Differential Susceptibility of Rat Embryos to Methyl Methanesulfonate During the Pregastrulation Period

Abstract

-The effects of exposure of pregnant rats to methyl methanesulfonate (MMS), an alkylating agent, during the pregastrulation period on embryonic and placental development were investigated. SD rats were treated orally with a single dose of MMS (200 mg/kg) in the morning of gestation days 0, 1, 2, 3, 4, 5, or 6 (GD0 to GD6 groups, respectively). The uterine contents including fetuses and placentas of the dams were examined on gestation day 20. The individual fetuses and placentas were weighed, and the fetuses were examined for external, visceral and skeletal anomalies. The progress of ossification was also evaluated. Both pre-and postimplantation embryonic mortalities were higher in the GD0 group than in the control group. The postimplantation loss was also increased for the GD3, GD4 and GD6 groups. Fetal malformations were rare in survivors of all the MMS-treated groups. Intrauterine growth retardation was apparent for fetuses in groups GD5 and GD6. In addition, placental weight was reduced in the GD6 group, but it was increased in the GD0 group. Effects of MMS on embryonic mortality or on fetal or placental growth were absent or minimal in the GD1 and GD2 groups. These results suggest that the susceptibility of rat embryos to MMS varies during the pregastrulation period.

Embryonic mortality and intrauterine growth retardation (IUGR) associated with placental alterations in pregnant rats treated with methyl methanesulfonate (MMS) at the peri-implantation stage

“…Flushing of blastocysts from dams treated with cyclophosphamide on GD3 and their transplantation into untreated female rats resulted in the formation of a small placental anlage on GD11 but the decidua was unaffected (Spielmann et al, 1977). The embryonic death resulting from treatment of dams Abbreviations: RBC, red blood cells; HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular a Values for GD20 are derived from our previous study (Yokoi et al, 2007), with the exception of those for glucose concentration. *P < 0.05 versus control group.…”

“…Treatment of rats during the pregastrulation stage with mutagens or other compounds has been shown to result in embryonic mortality or IUGR or in developmental abnormalities (Brock and von Kreybig, 1964;Spielmann et al, 1977;Giavini et al, 1984Giavini et al, , 1990Yokoi et al, 2007). Embryonic death and IUGR are thus common consequences of exposure to xenobiotic agents at the pregastrulation stage in rats and mice.…”

“…Treatment of mouse embryos at the 16-cell stage for 1 hr with MMS in vitro resulted in embryonic death and IUGR after their transplantation into the oviduct of female mice (Fabro et al, 1984). We have previously shown that the consequences for conceptal development of a single oral treatment of rat dams with MMS during the pregastrulation period are dependent on the precise time of such treatment (Yokoi et al, 2007). Embryonic death after implantation and IUGR for term fetuses were induced by treatment of dams at the peri-implantation stage (the morning of gestation day (GD) 6, with the were rare.…”

“…Female rats that had copulated successfully were treated orally with a single dose of MMS (200 mg/kg of body weight) in the morning of GD6. The dose level was the same as our previous study (Yokoi et al, 2007). MMS (99.9%; Aldrich, Milwaukee, WI, USA) was dissolved freshly in distilled water (JP grade; Otsuka Pharmaceutical Industries, Tokushima, Japan).…”

Modeling Trophoblast Cell-Guided Uterine Spiral Artery Transformation in the Rat

“…There have been numerous investigations examining the effects of an assortment of drugs and toxicants on the uterine-placental interface with the goal of determining the target tissue mediating negative fetal developmental outcomes [ 40 ]. Treatment with chlorpromazine, a phenothiazine used as a tranquilizer, a range of anticancer drugs (cisplatin, 6-mercaptopurine, methyl methanesulfonate, and methotrexate), dexamethasone (glucocorticoid agonist), aryl hydrocarbon receptor agonists (β-naphthoflavone and Arolor 1254), GW501516 (peroxisome proliferator receptor agonist), nicotine, and thyroid hormone dysregulation cause reductions in placental size and structure, including hypoplasia of the junctional zone, abnormalities in junctional zone glycogen trophoblast cell development, and/or decreased intrauterine interstitial trophoblast cell invasion [ 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. A potential relationship of junctional zone development and intrauterine trophoblast cell invasion is logical and informative.…”