The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis.

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.

Sirenomelia: two cases in Cali, Colombia.

We report two cases of sirenomelia, a rare congenital defect with a prevalence rate of 1:100 000 births; both cases were observed in Cali, Colombia. Both pregnant women were referred from Buenaventura, Colombia. The expecting mothers shared multiple adverse sociodemographic factors. Their homes were located in a city where the entire population is of low socioeconomic status living under conditions of extreme poverty. They were uneducated, with nutritional deficiencies and no access to drinking water most of the time. Both were exposed to water and fish from a nearby river contaminated with leachate from a poorly managed landfill. A similar relation was previously reported in Cali in 2005 between environmental factors and sirenomelia. We suggest that there is a common aetiological factor of environmental origin between these two sirenomelia cases and propose that exposure to derivatives from landfills should be included among the factors for this rare defect of multifactorial aetiological origin.

Defectos transversos terminales de miembros por exposición prenatal al misoprostol / Terminal Transverse Defects Members by Prenatal Exposure to Misoprostol

La exposición prenatal al misoprostol se ha asociado con la ocurrencia de defectos transversos terminales en miembros superiores e inferiores: gastroquisis, hipodactilia e hipoglosia entre otros defectos congénitos. El mecanismo de acción del misoprostol como agente teratogénico ha sido atribuido a un proceso de disrupción vascular con alteración del flujo sanguíneo al feto, lo cual deriva en perfusión inadecuada, hipoxia y hemorragia. Se presenta este caso de niño de dos años de edad con defectos transversos terminales de miembros superiores e inferiores cuya madre utilizó misoprostol en el primer trimestre del embarazo con fines abortivos. Se realiza esta investigación con el objetivo de brindar información sobre los efectos teratogénicos del Misoprostol y alertar sobre las posibles consecuencias de la continuación del embarazo después de su uso con fines abortivos para prevenir el nacimiento de niños con defectos congénitos incompatibles para la vida o con discapacidad permanente

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Sirenomelia apus after trimethoprim exposure: first-trimester ultrasound diagnosis-a case report.

We report the early prenatal ultrasound diagnosis of sirenomelia apus at 12+4 weeks in a patient with trimethoprim exposure in the vulnerable period. First-trimester scan revealed a malformed fetus with one femur, one small tibia, no feet, intraabdominal unilocular cystic structure, and two-vessel umbilical cord with allantoic cyst. Ultrasound visualization with two/three/four-dimensions was helpful in the process of parental counseling.

Effects of limited doses of retinyl palmitate at the critical time of limb morphogenesis in mouse embryos.

With a view to examine the effects of defined doses of retinyl palmitate (Vit. A) on limb morphogenesis and their effects at the critical time in mouse embryos, pregnant Swiss Webster albino mice were administered retinyl palmitate (10000 or 15000 IU/kg, i.p.) on different days of pregnancy. Vitamin A in 15000 IU/kg, i.p. dose was most effective as produced malformations in the forelimbs by day 10 in 28.6% mice and in the hindlimbs by day 11 in 20.6% mice. Further, two injections in a day with the lower dose (10000 IU/kg, i.p.) had more teratogenic effects than single 15000 IU/kg, i.p. injection. Two injections of either dose on day 10 resulted in higher embryo absorption.

Disrupted bone metabolism in contaminant-exposed white storks (Ciconia ciconia) in southwestern Spain.

In 1998, the Aznalcóllar mine tailings dyke in southwestern Spain broke, flooding the Agrio-Guadiamar river system with acid tailings up to the borders of one of the largest breeding colonies of white storks in the western Palearctic, Dehesa de Abajo. Over the following years, a high proportion of nestlings developed leg defects not seen before the spill, prompting this study. Nestlings with deformed legs had significantly lower plasma phosphorous (P) and higher Ca:P ratios than non-deformed cohorts in the first two years, but in the third year, when more, younger birds were studied, plasma P ranged from much higher to much lower in the affected colony compared with reference birds. Coefficients of variation for phosphorous were 19% and 60%, in reference and contaminated colonies, respectively. Storks from the contaminated colony were unable to control P levels and Ca:P ratios within the narrow limits necessary for normal bone development.

Placental improvement and reduced distal limb defects by maternal interferon-gamma injection in methylnitrosourea-exposed mice.

BACKGROUND: Methylnitrosourea (MNU), an alkylating agent derived from creatinine metabolism, is cytotoxic, genotoxic, and mutagenic. Mid-gestational exposure to MNU leads to distal limb defects in mice. Previous studies have shown that nonspecific maternal immune stimulation protects against MNU-induced teratogenesis. A role for immune-mediated placental improvement in this effect remains uncertain. METHODS: The immune system of timed-pregnant C57BL/6N and CD-1 mice was stimulated by GD 7 intraperitoneal (IP) injection with the cytokine interferon-gamma (IFN-gamma). A teratogenic dose of MNU was then administered by IP injection on the morning of GD 9 to disrupt distal limb formation. Fetal limb length, body length, digital deformities, and placental integrity were evaluated on GD 14. RESULTS: The incidence of syndactyly, polydactyly, and interdigital webbing in MNU-exposed mice was decreased by maternal IFN-gamma treatment. In C57BL/6N mice, these defects were reduced by 47, 100, and 63%, respectively, as compared to previous reports on CD-1 mice, by 39, 71, and 20%, respectively. Administration of IFN-gamma significantly diminished MNU-induced endothelial and trophoblast placental damage in both strains of mice. CONCLUSIONS: These findings support a possible link between maternal immunity, placental integrity, and fetal distal limb development. Further, these results suggest that IFN-gamma might act through placental improvement to indirectly protect against MNU-induced fetal limb malformations.

Skeletal pathology in white storks (Ciconia ciconia) associated with heavy metal contamination in southwestern Spain.

In 1998, a mine tailings dyke in southwestern Spain broke, flooding the Agrio-Guadiamar river system with acid tailings up to the borders of one of the largest breeding colonies of white storks in the western Palearctic, Dehesa de Abajo. Over the following years, a high proportion of nestlings developed leg defects, prompting this study. Ten fledglings with leg deformities from the spill area were compared with 11 normal storks of the same year class from another region far from the spill. However, metals were analyzed as a continuum rather than by site, as reference birds also contained high levels of metals. Gross pathology of the legs was supported by histopathology, which showed that bone remodeling activity was greater in the deformed storks, which also had more irregular subperiosteal bone, and tended to have higher residual islets of cartilage in their metaphyses, which, in turn were related to metal contaminant residues. Both Ca and P in bone were affected independently by metals. Deformed birds had lower serum bone alkaline phosphatase. Bone malformations, measured by leg asymmetry, was only partially explained by bone metals, indicating that a combination of factors was involved with the abnormal development in these young storks.