and most frequently used species of ecotoxicological bioindicator because of its high growth rate and sensitivity to toxicants. However, despite this organism’s, our knowledge of its cell biology—for example, the patterns of nuclear and cytoplasmic division in the mitotic stage—is limited. Although it has been reported that P. subcapitata proliferates by popularity forming four daughter cells (autospores) through multiple fission after two nuclear divisions, here, we report two additional reproductive patterns by which two autospores are formed by binary fission (“two-autospore type”) and eight autospores are formed by multiple fission (“eight-autospore type”). Moreover, we found that cell reproductive patterns differed markedly with the culture conditions or with exposure to either of two typical toxicants, potassium dichromate (K2Cr2O7) and 3,5-dichlorophenol (3,5-DCP). The eight-autospore type occurred at the highest frequency in the early phase of culture, but it disappeared under 3,5-DCP at 2.0 mg/L. Under 0.3 mg/L K2CrO7 (Cr(VI)) the eight-autospore type took substantially longer to appear than in control culture. The two-autospore type occurred only in the late phase of culture. To our knowledge, this is the first detailed evaluation of the reproductive patterns of P. subcapitata, which changed dramatically in the presence of toxicants. These findings suggest that observation of the reproductive patterns of P. subcapitata will help to elucidate different cell reactions to toxicants. PMID:28152022

  11. Cell reproductive patterns in the green alga Pseudokirchneriella subcapitata (=Selenastrum capricornutum) and their variations under exposure to the typical toxicants potassium dichromate and 3,5-DCP.

    PubMed

    Yamagishi, Takahiro; Yamaguchi, Haruyo; Suzuki, Shigekatsu; Horie, Yoshifumi; Tatarazako, Norihisa

    2017-01-01

    Pseudokirchneriella subcapitata is a sickle-shaped freshwater green microalga that is normally found in unicellular form. Currently, it is the best known and most frequently used species of ecotoxicological bioindicator because of its high growth rate and sensitivity to toxicants. However, despite this organism's, our knowledge of its cell biology-for example, the patterns of nuclear and cytoplasmic division in the mitotic stage-is limited. Although it has been reported that P. subcapitata proliferates by popularity forming four daughter cells (autospores) through multiple fission after two nuclear divisions, here, we report two additional reproductive patterns by which two autospores are formed by binary fission ("two-autospore type") and eight autospores are formed by multiple fission ("eight-autospore type"). Moreover, we found that cell reproductive patterns differed markedly with the culture conditions or with exposure to either of two typical toxicants, potassium dichromate (K2Cr2O7) and 3,5-dichlorophenol (3,5-DCP). The eight-autospore type occurred at the highest frequency in the early phase of culture, but it disappeared under 3,5-DCP at 2.0 mg/L. Under 0.3 mg/L K2CrO7 (Cr(VI)) the eight-autospore type took substantially longer to appear than in control culture. The two-autospore type occurred only in the late phase of culture. To our knowledge, this is the first detailed evaluation of the reproductive patterns of P. subcapitata, which changed dramatically in the presence of toxicants. These findings suggest that observation of the reproductive patterns of P. subcapitata will help to elucidate different cell reactions to toxicants.

  12. 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...

  13. 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...

  14. Final report on the reproductive toxicity of acrylamide (ACRL) (CAS No. 79-06-1) CD-1 (trade name) swiss mice. Laboratory supplement. Report for 1 February-30 December 1990

    SciTech Connect

    Not Available

    1993-01-01

    The document is the laboratory supplement to the Final Report on the Reproductive Toxicity of Acrylamide in CD-1 Swiss Mice. It provides a review of previous studies, experimental protocols, and data on the chemical analyses of the compound used.

  15. [Reproductive and developmental toxicity studies of lactitol (NS-4) (1)--Fertility study in rats by oral administration].

    PubMed

    Ninomiya, H; Kondo, J; Ide, Y; Yamashita, Y; Nishikawa, K; Kishida, K; Watanabe, M; Sumi, N

    1994-11-01

    A study of fertility and fetal development was conducted in Sprague-Dawley rats. Male rats were given lactitol, a hepatic encephalopathy drug, orally from 63 days before mating to the end of mating period. Female rats were given from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 0.7, 2.65 and 10 g/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. The decrease in food consumption in either male or female was observed in the intermediate and high dose groups. The high dose caused soft stool, diarrhea and increase in water consumption in either male or female. Moreover, the high dose caused salivation and suppression of body weight gain in male. In the pathological examination, the enlargement of cecum were observed in male of the intermediate and high dose groups. The increase in cecum weight were observed in male in all lactitol groups, and in female of the high dose group. Lactitol did not affect on copulation and fertility indexes in either male or female rats. Lactitol failed to affect on estrous cycle in female rats, and number of corpora lutea, implantations and preimplantation egg losses. In the fetal examination, lactitol did not affect on the development of live fetuses. The results show that no-effect dose levels of lactitol are less than 0.7 g/kg in male rats and 0.7 g/kg in female rats for general toxicity, and 10 g/kg for reproductive function in parent animals and fetuses.

  16. [Reproductive and developmental toxicity studies of landiolol hydrochloride (ONO-1101) (4). Perinatal and postnatal study in rats].

    PubMed

    Nishimura, T; Chihara, N; Shirakawa, R; Sugai, S; Sakamoto, T; Nakagawa, Y; Aze, Y; Shimouchi, K; Ozeki, Y; Fujita, T

    1997-12-01

    A perinatal and postnatal study of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley(SD) rats. ONO-1101 was administered intravenously at a dose level of 0 (control), 25, 50 or 100 mg/kg/day from day 17 of gestation to day 20 after parturition to examine the effects on pregnancy, delivery, lactation and the effects on postnatal growth and development of offspring. In the 100 mg/kg/day group, hypoactivity, reddish lacrimation, clonic convulsion and bradypnea/apnea were observed after administration and 5 animals died in the treatment period, and body weight on day 21 and food consumption on day 14-21 of dam at weaning were lower than control group. In the 50 mg/kg/day group, reddish lacrimation was occasionally seen in some animals. ONO-1101 had no effects on pregnancy, delivery, lactation and necropsy findings or organ weights of dams. In the 100 mg/kg/day group, viability of offspring on day 4 after birth decreased and body weight gain of the suckling suppressed, but those changes recovered after weaning. On the skeletal examination of offspring culled on day 4 after birth, decrease in the mean number of osiffied phalanges of hindpaw and increase in the incidence of unossified talus bone were seen in the 100 mg/kg/day group, however, no delay of ossification was found form the weanling. There were no influence of ONO-1101 on external differentiation, functional, behavioral or learning abilities or reproductive performance in offspring. From the above results, it is estimated that the no-toxic dose level of ONO-1101 under these experimental conditions is 50 mg/kg/day for dam and offspring.

  17. Use of the ES-D3 cell differentiation assay, combined with the BeWo transport model, to predict relative in vivo developmental toxicity of antifungal compounds.

    PubMed

    Li, Hequn; Rietjens, Ivonne M C M; Louisse, Jochem; Blok, Martine; Wang, Xinyi; Snijders, Linda; van Ravenzwaay, Bennard

    2015-03-01

    We investigated the applicability of the ES-D3 cell differentiation assay combined with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies. To this purpose, the in vitro developmental toxicity of five antifungal compounds was investigated by characterizing their inhibitory effect on the differentiation of ES-D3 cells into cardiomyocytes. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, was used to determine the relative placental transport velocity. The ES-D3 cell differentiation data were first compared to benchmark doses (BMDs) for in vivo developmental toxicity as derived from data reported in the literature. Correlation between the benchmark concentration for 50% effect (BMCd50) values, obtained in the ES-D3 cell differentiation assay, with in vivo BMD10 values showed a reasonable correlation (R(2)=0.57). When the ES-D3 cell differentiation data were combined with the relative transport rates obtained from the BeWo model, the correlation with the in vivo data increased (R(2)=0.95). In conclusion, we show that the ES-D3 cell differentiation assay is able to better predict the in vivo developmental toxicity ranking of antifungal compounds when combined with the BeWo transport model, than as a stand-alone assay.

  18. 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…

  19. 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...

  20. 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...

  1. Solubilization and bio-conjugation of quantum dots and bacterial toxicity assays by growth curve and plate count.

    PubMed

    Park, Soonhyang; Chibli, Hicham; Nadeau, Jay

    2012-07-11

    previous study, we showed that coupling of antibiotics to CdTe can increase toxicity to bacteria but decrease toxicity to mammalian cells, due to decreased production of reactive oxygen species from the conjugates. Although it is unlikely that cadmium-containing compounds will be approved for use in humans, such preparations could be used for disinfection of surfaces or sterilization of water. In this protocol, we give a straightforward approach to solubilizing CdTe QDs with mercaptopropionic acid (MPA). The QDs are ready to use within an hour. We then demonstrate coupling to an antimicrobial agent. The second part of the protocol demonstrates a 96-well bacterial inhibition assay using the conjugated and unconjugated QDs. The optical density is read over many hours, permitting the effects of QD addition and light exposure to be evaluated immediately as well as after a recovery period. We also illustrate a colony count for quantifying bacterial survival.

  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

    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.

  4. 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.

  5. General baseline toxicity QSAR for nonpolar, polar and ionisable chemicals and their mixtures in the bioluminescence inhibition assay with Aliivibrio fischeri.

    PubMed

    Escher, Beate I; Baumer, Andreas; Bittermann, Kai; Henneberger, Luise; König, Maria; Kühnert, Christin; Klüver, Nils

    2017-03-22

    The Microtox assay, a bioluminescence inhibition assay with the marine bacterium Aliivibrio fischeri, is one of the most popular bioassays for assessing the cytotoxicity of organic chemicals, mixtures and environmental samples. Most environmental chemicals act as baseline toxicants in this short-term screening assay, which is typically run with only 30 min of exposure duration. Numerous Quantitative Structure-Activity Relationships (QSARs) exist for the Microtox assay for nonpolar and polar narcosis. However, typical water pollutants, which have highly diverse structures covering a wide range of hydrophobicity and speciation from neutral to anionic and cationic, are often outside the applicability domain of these QSARs. To include all types of environmentally relevant organic pollutants we developed a general baseline toxicity QSAR using liposome-water distribution ratios as descriptors. Previous limitations in availability of experimental liposome-water partition constants were overcome by reliable prediction models based on polyparameter linear free energy relationships for neutral chemicals and the COSMOmic model for charged chemicals. With this QSAR and targeted mixture experiments we could demonstrate that ionisable chemicals fall in the applicability domain. Most investigated water pollutants acted as baseline toxicants in this bioassay, with the few outliers identified as uncouplers or reactive toxicants. The main limitation of the Microtox assay is that chemicals with a high melting point and/or high hydrophobicity were outside of the applicability domain because of their low water solubility. We quantitatively derived a solubility cut-off but also demonstrated with mixture experiments that chemicals inactive on their own can contribute to mixture toxicity, which is highly relevant for complex environmental mixtures, where these chemicals may be present at concentrations below the solubility cut-off.

  6. The applicability of conventional cytotoxicity assays to predict safety/toxicity of mesoporous silica nanoparticles, silver and gold nanoparticles and multi-walled carbon nanotubes.

    PubMed

    Mannerström, Marika; Zou, Jing; Toimela, Tarja; Pyykkö, Ilmari; Heinonen, Tuula

    2016-12-01

    Developing new, validated methods for screening of the effects of nanomaterials is a huge and expensive task. It is therefore necessary to try to employ already existing and validated methods, developed for chemicals. In the present study cytotoxicity of gold (Au) and silver (Ag) nanoparticles (NP), two different mesoporous silica nanoparticles (MSNP), and multi-walled carbon nanotubes (MWCNT) were investigated in BALB/c 3T3 fibroblasts, NR8383 macrophages, and U937 monocytes using standard assays, namely WST-1 and NRU. In addition, preliminary attempts were made to investigate ENM-mediated effects on cell motility as a potential end point for NP toxicity. AgNPs were most toxic to BALB/c 3T3 fibroblasts while other ENMs were insignificantly toxic. NR8383 macrophages were most sensitive cells, as in addition to AgNPs, also MWCNTs were toxic to NR8383 cells. AgNP was toxic also to U937 cells, other ENMs had minor effect. Different media resulted in different-sized aggregates of the same ENMs. AgNP inhibited BALB/c motility most, whereas NR8383 motility was inhibited most by MWCNTs. In conclusion, conventional cytotoxicity assays are better suited to rank the order of toxicity of different nanoparticles instead of producing accurate IC50 data. Moreover, using immune cells, especially macrophages together with fibroblasts, would bring more relevant predictions of ENM cytotoxicity as immune cells may discover cytotoxicity that is not captured by BALB/c 3T3 cells alone.

  7. 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.

  8. Assessment of the reproductive toxicity of inhalation exposure to ethyl tertiary butyl ether in male mice with normal, low active and inactive ALDH2.

    PubMed

    Weng, Zuquan; Ohtani, Katsumi; Suda, Megumi; Yanagiba, Yukie; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2014-04-01

    No data are available regarding aldehyde dehydrogenase 2 (ALDH2) polymorphisms related to the reproductive toxicity possibly caused by ethyl tertiary butyl ether (ETBE). In this study, two inhalation experiments were performed in Aldh2 knockout (KO), heterogeneous (HT) and wild type (WT) C57BL/6 male mice exposed to ETBE, and the data about general toxicity, testicular histopathology, sperm head numbers, sperm motility and sperm DNA damage were collected. The results showed that the 13-week exposure to 0, 500, 1,750 and 5,000 ppm ETBE significantly decreased sperm motility and increased levels of sperm DNA strand breaks and 8-hydroxy-deoxyguanosine in both WT and KO mice, the effects were found in 1,750 and 5,000 ppm groups of WT mice, and all of the three exposed groups of KO mice compared to the corresponding control; furthermore, ETBE also caused decrease in the relative weights of testes and epididymides, the slight atrophy of seminiferous tubules of testis and reduction in sperm numbers of KO mice exposed to ≥500 ppm. In the experiment of exposure to lower concentrations of ETBE (0, 50, 200 and 500 ppm) for 9 weeks, the remarkable effects of ETBE on sperm head numbers, sperm motility and sperm DNA damage were further observed in KO and HT mice exposed to 200 ppm ETBE, but not in WT mice. Our findings suggested that only exposure to high concentrations of ETBE might result in reproductive toxicity in mice with normal active ALDH2, while low active and inactive ALDH2 enzyme significantly enhanced the ETBE-induced reproductive toxicity in mice, even exposed to low concentrations of ETBE, mainly due to the accumulation of acetaldehyde as a primary metabolite of ETBE.

  9. 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,...

  10. 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.

  11. 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.

  12. Food Emulsifier Glycerin Monostearate Increases Internal Exposure Levels of Six Priority Controlled Phthalate Esters and Exacerbates Their Male Reproductive Toxicities in Rats.

    PubMed

    Gao, Hai-Tao; Xu, Run; Cao, Wei-Xin; Zhou, Xu; Yan, Ye-Hui-Mei; Lu, Lingeng; Xu, Qian; Shen, Yang

    2016-01-01

    Human beings are inevitably exposed to ubiquitous phthalate esters (PAEs). Processed, packaged foods are popular nowadays, in which emulsifiers are frequently added as food additives. It is unclear how emulsifiers affect the bioavailability of ingested PAEs contaminants and their toxicities. The purposes of our study were to explore whether food emulsifier Glycerin Monostearate (GMS) could increase the internal exposure levels of six priority controlled PAEs and affect their reproductive toxicities when male rats are exposed to PAEs mixture (MIXPs). The male rats were exposed to MIXPs by gavage for thirty days in combination with or without given GMS. Phthalate monoesters (MPAEs), primary metabolites of PAEs, in rat urine were used as biomarkers to predict the internal exposure levels of the six PAEs, and their concentrations were determined using UPLC-MS. The reproductive toxicity was evaluated using serum testosterone levels test and histopathology of testes. Results showed that compared to PAEs exposure alone, the internal exposure levels of PAEs increased by 30%-49% in the presence of GMS. PAEs exposure led to the reduction of testosterone level by 23.4%-42.1% in the presence and absence of GMS, respectively, compared to the baseline. Testosterone levels in MIXPs+GMS and DEHP+GMS group were decreased by 9.1% and 13.6%, respectively, compared with MIXPs and DEHP group. Histopathology showed that injuries of testis (deciduous spermatids) were observed, and GMS exacerbated the injuries. The results indicated food emulsifiers chronically taken up might increase safety risks of food PAEs contaminants.

  13. 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.

  14. Genotoxicity evaluation of individual cigarette smoke toxicants using the in vitro γH2AX assay by high content screening.

    PubMed

    Garcia-Canton, Carolina; Anadon, Arturo; Meredith, Clive

    2013-10-23

    Cigarette smoke is a complex mixture consisting of more than 5600 identified chemical constituents of which approximately 150 have been identified so far as "tobacco smoke toxicants". Proposals made by the World Health Organisation Framework Convention on Tobacco Control mandate the lowering of nine tobacco smoke priority toxicants, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosonornicotine (NNN), and benzo[a]pyrene (B[a]P) and monitoring the levels of a further nine including cadmium. Here, we evaluated the genotoxic potential in human bronchial epithelial BEAS-2B cells of four cigarette smoke toxicants; NNK, NNN, B[a]P and cadmium using the novel in vitro γH2AX assay by High Content Screening (HCS). We also examined the genotoxicity of binary mixtures of NNK and NNN reporting their relative contribution to the genotoxic end-point. The results of this preliminary assessment showed that the in vitro γH2AX assay by HCS could be used as a pre-screening tool to detect and quantify the genotoxicity effect of cigarette smoke toxicants individually and in binary mixture. Moreover, the data produced could contribute to the prioritisation of toxicant reduction research in modified tobacco products.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. Enzyme-linked immunosorbent assay for monitoring toxic dioxin congeners in milk based on a newly generated monoclonal anti-dioxin antibody.

    PubMed

    Okuyama, Mitsunobu; Kobayashi, Norihiro; Takeda, Wakako; Anjo, Takako; Matsuki, Yasuhiko; Goto, Junichi; Kambegawa, Akira; Hori, Shinjiro