scholarly journals Disruption of Folate Metabolism Causes Poor Alignment and Spacing of Mouse Conceptuses for Multiple Generations

2021 ◽  
Vol 9 ◽  
Author(s):  
Amy L. Wilkinson ◽  
Katerina Menelaou ◽  
Joanna Rakoczy ◽  
Xiu S. Tan ◽  
Erica D. Watson
Keyword(s):  
Developmental Delay ◽  
Subsequent Development ◽  
Blood Perfusion ◽  
Pedigree Analysis ◽  
Severe Form ◽  
Folate Metabolism ◽  
Neural Tube Closure ◽  
Multiple Generations ◽  
Implantation Sites ◽  
Post Implantation

Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with the hypomorphic Mtrrgt mutation. MTRR is necessary for methyl group utilisation from folate metabolism, and the Mtrrgt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrrgt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes. Notably, we report misalignment of some Mtrrgt conceptuses within their implantation sites from E6.5. The degree of misorientation occurs across a continuum, with the most severe form visible upon gross dissection. Additionally, some Mtrrgt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Skewed growth likely influences embryo development since developmental delay and heart malformations (but not defects in neural tube closure or trophoblast differentiation) associate with severe misalignment of Mtrrgt/gt conceptuses. Typically, the uterus is thought to guide conceptus orientation. To investigate a uterine effect of the Mtrrgt allele, we manipulate the maternal Mtrr genotype. Misaligned conceptuses were observed in litters of Mtrr+/+, Mtrr+/gt, and Mtrrgt/gt mothers. While progesterone and/or BMP2 signalling might be disrupted, normal decidual morphology, patterning, and blood perfusion are evident at E6.5 regardless of conceptus orientation. These observations argue against a post-implantation uterine defect as a cause of conceptus misalignment. Since litters of Mtrr+/+ mothers display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrrgt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe conceptus skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, the presence of conceptus skewing after embryo transfer into a control uterus indicates that misalignment is independent of the peri- and/or post-implantation uterus and instead is likely attributed to an embryonic mechanism that is epigenetically inherited. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. This study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.

scholarly journals Disruption of folate metabolism causes poor alignment and spacing of mouse conceptuses for multiple generations

2021 ◽  
Author(s):  
Amy L Wilkinson ◽  
Katerina Menelaou ◽  
Joanna Rakoczy ◽  
Xiu S Tan ◽  
Erica D Watson
Keyword(s):  
Developmental Delay ◽  
Subsequent Development ◽  
Blood Perfusion ◽  
Pedigree Analysis ◽  
Severe Form ◽  
Folate Metabolism ◽  
Hypomorphic Mutation ◽  
Multiple Generations ◽  
Implantation Sites ◽  
Folate Cycle

Abnormal uptake or metabolism of folate increases risk of human pregnancy complications, though the mechanism is unclear. Here, we explore how defective folate metabolism influences early development by analysing mice with an Mtrrgt hypomorphic mutation. MTRR is necessary for methyl group utilisation from the folate cycle, and the Mtrrgt allele disrupts this process. We show that the spectrum of phenotypes previously observed in Mtrrgt/gt conceptuses at embryonic day (E) 10.5 is apparent from E8.5 including developmental delay, congenital malformations, and placental phenotypes (e.g., eccentric chorioallantoic attachment). Notably, we report misalignment of some Mtrrgt conceptuses within their implantation sites from E6.5. The degree of skewed growth occurs across a continuum, with eccentric chorioallantoic attachment now re-characterised as a severe form of conceptus misalignment. Additionally, some Mtrrgt/gt conceptuses display twinning. Therefore, we implicate folate metabolism in blastocyst orientation and spacing at implantation. Embryo development is influenced by skewed growth since developmental delay and heart malformations (but not neural tube defects) associate with severe misalignment of Mtrrgt/gt conceptuses. Patterning of trophoblast lineage markers is largely unaffected in skewed Mtrrgt/gt conceptuses at E8.5 indicating trophoblast differentiation was normal when misaligned. Typically, the uterus guides conceptus orientation. Accordingly, we manipulate the maternal Mtrr genotype and assess conceptus alignment. Mtrr+/gt, and Mtrrgt/gt mothers, plus Mtrr+/+ mothers, exhibit misaligned conceptuses at E6.5. While progesterone and/or BMP2 signalling required for decidualisation might be disrupted, normal gross decidual morphology, patterning, and blood perfusion is evident regardless of conceptus alignment, arguing against a uterine defect. Given the important finding that Mtrr+/+ mothers also display conceptus misalignment, a grandparental effect is explored. Multigenerational phenotype inheritance is characteristic of the Mtrrgt model, though the mechanism remains unclear. Genetic pedigree analysis reveals that severe skewing associates with the Mtrr genotype of either maternal grandparent. Moreover, misalignment is independent of the uterus and instead is attributed to an embryonic mechanism based on blastocyst transfer experiments. Overall, our data indicates that abnormal folate metabolism influences conceptus orientation over multiple generations with implications for subsequent development. Our study casts light on the complex role of folate metabolism during development beyond a direct maternal effect.

Reproductive performance over repeated parities of lines of mice selected for appetite, lean growth and fatness

1986 ◽  
Vol 42 (3) ◽  
pp. 397-410 ◽  
Author(s):  
F. D. Brien ◽  
W. G. Hill
Keyword(s):  
Body Weight ◽  
Litter Size ◽  
Lean Mass ◽  
Reproductive Performance ◽  
Late Pregnancy ◽  
Reproductive Rate ◽  
Lean Growth ◽  
Implantation Sites ◽  
Average Total Number ◽  
Post Implantation

ABSTRACTFemale reproductive performance over four parities was studied for lines of mice selected for one three criteria: appetite (A), total lean mass (P), or proportion of fat (F). Female mice were first bred 8 weeks of age, and thereafter at intervals of about 7 weeks until fourth parity when they were dissected in late pregnancy to measure components of litter size.The high A lines had higher litter sizes at the first three parities and higher ovulation rates, numbers of implantation sites and live foetuses at the fourth parity than the low A lines. The high P lines were also higher than the low P lines for each of these traits. In contrast, litter sizes and ovulation rates differed little between the high and low F lines. Fitting body weight as a covariate removed the high-low differences in ovulation rate and litter size between the P lines, but not all the differences between the A lines.Pre-implantation survival at the fourth parity was slightly lower in the high than in low A and in high than in low P lines. Differences in post-implantation survival were very small. No component of prenatal survival differed substantially at fourth parity between the high and low F lines.Differences in fertility at each parity and the percentages of females surviving to the end of the study were small. At each litter, dams of the high A lines produced heavier total weights of litters at 12 and 21 days than dams of the low A lines and the corresponding high-low differences in the P lines were larger. There were only small differences in these traits between the F lines. When litter size, fertility and survival were summed over parities, the average total number of young produced per female was substantially higher in the high than in the low A lines (5·0 young born alive or dead) and the P lines (7·2), but the high-low difference was small in the F lines (2-0). For all lines, litter size at first parity gave a reliable indication of reproductive rate during a major portion of the reproductive lifespan.

scholarly journals Evaluation of the Reproductive Ability of Male Rats in Acute Toxoplasmosis

2021 ◽  
Vol 6 (4) ◽  
pp. 44-49
Author(s):  
M. S. Kosova ◽  
◽  
E. S. Pashinskaya ◽  
Keyword(s):  
Body Weight ◽  
Toxoplasma Gondii ◽  
Female Rats ◽  
Reproductive Capacity ◽  
Male Rats ◽  
Reproductive Ability ◽  
Male Wistar Rats ◽  
Implantation Sites ◽  
Acute Toxoplasmosis ◽  
Post Implantation

Toxoplasmosis is a parasitic disease of humans and animals caused by Toxoplasma gondii. Toxoplasma is an intracellular parasite that belongs to the simplest and has a complex development cycle. Infection with Toxoplasma is possible orally, transplacentally, percutaneously (if the integrity of the skin is damaged). This invasion is often the cause of problems with bearing pregnancy, as well as the development of congenital anomalies in children. The purpose of the study was to study the reproductive ability of male rats in acute toxoplasmosis. Materials and methods. The experiment was performed on 90 female and 45 male Wistar rats with a body weight of 180-200 g. The intact control males were orally injected with 2 ml of 0.2% starch gel. Experimental groups of males were infected with an invasive Toxoplasma gondii culture at a dose of 25 tachyzoites per 1 g of body weight (5000 tachyzoites per rat) and 50 tachyzoites per 1 g of body weight (10000 tachyzoites per rat). Then the males of all groups were coupled with the females for 3 days. The effect of toxoplasmas on the reproductive ability of male rats was assessed by the development of pregnancy and changes in the levels of pre- and post-implantation embryo death in female rats on the 7th, 14th, and 21st days after pregnancy. To account for changes in the pre- and post-implantation death of embryos in female rats after removal from the experiment, the uterus and ovaries were isolated, the uterine horns were opened, the number of implantation sites, the total number of embryos, the number of living and dead embryos, the number of resorption, and the number of yellow bodies in the ovaries were determined. Results and discussion. In the females of the 4th, 5th and 6th groups (coupling with males infected at the dose of 25 tachyzoites per 1 g of body weight), a decrease in the number of implantation sites in the uterus, the total number of embryos and the number of live embryos was recorded by 1.8-1.9 times compared to the control parameters. In female rats of the 7th, 8th and 9th groups (coupling with males infected at the dose of 50 tachyzoites per 1 g of body weight), there was a decrease in the number of implantation sites in the uterus, the total number of embryos and the number of live embryos by 5.6-6.8 times compared to the control. When compared to the results obtained from the females of the 4th, 5th and 6th groups, a decrease in these indicators was recorded by 3.1-3.5 times. Conclusion. Toxoplasma gondii has an effect on reproductive capacity in male rats expressed in changes of the levels of preimplantation mortality in female rats. The obtained effect depends on the dose of infection and the period of parasitosis development in males

scholarly journals Myelomeningocele Surgery over the 10 Years Following the MOMS Trial: A Systematic Review of Outcomes in Prenatal versus Postnatal Surgical Repair

Medicina ◽  
2021 ◽  
Vol 57 (7) ◽  
pp. 707
Author(s):  
Francesca Gabriela Paslaru ◽  
Anca Maria Panaitescu ◽  
George Iancu ◽  
Alina Veduta ◽  
Nicolae Gica ◽  
...  
Keyword(s):  
Systematic Review ◽  
Spina Bifida ◽  
Neural Tube ◽  
Severe Form ◽  
Neural Tube Closure ◽  
Reference List ◽  
Hand Search ◽  
Randomized Controlled ◽  
Associated Conditions

Background and Objectives: Myelomeningocele is the most severe form of spina bifida, a congenital neural tube defect arising from an incomplete neural tube closure during early development with damage worsening with advancing gestational age. The Management of Myelomeningocele Study (MOMS) Trial proved that surgery performed before 26 weeks of gestation significantly improved the prognosis, significantly changing treatment paradigms. This article aims to provide a review of the changes and updates in spina bifida repair over the 10-year period following the MOMS Trial. Material and methods: We performed a systematic review in the PubMed and Cochrane databases as well as a hand-search of high-impact journals using the reference list of all identified articles, searching for randomized controlled trials and observational studies. Results: We identified 27 articles published between 2011 and 2021 that fulfilled the inclusion criteria and review them in the present study. Conclusions: With growing experience and with the improvement of prenatal open and fetoscopic techniques, the outcome of SB-associated conditions could be improved and the risks to both the mother and the fetus reduced. A continuous follow-up of the treated infants and further randomized trials are essential to study the complications and advantages or disadvantages of any given treatment strategy.

scholarly journals Chronic Experimental Toxoplasmosis and Its Impact On Embryonic Development

2021 ◽  
Vol 6 (3) ◽  
pp. 102-107
Author(s):  
M. S. Kosova ◽  
Keyword(s):  
Body Weight ◽  
Toxoplasma Gondii ◽  
Embryonic Development ◽  
Wistar Rats ◽  
Female Rats ◽  
Experimental Animals ◽  
Female Wistar Rats ◽  
Starch Gel ◽  
Implantation Sites ◽  
Post Implantation

The purpose of the study was to study the effect of chronic toxoplasmosis on changes in the levels of pre- and post-implantation mortality in the experiment. Materials and methods. In the experiment there were 90 female Wistar rats with a body weight of 180-200 g. For the development of pregnancy, females of the control and experimental groups were coupled with males for 3 days. After the onset of pregnancy, females of intact controls were orally injected with 2 ml of 0.2 % starch gel. The females of the experimental groups were infected with an invasive culture of Toxoplasma gondii at a dose of 25 tachyzoites per 1 g of body weight (5,000 tachyzoites per rat) and 50 tachyzoites per 1 g of body weight (10,000 tachyzoites per rat). On the 35th day after infection, females of the experimental groups were coupled with males for 3 days before infection. The effect of Toxoplasma on changes in the levels of pre- and post-implantation death was assessed after killing female rats on the 42nd, 49th and 56th (7th, 14th and 21st days after pregnancy) days after infection. Results and discussion. In animals infected at a dose of 25 tachyzoites per 1 g of body weight, there is a decrease in the number of implantation sites in the uterus, the total number of embryos and the number of living embryos at all stages of the development of Toxoplasma by 1.8-2.1 times compared with the control. In females infected at a dose of 50 tachyzoites per 1 g of body weight, a decrease in the number of implantation sites in the uterus and the total number of embryos at all stages of the development of the parasite was recorded by 2.2-2.5 times compared with the control values. There is a decrease in the number of living embryos by the 42nd day after infection by 4.3 times, by the 49th day – by 3.8 times and by the 56th day – by 5.1 times compared to the control. When compared with the results obtained from females with a lower dose of infection, a decrease in this indicator was revealed on the 42nd day after the development of Toxoplasma by 2.1 times, on the 49th day – by 1.7 times and on the 56th day – by 2.5 times. An increase in the number of dead embryos by 0.2-0.4 times in comparison with intact indicators and the results of experimental animals infected at a dose of 5,000 tachyzoites per rat were recorded. There was an increase in the level of resorptions on the 49th and 56th days by 1.4 and 1.6 times in comparison with the control and animals infected at a dose of 25 tachyzoites per 1 g of body weight. Conclusion. Experimental chronic toxoplasmosis causes an increase in pre-implantation and post-implantation embryo death. The recorded effect of Toxoplasma invasion depends on the dose of infection and the duration of the disease

scholarly journals Severe neural tube defects due to failure of closure initiation can arise without abnormality of neuroepithelial convergent extension

2021 ◽  
Author(s):  
Oleksandr Nychyk ◽  
Gabriel L Galea ◽  
Matteo J Mole ◽  
Dawn Savery ◽  
Nicholas Greene ◽  
...  
Keyword(s):  
Neural Tube ◽  
Planar Cell Polarity ◽  
Gene Mutations ◽  
Initiation Site ◽  
Positive Control ◽  
Severe Form ◽  
Neural Tube Closure ◽  
Null Alleles ◽  
Convergent Extension ◽  
Partial Loss

Planar cell polarity (PCP) signalling is vital for initiation of neural tube closure in mice, with diminished convergent extension (CE) cell movements leading to a severe form of neural tube defect (NTD), termed craniorachischisis (CRN). Some human NTDs are also associated with PCP gene mutations, but affected individuals are generally heterozygous, whereas PCP homozygosity or compound heterozygosity is needed to produce CRN in mice. This suggests human NTDs may involve other genetic or environmental factors, that interact with partial loss of PCP function. We found that reduced sulfation OF glycosaminoglycans (GAGs) interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause CRN in mice. Here, we hypothesised that this GAG-PCP interaction may regulate convergent extension movements, and hence lead to severe NTDs in the context of only partial loss of PCP function. Both Lp and null alleles of Vangl2 gave similar findings. Culture of E8.5 embryos in the presence of chlorate (a GAG sulfation inhibitor), or enzymatic cleavage of GAG chains, led to failure of NT closure initiation in the majority of Lp/+ embryos, whereas few +/+ littermates exhibited CRN. The chlorate effect was rescued by exogenous sulphate. Surprisingly, DiO labeling of the embryonic node demonstrated no abnormality of midline axial extension in chlorate-treated Lp/+ embryos that developed CRN. In contrast, positive control Lp/Lp embryos displayed severe convergent extension defects in this assay. Morphometric analysis of the closure initiation site revealed abnormalities in the size and shape of somites that flank the closing neural tube in chlorate-treated Lp/+ embryos. We conclude that severe NTDs involving failure of closure initiation can arise by a mechanism other than faulty neuroepithelial convergent extension. Matrix-mediated expansion of somites, flanking the closing neural tube, may be required for closure initiation.

scholarly journals 227.An inhibitor of leukemia inhibitory factor signalling blocks embryo implantation in the mouse

2004 ◽  
Vol 16 (9) ◽  
pp. 227
Author(s):  
E. Dimitriadis ◽  
C. Stoikos ◽  
M. Baca ◽  
W. Fairlie ◽  
A. D. Uboldi ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Uterine Horn ◽  
Inhibitory Factor ◽  
Luminal Epithelium ◽  
Pregnant Uterus ◽  
Implantation Sites ◽  
Post Implantation

Embryo implantation is a critical step in the establishment of pregnancy. Endometrial leukemia inhibitory factor (LIF) is essential for embryo implantation in the mouse (1). Uterine LIF is expressed in the luminal epithelium on Day 3 of pregnancy (D3) (D0�=�day of plug detection) and signals via activation of signal transducer and activator of transcription (Stat) 3 (2). We examined the effect of a novel LIF signalling inhibitor on the phosphorylation (p) of Stat3 during early pregnancy and on embryo implantation in the mouse. We injected LIF inhibitor into one uterine horn and PBS into the other uterine horn of the mouse at D3 and examined the effect on pStat3 immunostaining in the luminal epithelium between 30 and 360�min later. We found no immunoreactive pStat3 in luminal epithelium following treatment with LIF inhibitor at 60 and 90�min but variable staining at other time points. The PBS-treated uterine horn showed intense immunostaining at all times. LIF inhibitor (1mg/kg body weight per day) or PBS was administered to mice (a) subcutaneously, (b) intraperitoneally, at 8-hourly intervals for 3�days from D2, or (c) continuously into the peritoneal cavity via Alzet pumps from D2. No effect was seen on implantation at D6. When LIF antagonist (3.5mg/kg/day) or PBS were administered by Alzet pumps from D2 together with ip injections, 4-hourly from D3 for 36�h, there were no implantation sites in the uteri of treated mice (n�=�5) while the control mice (n�=�4) had 3.6���0.5�sites (P�<�0.001). Histologically, the uteri of the treated mice resembled non-pregnant uterus, while the control uterus resembled post-implantation uterus. The results demonstrate that treatment of mice during early pregnancy with a novel LIF inhibitor blocks LIF action in vivo and embryo implantation. This knowledge is important for development of novel contraceptives. (1) Stewart, C. L., Kaspar, P., Brunet, L. J., Bhatt, H., Gadi, I., Kontgen, F., Abbondanzo, S. J. (1992) Nature 359, 76–79. (2) Cheng, J. G., Chen, J. R., Hernandez, L., Alvord, W. G., Stewart, C. L. (2001) Proc. Natl Acad. Sci. USA 98, 8680–8685.

scholarly journals The Prevalence of Myopia in Schoolchildren in Some Regions of Russia

2018 ◽  
Vol 15 (3) ◽  
pp. 348-353 ◽  
Author(s):  
O. P. Proskurina ◽  
E. Yu. Markova ◽  
V. V. Brzheskij ◽  
E. L. Efimova ◽  
M. N. Efimova ◽  
...  
Keyword(s):  
Pilot Study ◽  
Subsequent Development ◽  
Severe Form ◽  
Common Type ◽  
Entire Period ◽  
Refractive Errors ◽  
Russian Regions ◽  
Regions Of Russia

The frequency of myopia reached 26 % among of school graduates in 2000. In case of graduates from gymnasiums and lyceums — 50 %. The share of severe form of myopia 10–12 %. A pilot study was conducted. The prevalence of myopia was estimated in schoolchildren of 1, 5 and 11 classes in some Russian regions (Moscow, St. Petersburg, Igevsk, Ivanovo). Objectively cycloplegic refraction was studied in 3659 schoolchildren. During the entire period of being at school emmetropia was the most common type of refraction. In 5 and 11 classes myopia was more often refractive errors. The prevalence of myopia among 1th classes schoolchildren was 2.4 %, among 5th classes — 19.7 %, 11th classes — 38.6 %. In children studying in lyceums the prevalence of myopia was significantly higher (p < 0.01). Already in the 1 classes of gymnasiums and lyceums myopic children were 7.5 %, while in regular schools only 1.4 %. In 11 classes of lyceums the share of myopic children was 50.7%, in regular schools it was 30.9 %. This confirms the influence of education on the prevalence of myopia as an additive factor. The study of the myopia prevalence should be continued in different regions and municipalities to the subsequent development the rational programs for prevention of development and the progression of myopia in school.

Hydranencephaly: Insights into Pathophysiology and Management

2020 ◽  
Vol 17 (1) ◽  
pp. 5-9
Author(s):  
Gopal Sedain ◽  
Binod Rajbhandari
Keyword(s):  
Cerebrospinal Fluid ◽  
Cerebral Cortex ◽  
Developmental Delay ◽  
Ethical Issue ◽  
Severe Form ◽  
Clinical Judgement ◽  
Management Options ◽  
Middle Income ◽  
Middle Income Countries ◽  
Cerebrospinal Fluid Diversion

Hydranencephaly is a rare and severe form of congenital disorder in which there is absence of cerebral cortex which is replaced by fluid. The presentation is in the form of hydrocephalus and developmental delay. There are various reports on possible etiopathogenesis and management. However, the overall prognosis is grim and clinicians especially in low and middle-income countries like Nepal often face a clinical judgement dilemma regarding management options to offer to the patient family. The ethical issue whether to offer cerebrospinal fluid diversion or not is always there. This review is aimed at discussing the various aspects of management of this pediatric neurosurgical problem.

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