Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA–sponsored workshop, “Nonclinical Aspects of Biopharmaceutical Development,” industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.

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The reproductive toxicity of melamine in the absence and presence of cyanuric acid in male mice

Research in Veterinary Science ◽

10.1016/j.rvsc.2012.11.010 ◽

2013 ◽

Vol 94 (3) ◽

pp. 618-627 ◽

Cited By ~ 33

Author(s):

Rong H. Yin ◽

Xin Z. Wang ◽

Wen L. Bai ◽

Chang D. Wu ◽

Rong L. Yin ◽

...

Keyword(s):

Cyanuric Acid ◽

Reproductive Toxicity ◽

Male Mice

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Reproductive toxicity assessment of Senecio scandens extract in kunming mice

Indian Journal of Animal Research ◽

10.18805/ijar.b-1089 ◽

2019 ◽

Author(s):

Lartey Kwame Ayisi ◽

Nie Fang-Hong ◽

Yu Zeng-Jie ◽

Lin Hong-Ying ◽

Yang Fan ◽

...

Keyword(s):

Reproductive Toxicity ◽

Assessment Method ◽

Toxicity Assessment ◽

Low Doses ◽

Female Mice ◽

Three Phase ◽

Sperm Abnormality ◽

High Doses ◽

Dose Response Effect ◽

Toxicity Effects

This study assessed the effects of Senecio scandens Buch. Ham.extract on reproductive spectrum in female mice using a three phase reproductive assessment method. Sperm abnormality rate was used to evaluate effect on genetic reproductive toxicity. Senecio scandens extract was relatively non-toxic at low doses in all phases of reproduction in female mice. However, it showed a dose-response effect on sperm abnormality rate, and at high doses has the potential to induce genetic reproductive toxicity in male mice. It is suggested that the well-understood pharmacological benefits of S. scandens extract as an herbal medicine far outweigh the minimal reproductive toxicity effects observed in this study.

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Sperm Quality in Mouse After Exposure to Low Doses of TCDD

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190520090132 ◽

2019 ◽

Vol 19 (11) ◽

pp. 931-943 ◽

Cited By ~ 1

Author(s):

Heba Yehia Anwar Elsayed ◽

Esvieta Tenorio Borroto ◽

Alberto Barbabosa Pliego ◽

Jorge Acosta Dibarrat ◽

Fabiola Rivera Ramirez ◽

...

Keyword(s):

Sperm Quality ◽

Reproductive Toxicity ◽

Negative Control ◽

Environmental Pollutant ◽

The Body ◽

Control Group ◽

Low Doses ◽

Abnormal Head ◽

Harmful Use ◽

High Doses

Background: In the last decade, the harmful use of dioxin has been demonstrated in human health and in the whole environment. It is well known among scientists that 2, 3, 7, 8-tetrachloro dibenzo-p-dioxin (TCDD) is an environmental pollutant that causes endocrine disruption, which causes male reproductive toxicity. Objective: The objective of the present study was to evaluate the toxicity effect of low doses of TCDD in male CD1 mice. Materials and Methods: Three concentrations of TCDD (0.375, 0.75, 1.5 mg / kg) were analyzed and the effects on spermatozoa were evaluated 10 days after oral administration of the product. As bioindicators of TCDD toxicity, an exhaustive analysis of several spermatic parameters including motility, vitality, count, morphology and viability, flow cytometry was used to determine the affected sperm population by cytotoxicity and apoptosis. In addition, a morphometric analysis of testicles was performed. Results: The results show that the body weight of the treated animals was reduced in medium and high doses (0.75, 1.5 mg / kg) with respect to the control groups. In the groups treated with TCDD, the abnormal head of the sperm increased by 52.5% more than the control group. Significant differences in apoptosis were observed between the negative control and vehicle control, including the median dose (0.75 mg / kg). Conclusion: It is concluded that at these low doses there was an impact on the quality of the mouse sperm, adding an effect on apoptosis and cytotoxicity of sperm exposed to these doses of TCDD.

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Evaluation of the Reproductive Toxicity and Embryotoxicity of Insulin Glargine (LANTUS) in Rats and Rabbits

International Journal of Toxicology ◽

10.1080/10915810290096315 ◽

2002 ◽

Vol 21 (3) ◽

pp. 181-189 ◽

Cited By ~ 50

Author(s):

Thomas Hofmann ◽

Georg Horstmann ◽

Ingo Stammberger

Keyword(s):

Insulin Glargine ◽

Reproductive Toxicity ◽

Female Rats ◽

Nph Insulin ◽

Duration Of Action ◽

Prolonged Duration ◽

Female Wistar Rats ◽

Pregnancy And Lactation ◽

High Doses ◽

Premature Dropout

Insulin glargine (LANTUS) is a new insulin analog that has a prolonged duration of action with no pronounced peak of activity, rendering it an ideal basal insulin for the treatment of diabetes. The aim of these studies was to assess the reproductive and embryotoxicity of insulin glargine. Reproductive toxicity was assessed in 25 male and 25 female Wistar rats per group treated with a daily subcutaneous injection of control; 1 IU/kg, 3 IU/kg, and 10 IU/kg insulin glargine; or 3 IU/kg NPH insulin in the premating and mating periods, and throughout pregnancy and lactation in the females. Embryotoxicity was assessed in 20 female rats per group injected with daily subcutaneous doses of control; 2 IU/kg, 6.3 IU/kg, and 20 IU/kg insulin glargine; or 6.3 IU/kg NPH insulin from the 7th to 18th day of pregnancy. Embryotoxicity was also assessed in 20 female rabbits per group treated with 0 IU/kg, 0.5 IU/kg, 1 IU/kg, and 2 IU/kg insulin glargine, or 1 IU/kg NPH insulin from the 6th to 18th day of pregnancy. The data demonstrated that, with the exception of toxicologic effects induced by hypoglycemia in response to high doses of insulin glargine and NPH insulin (including the premature dropout of female rats in the reproductive toxicity study, and increased incidence of abortions, early intrauterine deaths, and single anomalies in the rabbit embryotoxicity study), insulin glargine had no effects on reproduction, embryofetal development, and postnatal development in rats. Maternal and embryofetal toxicity in rabbits treated with middle and high doses of insulin glargine was related to the hypoglycemic effect of insulin.

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Monosodium glutamate (MSG):promoter of neurotoxicity, testicular impairment, inflammation and apoptosis in male rats

Swedish Journal of BioScience Research ◽

10.51136/sjbsr.2020.78.90 ◽

2020 ◽

Vol 1 (2) ◽

pp. 78-90

Author(s):

Heba M. Abdou ◽

Eman H. Hassan ◽

Rania Gaber Aly

Keyword(s):

Sperm Count ◽

Monosodium Glutamate ◽

Food Additives ◽

Reproductive Toxicity ◽

Male Rats ◽

Sexual Hormones ◽

Group I ◽

Male Wistar Rats ◽

High Doses ◽

Testicular Impairment

Monosodium glutamate (MSG) is one of the most common food additives extensively used as a flavor enhancer. MSG induced lipid peroxidation and inflammation. The present study aimed to assess the neurotoxicity, testicular impairment, inflammation and apoptosis induced by MSG. Thirty adult male Wistar rats, weighing about 180-200 g were assigned equally into five groups, each consists of six rats. Animals of Group I are controls and they received distilled water, whereas animals of Groups II, III, IV and V were given oral daily doses of MSG 0.8, 1, 2 and 3 g/kg body weight, respectively for consecutive 70 days. Administration of different doses of MSG revealed a significant elevation in the levels of malondialdehyde (MDA), nitric oxide (NO), β amyloid 1-42, proinflammatory cytokines (IL-6, TNF-α), cholesterol and sperm abnormality while it showed reduction in the level of GSH and SOD, CAT and GST antioxidant enzymes activities, sperm count and sperm motility. MSG led to disruption in neurotransmitter levels; serotonin, norepinephrine, glutamate and GABA, also disorders in sexual hormones; testosterone, FSH and LH. The present results were confirmed by histological and immunohistochemical observations that obviously designate the neurodegeneration and reproductive toxicity. In conclusion, administration of low and high doses of MSG provoke deleterious effects on oxidant/ antioxidant markers, neurotransmitters, inflammatory cytokines, sexual hormones, brain and testes structures. Prominence hazards of lasting exposure to low and high doses of MSG on neuronal and testicular health. Therefore, its use should be restricted.

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Atrazine Induces the Cytotoxicity of Ovarian Granulosa Cells via Inhibition of Nrf2-Mediated Defense Response

10.21203/rs.3.rs-974961/v1 ◽

2021 ◽

Author(s):

Xiao-Wei Li ◽

Xue-Nan Li ◽

Milton Talukder ◽

Ying-Xin Zhao ◽

Jia-Gen Cui ◽

...

Keyword(s):

Reproductive Toxicity ◽

Control Group ◽

Defense System ◽

Main Metabolite ◽

Related Factors ◽

Uniform Size ◽

Normal Morphology ◽

Ovarian Granulosa Cells ◽

Potential Risks ◽

High Doses

Abstract Atrazine (ATR) is a commercial herbicide, which is widely used worldwide. Diaminochlorotriazine (DACT) is the main metabolite of ATR, which poses potential risks to ecosystem and health. However, the mechanism of ATR and DACT on ovarian granulocyte cells (GCs) is still not clear. To investigate the toxic effect of ATR and DACT in quail ovarian GCs. We established primary ovarian GCs as models. GCs were cultured with ATR (20, 100, and 250 µM) and DACT (20, 100 and 200 µM). Which showed normal morphology and uniform size in GCs of the control group, ovarian GCs are specifically identified, in which cell purity was above 90%. The half-inhibitory concentrations (IC50) of ATR and DACT were 261.20 µM and 214.17 µM, respectively. High doses of ATR and DACT caused changes in the ultrastructure of mitochondria, leading to oxidative stressand changes in apoptosis-related indicators, ATR and DACT activated Nrf2-mediated defense system-related factors. Our research showed that ATR and DACT are cytotoxic to GCs. ATR induced oxidative stress in ovarian GCs and activated Nrf2-mediated antioxidant signaling pathway to alleviate the toxicity of ATR. These results suggested useful evidence to investigate the female reproductive toxicity of ATR and DACT.

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Ultrastructural Localization of Acetylcholinesterase in the Arcuate Nucleus and Median Eminence of the Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100079644 ◽

1977 ◽

Vol 35 ◽

pp. 440-441

Author(s):

K.A. Carson ◽

C.B. Nemeroff ◽

M.S. Rone ◽

J.S. Kizer ◽

J.S. Hanker

Keyword(s):

Choline Acetyltransferase ◽

Median Eminence ◽

Arcuate Nucleus ◽

Cholinergic Neurons ◽

Ultrastructural Localization ◽

Male Rats ◽

Neonatal Rats ◽

Good Marker ◽

Chemical Studies ◽

High Doses

Biochemical, physiological, pharmacological, and more recently enzyme histo- chemical data have indicated that cholinergic circuits exist in the hypothalamus. Ultrastructural correlates of these pathways such as acetylcholinesterase (AchE) positive neurons in the arcuate nucleus (ARC) and stained terminals in the median eminence (ME) have yet to be described. Initial studies in our laboratories utilizing chemical lesioning and microdissection techniques coupled with microchemical and light microscopic enzyme histo- chemical studies suggested the existence of cholinergic neurons in the ARC which project to the ME (1). Furthermore, in adult male rats with Halasz deafferentations (hypothalamic islands composed primarily of the isolated ARC and the ME) choline acetyltransferase (ChAc) activity, a good marker for cholinergic neurons, was not significantly reduced in the ME and was only somewhat reduced in the ARC (2). Treatment of neonatal rats with high doses of monosodium 1-glutamate (MSG) results in a lesion largely restricted to the neurons of the ARC.

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Hexachlorobenzene toxicity in the monkey ovary: III. Ultrastructure induced by high (10 mg/kg) dose exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084958 ◽

1991 ◽

Vol 49 ◽

pp. 130-131

Author(s):

A. Singh ◽

A. Dykeman ◽

J. Jarrelf ◽

D. C. Villeneuve

Keyword(s):

Present Report ◽

Reproductive Toxicity ◽

Control Group ◽

Primate Model ◽

Human Follicular Fluid ◽

Thin Sections ◽

Cynomolgus Monkeys ◽

Cacodylate Buffer ◽

Induction Cycle ◽

Comprehensive Study

Hexachlorobenzene (HCB), a persistent and mobile organochlorine pesticide, occurs in environment. HCB has been shown to be present in human follicular fluid. An objective of the present report, which is part of a comprehensive study on reproductive toxicity of HCB, was to determine the cytologic effects of the compound on ovarian follicles in a primate model.Materials and Methods. Eight Cynomolgus monkeys were housed under controlled conditions at Animal facility of Health and Welfare, Ottawa. Animals were orally administered gelatin capsules containing HCB mixed with glucose in daily dosages of 0.0 or 10 mg/kg b.w. for 90 days; the former was the control group. On the menstrual period following completion of dosing, the monkeys underwent an induction cycle of superovulation. At necropsy, one-half of an ovary from each animal was diced into ca. 2- to 3-mm cubed specimens that were fixed by immersion in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3). Subsequent procedures followed to obtain thin sections that were examined in a Hitachi H-7000 electron microscope have been described earlier.

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Hexachlorobenzene toxicity in the rat ovary: II. Ultrastructure induced by medium (10 mg/kg) dose exposure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012374x ◽

1992 ◽

Vol 50 (1) ◽

pp. 668-669

Author(s):

Amreek Singh ◽

Warren G. Foster ◽

Anna Dykeman ◽

David C. Villeneuve

Keyword(s):

Germ Cells ◽

Primordial Germ Cells ◽

Surface Epithelium ◽

Morphological Parameters ◽

Comprehensive Investigation ◽

Ovary Surface Epithelium ◽

Rat Ovary ◽

High Doses

Hexachlorobenzene (HCB) is a known toxicant that is found in the environment as a by-product during manufacture of certain pesticides. This chlorinated chemical has been isolated from many tissues including ovary. When administered in high doses, HCB causes degeneration of primordial germ cells and ovary surface epithelium in sub-human primates. A purpose of this experiment was to determine a no-effect dose of the chemical on the rat ovary. The study is part of a comprehensive investigation on the effects of the compound on the biochemical, hematological, and morphological parameters in the monkey and rat.

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