Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats.

Metronidazole is the primary antimicrobial drug for treating acute and chronic vaginal pathogens during pregnancy; however, there has been insufficient research on placental disorders, early pregnancy loss, and preterm birth. Here, the potential activity of metronidazole on pregnancy outcomes was investigated. 130 mg/kg body weight of metronidazole was orally given individually to pregnant rats on gestation days 0-7, 7-14, and 0-20. Pregnancy outcome evaluations were carried out on gestation day 20. It was demonstrated that metronidazole could induce maternal and fetal hepatotoxicity. There is a significant increase in the activities of maternal hepatic enzymes (ALT, AST, and ALP), total cholesterol, and triglycerides compared with the control. These biochemical findings were evidenced by maternal and fetal liver histopathological alterations. Furthermore, metronidazole caused a significant decrease in the number of implantation sites and fetal viability, whereas it caused an increase in fetal lethality and the number of fetal resorptions. In addition, a significant decrease in fetal weight, placental weight, and placental diameter was estimated. Macroscopical examination revealed placental discoloration and hypotrophy in the labyrinth zone and the degeneration of the basal zone. The fetal defects are related to exencephaly, visceral hernias, and tail defects. These findings suggest that the administration of metroniazole during gestation interferes with embryonic implantation and fetal organogenesis and enhances placental pathology. We can also conclude that metronidazole has potential maternal and fetal risks and is unsafe during pregnancy. Additionally, it should be strictly advised and prescribed, and further consideration should be given to the associated health risks.

In ovo Inoculation of Bacillus subtilis and Raffinose Affects Growth Performance, Cecal Microbiota, Volatile Fatty Acid, Ileal Morphology and Gene Expression, and Sustainability of Broiler Chickens (Gallus gallus).

Banning antibiotic growth promoters has negatively impacted poultry production and sustainability, which led to exploring efficient alternatives such as probiotics, probiotics, and synbiotics. Effect of in ovo injection of Bacillus subtilis, raffinose, and their synbiotics on growth performance, cecal microbial population and volatile fatty acid concentration, ileal histomorphology, and ileal gene expression was investigated in broilers (Gallus gallus) raised for 21 days. On 300 h of incubation, a total of 1,500 embryonated eggs were equally allotted into 10 groups. The first was non-injected (NC) and the remaining in ovo injected with sterile distilled water (PC), B. subtilis 4 × 105 and 4 × 106 CFU (BS1 and BS2), Raffinose 2 and 3 mg (R1 and R2), B. subtilis 4 × 105 CFU + raffinose 2 mg (BS1R1), B. subtilis 4 × 105 CFU + raffinose 3 mg (BS1R2), B. subtilis 4 × 106 CFU + raffinose 2 mg (BS2R1), and B. subtilis 4 × 106 CFU + raffinose 3 mg (BS2R2). At hatch, 60 chicks from each group were randomly chosen, divided into groups of 6 replicates (10 birds/replicate), and fed with a corn-soybean-based diet. In ovo inoculation of B. subtilis and raffinose alone or combinations significantly improved body weight, feed intake, and feed conversion ratio of 21-day-old broilers compared to NC. Cecal concentrations of butyric, pentanoic, propionic, and isobutyric acids were significantly elevated in R1, R2, BS2R1, and BS2R2, whereas isovaleric and acetic acids were significantly increased in R1 and BS2R1 compared to NC. Cecal microbial population was significantly altered in treated groups. Ileal villus height was increased (p < 0.001) in BS1, R2, and BS2R2 compared to NC. The mRNA expression of mucin-2 was upregulated (p < 0.05) in synbiotic groups except for BS1R1. Vascular endothelial growth factor (VEGF) expression was increased (p < 0.05) in BS2, R1, BS1R1, and BS1R2 compared to NC. SGLT-1 expression was upregulated (p < 0.05) in all treated birds except those of R1 group compared to NC. The mRNA expressions of interleukin (IL)-2 and toll-like receptor (TLR)-4 were downregulated (p < 0.05) in BS2 and R1 for IL-2 and BS1R1 and BS2R2 for TLR-4. It was concluded that in ovo B. subtilis, raffinose, and synbiotics positively affected growth performance, cecal microbiota, gut health, immune responses, and thus the sustainability of production in 21-day-old broilers.

Managing Gut Microbiota through In Ovo Nutrition Influences Early-Life Programming in Broiler Chickens.

The chicken gut is the habitat to trillions of microorganisms that affect physiological functions and immune status through metabolic activities and host interaction. Gut microbiota research previously focused on inflammation; however, it is now clear that these microbial communities play an essential role in maintaining normal homeostatic conditions by regulating the immune system. In addition, the microbiota helps reduce and prevent pathogen colonization of the gut via the mechanism of competitive exclusion and the synthesis of bactericidal molecules. Under commercial conditions, newly hatched chicks have access to feed after 36-72 h of hatching due to the hatch window and routine hatchery practices. This delay adversely affects the potential inoculation of the healthy microbiota and impairs the development and maturation of muscle, the immune system, and the gastrointestinal tract (GIT). Modulating the gut microbiota has been proposed as a potential strategy for improving host health and productivity and avoiding undesirable effects on gut health and the immune system. Using early-life programming via in ovo stimulation with probiotics and prebiotics, it may be possible to avoid selected metabolic disorders, poor immunity, and pathogen resistance, which the broiler industry now faces due to commercial hatching and selection pressures imposed by an increasingly demanding market.

Disruption of brain conductivity and permittivity and neurotransmitters induced by citrate-coated silver nanoparticles in male rats.

As one of the most exonerative, competitive, and abundant nanoparticles in curative uses, silver nanoparticles (AgNPs) play a growing important role in developing global neurodegeneration. Herein, we inspected the neurotoxic and histopathological effects of the oral dose of 26.9 nm citrate-coated AgNPs (100 and 1000 mg/kgbw, 28 days) on the brain conductivity and permittivity combined with neurotransmitter assays. While male mice in the control group were given deionized water. In terms of biophysical levels, the brain electric conductivity and relative permittivity were significantly decreased in the 26.9 nm citrate-coated AgNP treated groups versus the controls. Besides, 26.9 nm citrate-coated AgNP treatment resulted in a significant deficiency in the concentrations of brain acetylcholine esterase, dopamine, and serotonin. Total brain contents of silver ion significantly increased in a dose-dependent manner. Further, light and electron microscopy revealed a progressive disruption in the lamellar pattern of the myelinated axons of the nerve fibers, in addition to the accumulation of nanosilver in lysosomes and swollen mitochondria in axoplasm. In conclusion, 26.9 nm citrate-coated AgNPs are capable of gaining access to the brain of mice and causing electric conductivity and relative permittivity damage along with a high degree of cellular toxicity in the brain tissue. Therefore, the present study highlights, for the first time, the adverse effects of the citrate-coated AgNPs to the brain of mice and raises the concern of their probable neurotoxic impacts which is helpful for conclusive interpretation of future behavioral and potential neurodegeneration-based aspects. It would be of interest to investigate citrate-coated AgNPs mediated axonal relevant-signal transduction levels in future studies.

Corrigendum to "Dietary Lipids in Health and Disease".

[This corrects the article DOI: 10.1155/2019/5729498.].

Developmental effects on hypothalamic, hypophyseal, testicular and steroidogenic patterns of sertraline-exposed male rats by accumulated doses from juvenile to puberty.

Since the enduring exposure to selective serotonin reuptake inhibitors medications from juvenile period to puberty poses a growing concern, the aim is an attempt to evaluate the reproductive aspects of sertraline-treated postnatal male rats. Total 80 male rats were orally given 1.2 mg/kg bw/day from postnatal day 28 to puberty (balano-preputial separation). Necropsy takes place at 56th, 84th, 126th postnatal day (SGII, SGIII, and SGIV, respectively), along with the control group (SGI). Final body weight, weight gain, and weights of liver, kidneys, testes and epididymis were significantly decreased in the SGIII and SGIV groups compared to the controls. Levels of LH, FSH, and testosterone and 17ß-HSD concentrations were significantly decreased in all groups. Male rats in SGIV group displayed a significant decline in sperm counts, motility and viability and increase in sperm morphological defects compared to control. The cumulative dose of 1.2 mg/kg of sertraline at the 126th postnatal days produced a significant depression in male virility (mating and fertility indices) compared to the control group. In addition, the cumulative treatment significantly increased the number of fetal resorptions in outcomes of female rats copulated by males in the SGIV group and decrease in both the number of implant sites and the viable fetuses. It is concluded that the sertraline-mediated reproductive deficits could entirely dependent on the robust spreading of the serotonergic receptors in the Leydig, Sertoli and germ cells, testis, epididymis, and vas deferens and simultaneously on the developmental-mediated timing of reproductive processes during the postnatal period to puberty.

Chronic neurodegeneration by aflatoxin B1 depends on alterations of brain enzyme activity and immunoexpression of astrocyte in male rats.

Aflatoxin B1 poses the greatest risk among the mycotoxins to target-organisms particularly human, however, no studies addressed the neurotoxicity of chronic exposure of aflatoxin. The oral dose level 1/600th of LD50 for 30, 60, and 90 days was used for three aflatoxin groups, respective to negative and vehicle control groups. Activity levels of brain antioxidants viz: superoxide dismutase, catalase, glutathione, and glutathione peroxidase significantly decreased in the three experimental durations in time-dependent trend, in contrast, lipid peroxidation showed a significant increase compared to controls. Significantly, chronic-dependent increase trend was noticed in the AF60 and AF90 group for acid phosphatase (16.1%, 35.2%), alkaline phosphatase (32.1%, 50.8%), aspartate aminotransferase (38.7%, 120.0%) and lactate dehydrogenase (30.6%, 42.1%) activities, respectively. However, a significant 23.7% decrease in the brain creatine kinase activity following 90 days of AFB1administration. Chronic administration of aflatoxin also causes alterations in activities of protein carbonyl with a maximum increase (twofold) after 90 days. Further, histopathological and immunohistochemical results confirmed time-related vasodilation, necrosis and astrocytes gliosis by high glial fibrillary acidic protein immunostaining in response to AFB1. These findings infer that long-term exposure to AFB1 results in several pathophysiological circumstances in a duration-dependent manner concerning neurodegeneration especially Alzheimer's disease.

Ginger causes subfertility and abortifacient in mice by targeting both estrous cycle and blastocyst implantation without teratogenesis.

BACKGROUND: Due to renowned medicinal properties, Ginger rhizomes (Zingiber officinale Roscoe) used traditionally in the treatment of arthritis, rheumatism, muscular aches, constipation, indigestion, hypertension, dementia, fever, and infectious diseases. As an antiemetic, Ginger is consumed by approximately 80% of pregnant women to treat nausea and vomiting of early pregnancy. PURPOSE: The aim of this study is to evaluate the impact of ginger extract on the oestrous cycle and implantation in female mice. STUDY DESIGN AND METHODS: Four experimental episodes were identified. One considered the main study of outcomes and lasted 90 days; one lasted 35 days and considered the oestrous cycle; while the third and fourth intended antifertility and abortifacient and continued 20 days for each. Mice dosed Ginger orally at 0, 250, 500, 1000 or 2000  mg/kgbw/day (GNC, GN1, GN2, GN3, GN4, respectively). RESULTS: GN3 and GN4 dams showed maternal toxicity. High dose significantly reduced the number of live fetuses and increased fetal death and resorption. Mice treated with 2000  mg/kgbw/day displayed significant decreases in implantation sites. At a dose of 2000  mg/kgbw/day, Ginger prolonged the length of oestrous cycle with a significant decrease in the duration of diestrous-metestrus (luteal) phase, prolonged proestrus-estrus (ovulatory) phase and reduced the number of cycles as well. Therefore, Ginger impairs the normal growth of corpus luteum because of progesterone insufficiency during early pregnancy. The observed-adverse-effect dose set at 2000  mg/kgbw, but no-observed-adverse-effect dose set at 250 and 500  mg/kgbw. CONCLUSION: These findings suggest that Ginger can disrupt the oestrous cycle and blastocyst implantation without teratogenesis.

In ovo toxico-teratological effects of aluminum on embryonic chick heart and vascularization.

In spite of extensive research and persistent arguments, the mechanism of aluminum (Al) toxicity is still obscure. It is firmly established that aluminum is a potent neurotoxicant. So, the aim based on is aluminum damage chicken heart, as well as the vitelline circulation. In the first 3 days of incubation (D0-D2), 1.0, 2.0, or 4.0 mg aluminum chloride/0.3 ml avian saline was injected into the center of each viable fertilized egg yolk (AL1, AL2, and AL3 groups, respectively). Control eggs were either uninjected (AL0) or injected (ALS, 0.3 ml saline). Crown rump length was significantly decreased, while, embryonic mortalities, growth delay, as well as congenital heart defects were increased in the eggs injected 2.0 or 4.0 mg of Al. Although no relationship is clear about the embryonic mortality induced by Al in chicken embryos to the dose concentration, the higher mortality occurs in early developmental stages in developing chick embryos. Furthermore, chick embryos exposed to 4.0 mg/Al showed a high incidence of defects of ventricular septation and ventricular myocardium. Configuration and density of branched vitelline vessels were also significantly deteriorated after injection with 4.0 mg/Al. It concluded that Al is a cardiac teratogen for a chick in a dose-dependent way. These data highlight a novel approach for aluminum in congenital cardiovascular defects. Therefore, further research is needed to explain the teratogenicity of Al on the embryonic heart development.

Kidney antioxidant status, biochemical parameters and histopathological changes induced by methomyl in CD-1 mice.

The widespread of pesticide in public health and agriculture has caused severe environmental pollution and health hazards. Methomyl is used worldwide in agriculture and health programs. Besides its advantages in the agriculture, it causes several toxic effects. In this study, we aimed to investigate the effects of methomyl at different time intervals on lipid peroxidation, reduced glutathione (GSH), total sulfhydryl group (T-SH), antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and histopathological changes in mice kidney. Ten CD-1 mice per group were assigned to one of four treatment groups. Group one served as control while groups 2, 3 and 4 were orally treated with 1mgmethomyl/kg BW for 10, 20 and 30 days, respectively. Methomyl significantly increased lipid peroxidation in kidney as compared to control group. Levels of GSH and T-SH and activities of SOD, CAT and GST were found to be decreased. On the other hand, methomyl significantly increased the levels of urea, uric acid and creatinine in serum. The histological examination of kidney revealed damage involving the entire renal nephrons in both 20 and 30 days of methomyl exposure. Severe dilatation of the cortical tissue, congested glomerulus with swelling of the endothelial cells and degeneration of the epithelium cells lining the tubules were observed. In conclusion, the results suggest that methomyl exposure can cause renal damage, oxidative stress, perturbations in antioxidant defense system and histopathologic changes in mice kidney in a time dependent manner.

Efficacy of Ginkgo biloba on vaginal estrous and ovarian histological alterations for evaluating anti-implantation and abortifacient potentials in albino female mice.

Ginkgo extract, EGb 761 is known as a vasoregulatory variable for the conventional reproduction therapy. EGb 761 was orally administered in 0 (control), 3.7, 7.4, and 14.8 mg/kg bw/day for 28 days (thereafter mated with normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy, respectively. Vaginal smears were performed daily. On 20th day of pregnancy, the females were killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were counted. Maternal toxicity, estrous cycle, reproductive hormones, ovarian follicle counts, resorption index, implantation index, fetal viability and fetuses, and placenta mean weights were evaluated. There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index, implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment with 14.8 mg/kg bw/day EGb 761 induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal toxicity. Therefore, the data obtained indicate that Ginkgo biloba extract at 14.8 mg/kg bw/day dose level exhibit toxic effect on reproductive cyclicity and could have anti-implantation and abotifacient properties in female mice.

Biochemical and histopathological changes induced by different time intervals of methomyl treatment in mice liver.

The present study was designed to evaluate the toxic effects induced by different time intervals of methomyl exposure on liver antioxidant defense system, oxidative stress, liver function biomarkers and histopathology in CD-1 mice. Ten male mice per group were assigned to one of four treatment groups. Group one served as control while group 2, 3 and 4 were orally treated with one mg methomyl/kg BW for 10, 20 and 30 days, respectively. Results obtained showed that methomyl significantly induced TBARS and decreased the activity of antioxidant enzymes, glutathione S-transferase, superoxide dismutase and catalase and the levels of reduced glutathione in mice liver. Aminotransferases and alkaline phosphatase activities were significantly decreased in liver due to methomyl administration, while the activities of these enzymes were significantly increased in serum. In addition, liver lactate dehydrogenase activity was significantly increased. On the contrary, methomyl treatment caused a significant decrease in liver acid phosphatase. The histology of mice liver treated with methomyl for 10, 20 and 30 days of duration showed dilation of central vein, sinusoids between hypertrophied hepatocytes and nuclear degeneration with mononuclear cell infiltration. In conclusion, exposure to methomyl induced toxicity and oxidative stress in mice liver via free radicals mechanism. Also, methomyl might have affected cell metabolism, cell membrane permeability and the detoxification system in liver.

Endocrine-disrupting and cytotoxic potential of anticholinesterase insecticide, diazinon in reproductive toxicity of male mice.

We evaluated the effects of diazinon (2, 4.1 and 8.2mg/kg bw/day for 4 weeks) in gonadotropins, testosterone and estrogen levels, whether the regulatory interactions in the hypothalamic-pituitary-testicular axis are modified by acetylcholinesterase inhibition and histopathological changes in adult mice testes. Diazinon at doses higher than 2mg/kg bw/day resulted in decreased testis weight, inhibition in acetylcholinesterase activities, decrease in levels of luteinizing hormone and follicle stimulating hormone, following reduction in mating and fertility indices. Diazinon increased testosterone content in 4.1mg/kg group, but decreased testosterone concentration in 8.2mg/kg group. Diazinon increased estrogen, prolactine and decreased levels of acetylcholinesterase activities in 4.1mg/kg group but levels of luteinizing hormone and follicle stimulating hormone remained unmodified. It may be simply postulated a scenario that acetylcholine in the cholinergic neurons has a potential threshold to perform a crucial part in the complex circuitry of neuroendocrine regulatory mechanisms. On overaccumulation, other neurotransmitters can be appropriately recruited to modulate the mechanisms of circuitry.

Evaluation of developmental toxicity induced by anticholinesterase insecticide, diazinon in female rats.

Developmental toxicities, including birth defects, are significant public health problems. This study was planned to assess the cholinergic and developmental potentials of diazinon that is widely used as an organophosphate insecticide. Pregnant female Sprague-Dawley rats were given diazinon orally at doses of 0, 1.9, 3.8, and 7.6 mg/kg body weight (b.w.)/day on gestation days 6 to 15. Maternal brain acetylcholinesterase activities, measured on gestation day20, were significantly decreased at 3.8 and 7.6 mg/kg b.w./day, but fetal acetylcholinesterase activity was not altered. Maternal toxicities, as evidenced by cholinergic symptoms including diarrhea, tremors, weakness, salivation, and decreased activities, were observed at the 3.8 and 7.6 mg/kg b.w./day dose groups. Net gravid uterine weight was decreased at a dose of 7.6 mg/kg b.w./day. No maternal effects were apparent in the 1.9 mg/kg b.w./day dose group. Maternal toxicity at a dose of 3.8 mg/kg b.w./day did not induce fetotoxicity or teratogeneicity. However, 7.6 mg/kg b.w./day doses significantly resulted in fetal toxicity and malformations in addition to maternal toxicity in animals. In conclusion, teratogenic disorders only outlined by doses that produced marked maternal toxicity. Since the malformations were not morphologically related, they were considered to be secondary to maternal toxicity; hence, the malformations were not related to cholinesterase inhibition.

Developmental toxicity of fungicide carbendazim in female mice.

This study investigated the developmental toxicity of carbendazim during the organogenesis period in mice. Mated CD-1 mice were administered carbendazim at dose levels 0, 150, 300, and 600 mg/kg/day by gavage. Body weights, weight gains, and feed consumption were significantly reduced in mice administered with 300 and 600 mg/kg/day. Carbendazim exposure increased maternal levels of cholesterol, triglyceride, glucose, protein, and creatinine; and reduced the levels of estradiol and progesterone in the 300- and 600-mg/kg/day groups. In addition, exposure to carbendazim significantly reduced the number of live fetuses and increased the number of dead and resorptions at the same dose levels. External, visceral, and skeleton malformations were observed in the 300- and 600-mg/kg/day. In conclusion, exposure of pregnant mice to carbendazim induced maternal and developmental toxicity at 300 and 600 mg/kg/day. 150 mg/kg/day carbendazim produced a very slight increase in postimplantation loss, which was within the range of historical controls, and no evidence of maternal toxicity.