Differences between NMRI and DBA/2J mice in the development of somites and susceptibility to methylnitrosourea-induced skeleton anomalies

ABSTRACT The development of DBA/2J mouse strain embryos is nearly 12 h - or 6 somite pairs - delayed as compared to the outbred NMRI mouse embryos of the same age on gestation days (GD) 8-12. To evaluate inter-strain differences in susceptibility to teratogens, dams were treated with methylnitrosourea (MNU, 5 mg/kg body weight i.p.) on defined gestation days (NMRI: GD 9, 91/2 or 10; DBA/2J: GD 10 or 101/2). Skeletal anomalies produced by MNU on both mouse strains varied with the GD of treatment. The pattern of anomalies produced by MNU on a given GD markedly differed between the two mouse strains, yet they were similar -with a few exceptions- when exposures at equivalent embryonic stages are compared. Findings from this study indicated that strain-dependent differences in the developmental stage of mouse embryos of the same gestational age occur, a possibility that has been often neglected when inter-strain differences in susceptibility to developmental toxicants are interpreted.

Perceptions by pregnant and childbearing-age women in southern Brazil towards teratogenic risk from medicines and radiotherapy / Percepções de risco teratogênico de medicamentos e radioterapia por gestantes e mulheres em idade fértil no Sul do Brasil / Percepciones de riesgo teratogénico de medicamentos y radioterapia en mujeres embarazadas y en edad fértil en el sur de Brasil

Mistaken perception of teratogenic risk can keep pregnant women from using safe medicines. The current study analyzed women’s concepts and perceptions towards teratogenic risk from medicines and exposure to radiotherapy during pregnancy. The quantitative data resulted from interviews with 287 pregnant and non-pregnant women. Two qualitative focus groups were conducted. No significant differences were observed between the two groups in terms of perceptions of teratogenic risk. Median perceptions of non-teratogenic exposures (paracetamol and metoclopramide) were close to the expected values, while higher values were found for teratogenic exposures (misoprostol and radiotherapy). The logic women used to estimate risk was classification of medicines as “strong” or “weak”. Medicines perceived as “weak” by the women do not pose any teratogenic risk, as shown by the median perceptions close to the true values. Meanwhile, “strong” medicines were viewed as dangerous, thus explaining the high median perceptions of teratogenic exposures.

Percepção de risco teratogênico equivocada pode privar a gestante do uso de medicamentos seguros. O estudo analisou concepções e percepções de risco teratogênico de mulheres sobre o uso de medicamentos e exposição à radioterapia durante a gestação. Dados quantitativos resultaram da realização de entrevistas com 287 gestantes e não gestantes. Qualitativamente, dois grupos focais foram realizados. Não se observaram diferenças significativas nas percepções de risco teratogênico entre grupos. As medianas das percepções para as exposições não teratogênicas – paracetamol e metoclopramida – foram próximas do valor esperado, e para as exposições teratogênicas – misoprostol e radioterapia – valores maiores foram encontrados. A lógica acionada pelas mulheres na estimação do risco é a da classificação dos medicamentos em fortes e fracos. Medicamentos percebidos pelas mulheres como fracos não apresentam risco, evidenciado pela aproximação das medianas ao valor esperado. Já medicamentos fortes são vistos como perigosos, justificando as altas medianas das exposições teratogênicas.

Percepción equivocada del riesgo teratogénico puede privar a las embarazadas de la utilización de medicamentos seguros. En este estudio se analizan las concepciones y la percepción de riesgo teratogénico de mujeres con respecto al uso de medicamentos y exposición a la radioterapia durante el embarazo. Los datos cuantitativos resultan de la administración de entrevistas a 287 mujeres embarazadas y no embarazadas; los cualitativos, de dos grupos focales. No se encontraron diferencias significativas en la percepción de riesgo entre los grupos. Las medianas para la percepción de riesgo a las exposiciones no teratogénicas resultaron cerca del valor esperado, mientras que para las exposiciones teratogénicas se encontraron valores más altos. La lógica usada por las mujeres para estimar el riesgo clasifica los medicamentos en fuertes y débiles. Aquellos percibidos como débiles no suponen riesgo (lo que se evidencia por la aproximación de las medianas al valor real). Por otra parte, los fuertes son vistos como peligrosos, lo que justifica las medianas altas para los riesgos teratogénicos.

Study of embryotoxicity of mentha piperita L. during organogenesis in balb/c mice / Estudio de la embriotoxicidad de mentha piperita L. durante la organogénesis en ratones balb/c

Mentha piperita (Labiatae), commonly known as peppermint is a native Iranian herb which is used in folk medicine for various purposes. This study was carried out to reveal the teratogenic effect of Mentha piperita on mice fetuses. In this experimental study, pregnant Balb/c mice divided to four groups. Case group received 600 (treatment I) and 1200 (treatment II) mg/kg/day the hydroalcoholic extract of Mentha piperita during 6-15 of gestational days and one control group received normal saline during GD6-GD15 by gavages and other control group did not receive any matter during 6-15 of gestational days. Mice sacrificed at GD18 and embryos were collected. Macroscopic observation was done by stereomicroscope. 20 fetuses of each group were stained by Alizarin red-S and Alcian blue staining method. The Mean weight of fetuses decreased in treatment groups rather than control (P<0.05) but CRL there was no significant difference between treatments and controls groups. In the treatment I (600 mg/kg/day) and treatment II (1200 mg/kg/day), normal saline and control group, no gross congenital malformations were observed in fetuses. Treated fetuses also had no delayed bone ossification as determined by Alizarin red-S and Alcian blue staining method. This study showed that the hydroalcoholic extract of Mentha piperita (600 and 1200 mg/kg/day) has no teratogenic effect in mice fetuses if used continuously during embryonic period.

Mentha piperita (Labiatae), comúnmente conocida como menta, es una hierba nativa de Irán, que se utiliza en la medicina tradicional para diversos fines. Este estudio fue realizado para descubrir el efecto teratogénico de la Mentha piperita en fetos de ratones. Los ratones Balb/c preñadas fueron divididas en cuatro grupos. Los grupos recibieron 600 (tratamiento I) y 1200 (tratamiento II) mg/kg/día del extracto hidroalcohólico de Mentha piperita durante los días 6-15 de gestación (DG), mientras que un grupo control recibió solución salina normal durante los DG 6-15 vía oral y otro grupo control sano no recibió substancia durante los DG 6-15. Los ratones fueron sacrificados el DG 18, recolectando los fetos. Se realizó la observación macroscópica mediante un estereomicroscopio. 20 fetos de cada grupo se tiñeron por el método de rojo de alizarina-S y azul de Alcián. La media de peso de los fetos disminuyó más en los grupos de tratamientos que los controles (p <0,05), pero CRL no presentó diferencias significativas entre los tratamientos y los grupos control. En los fetos del grupos tratamiento I (600 mg/kg/día), tratamiento II (1200 mg/kg/día), solución salina normal y control no se observó ninguna malformación congénita grave. Los fetos tratados tampoco tuvieron osificación ósea retrasada según lo determinado por el método de rojo de alizarina-S y azul de Alcián. Este estudio mostró que el extracto hidroalcohólico de Mentha piperita (600 y 1200 mg/kg/día) no tiene efectos teratogénicos en fetos de ratones al ser utilizado continuamente durante el período embrionario.

Teratogenic effect of ethylene glycol-methyl cellosolve mixture in rats: I: reproductive damage / Teratogénesis por etilenglicol-metilcelosolve en ratas: I: daño reproductivo

We investigated the reproductive damage and teratogenic effect of an ethylene glycol-methyl cellosolve mixture on gestating Wistar rats, which received a daily intraperitoneal dose of different concentration of the mixture on day 8 of gestation until day 20. In rats treated with the mixture the number of live fetuses decreased and reabsorptions increased with increasing concentrations of the mixture, as well as the number of abnormal fetuses. We conclude that the ethylene glycol-methyl cellosolve mixture possesses a higher teratogenic potential than each of its constituents separately, producing reproductive damage, external fetal abnormalities, growth delay, and increased fetal death.

Se investigó el daño reproductivo y efecto teratogénico de una mezcla de etilenglicol y metilcelosolve en ratas gestantes, las cuales recibieron por vía intraperitoneal una dosis diaria, a diferentes concentraciones de la mezcla, del día 8 al día 20 de gestación. En las ratas tratadas con la mezcla el número de fetos vivos disminuyó y las reabsorciones y el número de fetos anormales aumentaron a mayor concentración de los solventes. Concluimos que la mezcla de etilenglicol-metilcelosolve tiene mayor efecto teratogénico que cuando actúan cada uno de los solventes por separado, produciendo daño reproductivo, anormalidades fetales externas, retraso del crecimiento y aumento de muerte fetal.

Histopathological changes in incisive teeth of the newborn pups of cadmium-applied female rats during pregnancy / Cambios histopatológicos en dientes incisivos de crías neonatos de ratas hembras bajo suministro de cadmio durante la preñez

Cadmium Chloride is a well known teratogen compared to other metals. Cadmium affects placental function, may cross the placental barrier and modify fetal development. In this study, 12 female Wistar albino rats weighted between 180-200gr were used. They were divided into two groups as experimental and control groups each comprising 6 female animals. 2mg/kg/day cadmium chloride dissolved in 1ml isotonic solution were intravenously injected from tail vein of experimental rats during 17-21 days of pregnancy. At first day of birth, the total body weights of control and experimental newborn pups were taken. This study aims to evaluate morphologically the effects of cadmium chloride on the incisive teeth development of pups born to the cadmium-applied female rats during pregnancy.

Cloruro de cadmio es un teratógeno conocido en comparación con otros metales. El cadmio afecta la función placentaria, pudiendo atravesar la barrera placentaria y modificar el desarrollo del feto. Fueron utilizadas 12 ratas hembras Wistar albinas, entre 180-200g de peso. Se dividieron en dos grupos de seis hembras cada uno, grupo experimental y control. Se inyectó, a través de una vena de la cola de las ratas del grupo experimental por vía endovenosa 2mg/kg/día de cloruro de cadmio disuelto en 1 ml de solución isotónica, durante 17-21 días de gestación. Al primer día de nacimiento, se pesaron las crías de los grupos control y experimental. Este estudio tiene como objetivo evaluar morfológicamente los efectos del cadmio sobre el desarrollo de los dientes incisivos de crías recién nacidas de ratas hembras a quienes se les inyectó cadmio durante la preñez.

Teratogenic effect of ethylene glycol-methyl cellosolve mixture in rats: II: craniofacial and limb abnormalities / Teratogénesis por etilenglicol-metilcelosolve en ratas: II: anormalidades craneofaciales y de miembros

We investigated the teratogenic effect of an ethylene glycol-methyl cellosolve mixture on gestating Wistar rats, that received a daily intraperitoneal dose of different concentration of the mixture on day 8 of gestation until day 20. Multivariate analysis and Post-Hoc Bonferroni tests were used and relative risk and attributable fraction were calculated. In rats treated with the mixture the number of live fetuses decreased and reabsorptions increased with increasing concentrations of the mixture, as well as the number of abnormal fetuses. Abnormalities consisted mainly in atypical craniofacial morphology, protruding tongue, edema, signs of growth delay and shorter limbs, their frequency and severity increased at higher concentrations of the mixture. We conclude that the ethylene glycol-methyl cellosolve mixture possesses a higher teratogenic potential than each of its constituents separately, producing external fetal abnormalities, growth delay, and increased fetal death.

Se investigó el efecto teratogénicos de una mezcla de etilenglicol y metilcelosolve en ratas gestantes, las cuales recibieron por vía intraperitoneal una dosis diaria, a diferentes concentraciones de la mezcla, del día 8 al día 20 de gestación. Se utilizaron las pruebas de análisis multivariado y Post-Hoc de Bonferroni, y se calcularon el riesgo relativo y la fracción atribuible. En las ratas tratadas con la mezcla el número de fetos vivos disminuyó y las reabsorciones y el número de fetos anormales aumentaron a mayor concentración de los solventes. Las anormalidades fetales consistieron principalmente en morfología atípica craneofacial, protrusión de la lengua, edema, signos de retraso de crecimiento y acortamiento de extremidades, y su frecuencia y severidad se incrementó a mayor concentración de la mezcla. Concluimos que la mezcla de etilenglicol-metilcelosolve tiene mayor efecto teratogénico que cuando actúan cada uno de los solventes por separado, produciendo anormalidades fetales externas, retraso del crecimiento y aumento de muerte fetal.

Consumo de fumonisinas y daños a la salud humana / Fumonisin intake and human health

Las fumonisinas son una familia de micotoxinas que contaminan al maíz, alteran el metabolismo de los esfingolípidos y del folato, se asocian con defectos del tubo neural y están catalogadas por la Agencia Internacional de Investigación en Cáncer (IARC por sus siglas en inglés) como posibles carcinógenos humanos. Debido a que en México los derivados de maíz constituyen una parte importante de la dieta y existe alta prevalencia de población genéticamente susceptible a la deficiencia de folato, en este ensayo se presentan las evidencias mundiales y nacionales de la exposición a fumonisinas y la relevancia que para México representa la evaluación de esta exposición.

Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.

Assessment of teratogenecity and embryotoxicity of sludge from textile industries at Pali (India) in Swiss albino mice exposed during organogenetic period.

The present investigation was carried out to assess the teratological effects of in-utero exposure of sludge leachate from textile and dyeing industries located in Pali, Rajasthan. Sludge was collected at the combined effluent treatment plant (CETP). Two groups of 10 pregnant Swiss albino mice each, were given sludge leachate of 1/10 and 1/100 dilutions with water ad libitum from 6th day to 15th day of gestation covering the critical period of organogenesis. Cesarean sections were performed on day 18 of gestation and all foetuses were examined for reproductive and teratological tests. Sludge induced maternal toxicity was evidenced by significant increase in leachate consumption, reduction in body weight gain and reduction in fur of the body. Developmental toxicity was evidenced by a significant decrease in foetal weight per litter increase in the number of resorptions and an increase in total number of foetuses showing bone retardation and skeletal variations (specially of skull, sternebrae and vertebrae). The leachate of the sludge that is being dumped in the open areas of the town Pall seems to elicit teratogenic as well as embryotoxic potential as indicated by the findings of the present investigation.

Manifestaciones cutáneas como parámetro de teratogenicidad en la intoxicación con metales pesados / Cutaneous signs as parameter in teratogenicity by heavy metal intoxication

Se estudiaron los efectos teratogénicos de metales pesados (acetatos de Cd2+ y Pb2+ y sulfato de Cu2+), en embriones de pollo en desarrollo, después de la administración de una monodosis del metal. Los huevos embrionados fueron inyectados en la yema en el día 12 de incubación. Las concentraciones de los iones fueron (nmoles/g huevo): Cd2+: Dosis 1 (D1): 0,16 y Dosis 2 (D2): 0,32; Pb2+: D1: 8,0 y D2: 16,0 y Cu2+: D1: 1,7 y D2: 3,3. Los resultados se evaluaron después de continuar la incubación in ovo durante 12 y 60 hs Cu2+ y Pb2+ no aumentaron la mortalidad de los embriones, en cambio, la presencia de Cd2+ produjo entre 30 y 86 % de mortalidad de los embriones, con efectos dosis y tiempo dependientes. Los embriones intoxicados con la D2 de Cd2+ durante 60 hs fueron los únicos ejemplares que presentaron disminución en su peso promedio, respecto de los ejemplares de control. La administración de Cd2+ causó efectos teratogénicos más severos que los tratamientos con Cu2+ y Pb2+. Se puede concluir que los metales pesados son embriotóxicos e inducen teratogenia en embriones de pollo en desarrollo. Se sugiere que los mejores parámetros para evaluar la teratogenicidad producida por la intoxicación Cd2+, Cu2+ y Pb2+ son los derrames cutáneos y hepáticos.

Teratogenic effects of heavy metals (Cd2+- and Pb2+- acetates and Cu2+- suphate) were studied on chick embryos, after the administration as a single dose. Test materials were injected into the yolk on day 12 of incubation. Tested concentrations were (nmole/g egg): Cd2+ Dose 1 (D1): 0.16 and Dose 2 (D2): 0.32; Pb2+: D1: 8.0 and D2: 16.0 and Cu2+: D1: 1.7 and D2: 3.3. Evaluations were performed after in ovo incubation for 12 and 60 hours. Embryonic mortality did not increase at the two dose levels of Cu2+ and Pb2+, while Cd2+ caused 30 and 86% of mortality, showing dose and time responses. Eggs treated with D2 of Cd2+ for 60 hs, significantly decreased the average of body mass embryo, when compared to the control group. Cd2+ administration was responsible for the most severe teratogenic signs compared to Cu2+ and Pb2+ treatments. It can be concluded that heavy metals are embryotoxic and teratogenics. We suggest that cutaneous and liver hemorrhages are the best signs to evaluate teratogenicity induced by Cd2+, Cu2+ and Pb2+.

Teratogenicity of Asparagus racemosus Willd. root, a herbal medicine.

Asparagus racemosus (AR) is a herb used as a rasayana in Ayurveda and is considered both general and female reproductive tonic. Methanolic extract of A. racemosus roots (ARM; 100 mg/kg/day for 60 days) showed teratological disorders in terms of increased resorption of fetuses, gross malformations e.g. swelling in legs and intrauterine growth retardation with a small placental size in Charles Foster rats. Pups born to mother exposed to ARM for full duration of gestation showed evidence of higher rate of resorption and therefore smaller litter size. The live pup showed significant decrease in body weight and length and delay of various developmental parameters when compared to respective control groups. AR therefore, should be used in pregnancy cautiously as its exposure during that period may cause damage to the offspring.

Uso de medicamentos na gravidez / Pregnancy medicines use

A despeito das recomendações quanto ao emprego cauteloso de medicamentos durante a gestação, estudos recentes, como os de Osório de Castro et al. (1) e de Gomes et al. (2), comprovam significativo descaso na sua aplicação prática. Considerando a relevância sociocientífica-econômica desses dados, visto o alto índice de teratogenicidades atribuído à utilização iatrogênica de medicamentos durante o período gestacional, realizou-se este estudo, que tem por finalidade elucidar a importância da regulamentação dos medicamentos que podem ser empregados na gestação; definir teratogenicidade; discutir sobre alguns aspectos da farmacodinâmica e farmacocinética das drogas durante o período gravídico; exemplificar a diversidade dos riscos e efeitos observados entre fármacos de grupos distintos sobre o organismo materno e fetal; e, essencialmente, informar sobre os cuidados que devem ser considerados na terapêutica da mulher grávida.

Efeitos genotóxicos e alterações de enzimas hepáticas em trabalhadores do refino de petróleo / Genotoxic effects and hepatic enzymes alterations among petroleum refinery workers

Um estudo de casos e controles, aninhado num estudo de coorte, investigou a associação entre efeitos genotóxicos e alteração de enzimas hepáticas em trabalhadores de uma refinaria de petróleo do Nordeste. Foram examinados todos os dez novos casos de alterações de enzimas hepáticas - gama-glutamil transferase (GGT) e alanina aminotransferase (ALT) - ocorridos em 2002. Dez trabalhadores sem alterações de GGT ou ALT foram selecionados como controles. Os efeitos do fumo, sexo, idade e consumo de café foram controlados. O efeito genotóxico foi avaliado pela técnica de trocas entre cromátides irmãs (TCI) e alterações cromossômicas (AC) estruturais. As médias de TCI por célula (3,92 ± 1,04 versus 4,25 ± 1,47) e de ACE (8,85 ± 3,4 versus 9,1 ± 3,7) não diferiram de forma significante entre casos e controles respectivamente.

Mecanismo embrionário das malformações decorrentes de fármacos / Embrional mechanisms of malformations current of pharmacs

As malformações congênitas decorrentes de teratógenos atingem um ou mais folhetos, ou camadas germinativas, do embrião, originando alterações em sistemas orgânicos, entre os quais os mais atingidos são o cardiovascular, o osteolocomotor e o nervoso. Os tecidos interagem reciprocamente, ora induzindo, ora sendo induzido, através de mecanismos moleculares controlados por genes específicos da família sonic hedgehog, presentes nas células embrionárias em proliferação, onde o mesoderma intra-embrionário é o folheto-chave nestas induções. Neste trabalho, mais uma vez os autores chamam a atenção para a necessidade da prevenção primária das malformações congênitas, inclusive a análise do custo-benéficio em se administrar drogas às gestantes, sobretudo na saúde pública preventiva, no sentido de evitar que as malformações aconteçam

Simultaneous induction of ectopic pelvic zone and duplication of regenerated limbs in tadpoles of Polypedates maculatus by vitamin A.

With a view to determine ectopic limb developing capacity along with normal hind limb regeneration in response to vitamin A palmitate in well-differentiated hind limb stage tadpoles of P. maculatus, higher doses of vitamin A (30 IU/ml and 20 IU/ml) were administered for a longer period (120 hr) to the tadpoles following tail amputation through middle and hind limb amputation through middle of thigh. Simultaneous development of ectopic pelvic zone was observed along with hind limbs from the cut end of tail and duplication of regenerated hind limbs in the same tadpole for the first time. Besides, development of double ectopic pelvic girdle was also reported in one case. Results also indicate that induction of pelvic zone and duplication of regenerated limbs are concentration dependent.

Effect of arsenite on certain aspects of protein metabolism in fresh water teleost, Tilapia mossambica (Peters).

The sublethal toxicity of sodium arsenite on protein metabolism was investigated in teleost fish, Tilalpia mossambica at the end of 24, 48, 72 and 96 h of exposure. Total protein content, free amino acid content and activities of the enzymes aspartate amino transferase (AAT) and alanine amino transferase (ALAT) in liver, gill, brain and muscle exhibited significant (P<0.05) alterations throughout the investigation in relation to that of control. It is suggested that the fish is able to respond to the stressful situations by gearing up the metabolic activity as revealed by the elevated protein, amino acid content and the activities of AAT and ALAT.

An analysis of the teratagenic effects that could possibly be due to alcohol consumption by pregnant mothers.

It can be concluded that alcohol is definitely harmful to the developing fetus. The effect can manifest in various ways, the most extreme of which is a condition called Fetal Alcohol Syndrome (FAS). The diagnosis of maternal alcoholism leading onto cases of FAS is difficult due to absence of accurate diagnostic tests. The diagnosis of FAS in a child is easier by a proper examination. There is no specific treatment of FAS in a child. The only management is by institution of corrective and rehabilitative measures. The exact mechanism of the teratogenic action of alcohol is not known. It is probably due to the harmful effect of alcohol on the epiblast layer of the bilaminar germ disc. In the absence of adequate knowledge regarding FAS, not much can be done to remedy the deleterious effects of alcohol. Hence, a word of advice to all pregnant women is to avoid drinking during pregnancy.

Aspectos fisiologicos da permeabilidade placentaria e riscos fetais pela exposicao materna / Phisiologic aspects of placental permeability and fetal risks caused by maternal exposition

Este artigo faz uma revisao da estrutura placentaria, seus mecanismos fisiologicos de transporte, e o reflexo sobre o feto da passagem de algumas substancias capazes de determinar alteracoes no seu bem estar e desenvolvimento.

Teratological effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): induction of cleft palate in the ddY and C57BL/6 mouse

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic halogenated aromatic hydrocarbon, is a teratogen to induce cleft palate when exposed during the pregnancy. There are inter-strain differences in the sensitivity to cleft palate induced by TCDD and other chemicals including polychlorinated terphenyls (PCTs). The C57BL/6 mouse and the ddY mouse had been shown to be different in the induction of cleft palate following the treatment of PCTs, which attempts us to evaluate the TCDD-induced cleft palate in two mouse strains to understand the mechanism through which TCDD and PCTs induce cleft palate. This study evaluated the induction of cleft palate in the fetuses of ddY and C57BL/6 mice after subcutaneous treatment of TCDD on gestation day (GD) 10.5-14.5 or oral treatment on GD 8.5-13.5. Our results clearly showed that ddY mice, a susceptible strain to PCTs-induced cleft palate, are resistant to the induction of cleft palate by TCDD comparably to the high susceptibility of C57BL/6 mice, suggesting a different teratological mechanism between TCDD and PCTs. In addition, at the low doses, our study supported the concept of "window effect" of TCDD on around GD 12 for the induction of cleft palate in C57BL/6 and ddY mice.