Change of Embryotoxic Effects of Metal Citrates Depending on the Duration of Their Introduction

Given the increase in cadmium in the environment (air, soil, water) through modern industrial processes, the absorption of significant amounts from cigarette smoke is relevant to studying the effect of cadmium compounds on embryogenesis. The purpose of the study: experimental study and comparison of embryolethality and embryotoxicity of metal citrates depending on the duration of their intragastric administration (during 13 and 20 days of gestation). Materials and methods. The study was performed on 120 white adult female Wistar rats that weigh 170-200 g. They were divided into 6 groups due to the intragastric administration of solutions of the studied metals – rats treated with citrates: cadmium at a dose of 1.0 mg/kg – 1st group (nfemale = 20, nemb = 166); cadmium at a dose of 1.0 mg/kg and cerium (1.3 mg/kg) – 2nd group (nfemale = 20, nemb = 185); cadmium in a dose of 1.0 mg/kg and germanium (0.1 mg/kg) – 3rd group (nfemale = 20, nemb = 184); cadmium at a dose of 1.0 mg/kg and zinc (1.5 mg/kg) – 4th group (nfemale = 20, nemb = 179); cadmium at a dose of 1.0 mg/kg and nanocomposite (iodine + sulfur + selenium) at a dose of 2.0 mg/kg – 5th group (nfemale = 20, nemb = 180), 6th group – control (nfemale = 20, nemb = 212) – proportional volume of sterile saline in the same way. Females were divided into 2 subgroups of 10 animals each, depending on the duration of administration of test substances. The embryotoxic and embryolethal effects of the test substances were evaluated according to generally accepted criteria, which were calculated according to well-known formulas. Results and discussion. Cadmium compounds harm the embryogenesis of rats in the experimental groups and increase the rates of embryolethality. The most pronounced differences in these parameters concerning the control were found in animals with isolated exposure to cadmium citrate: the rates of total embryonic mortality increased by 4.0 times in both study periods of embryogenesis and 20% from the 13th to the 20th day; increased pre-implantation mortality by 6.0 times with an increase in post-implantation mortality by 3 times on the 13th day and by 15.0 times and 2.8 times on the 20th day of embryogenesis, respectively. Depending on the duration of introduction, the indicators of pre-implantation mortality increased by 25.0% with an increase in post-implantation mortality by 22.2% in the same period. The experimental group of exposure to cadmium citrate at a dose of 1.0 mg/kg recorded the lowest indicators of the number of live fetuses and intrauterine survival with the highest resorption rate studied of embryonic development. At the same time, in the groups of combined exposure to cadmium citrate with metal citrates, a decrease in the indicators of total embryonic mortality was 50.0% - 30.0%, pre-implantation mortality – 50.0% - 25.0%, post-implantation mortality – 60.0% - 44.4 % and increase in the number of fetuses per female – 12.7% - 25.3%. Conclusion. Analysis of the results shows a pronounced embryotoxic effect of cadmium citrate at a dose of 1.0 mg/kg on the processes of embryogenesis, which is a significant increase in overall embryonic mortality, preimplantation, and postimplantation mortality compared with the control group in all studied terms. In the groups of combined action of cadmium citrate with metal citrates, the data obtained indicate a decrease in the accumulation of cadmium under the influence of the studied citrates, which allows them to be considered as potential bioantagonists of cadmium citrate

Do Single-Component and Mixtures Selected Organic UV Filters Induce Embryotoxic Effects in Zebrafish (Danio rerio)?

UVs are important ingredients in common cosmetic products (e.g., sunscreens, hairsprays, soap). After their use, they can enter the aquatic ecosystem and negatively affect non-target aquatic organisms. The aim of our study was to evaluate acute embryotoxicity of selected organic UVs 2-phenylbenzimidazole-5-sulfonic acid (PBSA), ethylhexyl methoxycinnamate (EHMC), octocrylene (OC), 4-methylbenzylidene camphor (4-MBC) and benzophenone-3 (BP-3). The chemicals were tested both as a single substance and their mixtures. The types of mixtures were chosen as follows: the combination of OC and 4-MBC; the combination of PBSA, EHMC and BP-3 and the combination of all five UV filters. The embryotoxicity was evaluated using a modified method of the Fish Embryo Acute Toxicity Test-OECD guideline 236 and zebrafish (Danio rerio) was selected as a suitable fish model organism. The toxic effects were studied by assessing mortality, hatching and the occurrence of malformations at 24, 48, 72 and 96 h post fertilization. The obtained results indicate that especially the mixture of OC and 4-MBC presents a potential risk of embryotoxicity for zebrafish due to a significant increase in mortality, which was 41.7% in the experimental group exposed to 10 μg/L at 96 h post fertilization. Based on our results, the most effected sub-lethal endpoints were hatching and malformation (e.g., edema of pericard, bent spine, yolk edema), but with no statistically significant effect. These results differ within groups with single UVs and with their mixtures, suggesting the interaction of these substances when they are exposed together.

The Embryotoxic Effects of in Ovo Administered Sunset Yellow FCF in Chick Embryos

Sunset yellow (SY) at prescribed concentrations has been approved by regulatory authorities in several countries as an additive dye in the food, beverage, cosmetic, and pharmaceutical industries. However, there are some reports that it may cause several health problems. The aim of this study is to evaluate embryotoxic effects of SY on liver and kidney in chick embryos. Babcock white Leghorn eggs were randomly divided into four groups. Non-treated eggs served as control group. The eggs in groups SY200, SY1000, and SY2000 were treated with a single injection of 200, 1000, and 2000 ng SY into the air sac just before incubation. The developmental stages of embryos were determined on the 10th, 13th, 16th, and 21st days of incubation. Samples of the liver and kidney were taken and routine histological procedures were performed. The highest relative embryo weight was seen in all SY treated groups on the 16th day of incubation. Necrosis of some hepatocytes and cytoplasmic degenerations were observed in all SY groups in the liver. There were degenerated or destructed renal cortex structures and necrosis in the kidney. The cell’s nuclear areas and diameters of renal cortex structures were different in all SY groups compared to the control group (p < 0.05). It was concluded that in ovo administered SY has many unfavorable effects on liver and kidney in chick embryos. The results obtained in this study suggest that it may be advisable to re-assess safety levels of SY in many industries.

Premature senescence of placental decidua cells as a possible cause of miscarriage produced by mycophenolic acid

Background Successful pregnancy is supported by a healthy maternal–fetal interface (i.e., the decidual tissues) which holds the conceptus and safeguards it against stressors from the beginning of pregnancy. Any disturbance of this interface can presumably lead to the loss of pregnancy. The use of the immunosuppressive drug mycophenolic acid (MPA) should be discontinued in pregnancy given its abortive and embryotoxic effects. Direct teratogenic effects have been observed in mammalian embryos cultured in MPA, but the underlying mechanisms of abortion by MPA are less understood. Methods Decidual stromal cells isolated from human placentas are cultured in the presence of clinically relevant doses of MPA. Data regarding the effects of MPA on the proliferation and viability of decidua cultures are first analysed and then, molecular pathways contributing to these effects are unravelled. Results MPA treatment of decidual stromal cells results in loss of proliferation capacity and a decrease in the viability of decidua cultures. The molecular pathways involved in the effects of MPA on decidual stromal cells are a reduction in pre-rRNA synthesis and subsequent disruption of the nucleolus. The nucleolar stress stabilizes p53, which in turn, leads to a p21–mediated cell cycle arrest in late S and G2 phases, preventing the progression of the decidua cells into the mitosis. Furthermore, MPA does not induce apoptosis but activate mechanisms of autophagy and senescence in decidual stromal cells. Conclusion The irreversible growth arrest of decidua cells, whose role in the maintenance of the pregnancy microenvironment is known, may be one cause of miscarriage in MPA treated pregnant women.

Pharmacotherapy in pregnant women

Aim: to analyze the prescription of medications in pregnant women based on outpatient charts of women’s clinics. Patients and Methods: retrospective cohort study was conducted in three women’s clinics of Perm and two women’s clinics of Izhevsk. Data on the prescription of medications in 361 pregnant and postpartum women during pregnancy (2017–2018) were obtained by copying individual medical charts. Additionally, we compared our findings with the results of the Russian Pharmacoepidemiologic Study (2007). Results: pharmacotherapy was prescribed in 100% of women. On average, 12.6 medications were prescribed during gestation. Most medications were prescribed in the second trimester (on average, 5.5 medications). In the first and third trimesters, 2.4 and 4.7 medications were prescribed, respectively. The most prescribed drugs were vitamins and minerals (70.4%), feminine hygiene products (37.1%), progestogens (33.1%), herbal urinary antiseptics (29.8%), and systemic antibiotics (14.2%). Pharmacotherapy defects included medications inconsistent with diagnosis (48.6%), a combination of several drugs with similar pharmacological effects (16.5%), and polypharmacy defined as the use of five or more medications (25.8%). A two-fold reduction in drug aggression as well as an increase in the dotation of vitamin-mineral complexes compared to 2007 were reported. Conclusions: our findings illustrate positive trends for treating pregnant women in the last 9–10 years and increased safety of treatment (the lack of drugs with potential teratogenic or embryotoxic effects) but also indicate the need in the permanent audit and adjustment of prescriptions based on clinical guidelines. Pre-pregnancy preparation is a perspective way to reduce the intensity of drug therapy during pregnancy. As a result, drug burden shifts to a pre-gestational period. Pre-pregnancy preparation provides favorable conditions for developing an embryo and fetus. KEYWORDS: pharmacotherapy, pregnancy, polypharmacy, micronutrients, vaginal hygiene, progestogens, urinary antiseptics. FOR CITATION: Sandakova E.A., Zhukovskaya I.G., Semenova M.V. et al. Pharmacotherapy in pregnant women. Russian Journal of Woman and Child Health. 2021;4(2):115–118. DOI: 10.32364/2618-8430-2021-4-2-115-118.

The protective effect of Zataria Multiflora on the embryotoxicity induced by bisphenol A in the brain of chicken embryos

Bisphenol A (BPA), is one of the main industrial chemicals synthesized for various purposes. In the present study, the brain tissue of chicken embryos was used to evaluate the embryotoxic effects of BPA and also the preventive effects of Zataria multiflora. To that end, fertile eggs were categorized into four groups (n=10). The eggs air sacs of the experimental groups were injected BPA (200 ppm) after four days.. The Zataria multiflora (100 and 200 µg/egg) was administered into chick embryos 6 hours prior to administration of BPA. The control group simply was treated with olive oil. The eggs were incubated at 37°C and a humidity of 63%. After 20 days, the embryos were beheaded and the brains were gathered for biochemical measurements. The findings indicated that Zataria multiflora (200 µg/egg) significantly reversed the increased levels of MDA (p<0.05) and protein (p<0.001) in the brain of BPA-exposed group and also the decreased levels of total antioxidant and GSH as well as the CAT and SOD activities in the brain of BPA-exposed group. Zataria multiflora reversed the toxic effects of BPA on the embryonic development stages of the brain via modulating oxidative stress.

Effects of cannabinoids on the development of chick embryos in ovo

We have examined the effects of the synthetic cannabinoids HU 210 and HU 211, the plant-derived cannabidiol and the endogenous cannabinoid anandamide on the viability and development of chick embryos. Fertilized White Leghorn chicken eggs were injected with the test compounds or carrier vehicle, via a drilled small hole in the egg, directly into the egg yolk. After nine days of exposure, the embryonal viability, length and wet weight of embryos, and wet weight of brains were measured, and the development stages were assessed according to the Hamburger and Hamilton (HH) scale. The potent synthetic cannabinoid receptor agonist HU 210 and the non-psychotropic cannabidiol were embryotoxic at the highest concentrations examined (10 µM and 50 µM, respectively), with no viable embryos after the HU 210 injection, and 20% viability after the cannabidiol injections. The effects of HU 210 on the chick embryo were attenuated by α-tocopherol and the cannabinoid receptor antagonist AM251, whereas only α-tocopherol gave a statistically significant protection against the embryotoxic effects of cannabidiol. This study shows that exposure to plant-derived or synthetic cannabinoids during early embryonal development decreases embryonal viability. Extrapolation of data across species is of course difficult, but the data would argue against the use of cannabinoids, be it recreationally or therapeutically, during pregnancy.