The effect of acute maternal toxicity on fetal development in the mouse

Abstract

The effects of acute alterations in maternal health status upon fetal development were assessed following exposure of pregnant CD-1 mice on day 8 of gestation to one of ten chemicals at doses calculated to exert either a low or a moderate degree of maternal lethality. The dams were killed on day 18 of gestation, and the fetuses were examined by routine teratological techniques. The chemicals were cacodylic acid, caffeine, deltamethrin, dinoseb, ethylene bisisothiocyanate sulfide (EBIS), endrin, guthion, kepone, sodium salicylate, and toxaphene. Three (cacodylic acid, EBIS, and kepone) produced dose-related increases in the incidence of dams with completely resorbed litters. Prenatal mortality in litters that contained live fetuses at term was elevated only for one chemical (cacodylic acid). Fetal weight was reduced in three instances (cacodylic acid, endrin, and guthion), while the incidence of terata was markedly elevated for two (cacodylic acid and kepone). For two other chemicals (endrin and sodium salicylate), a low incidence was found of defects that were similar to defects induced by those chemicals in other species. These effects appear to be chemospecific in nature and not the result of some indirect maternal action. Thus, maternal health status, as measured by the incidence of lethality in the treated groups and by the magnitude of maternal weight gain in surviving females, presents no simple explanation for many manifestations of fetal toxicity. However, for seven chemicals (excluding deltamethrin, EBIS, and kepone) an increased incidence of supernumerary ribs was observed. For three of these seven chemicals (caffeine, dinoseb, and toxaphene), supernumerary ribs was the only observed fetal effect. There was a significant linear inverse relationship between maternal weight gain during gestation and the incidence of extra ribs in the treated groups compared to their respective controls. Under the experimental conditions of this study, it appears that the incidence of supernumerary ribs increased in response to a nonspecific maternal toxicity.

The problem of maternal toxicity in developmental toxicity studies

“…These data seem to suggest a correlation between the severity of maternal toxicity and the effects on the conceptuses, however a definite relationship cannot be extrapolated because the concurrent role of the test compound in inducing the effects must be taken into account. The role of maternal toxicity in the induction of adverse effects on conceptuses is a very long standing problem that has been faced by a number of researchers (Chahoud et al, 1999;Chernoff et al, 1989;ECETOC, 2004;Kavlock et al, 1985;Khera, 1984Khera, , 1985Paumgartten, 2010;Rogers et al, 2005), apparently without a definite solution. First of all the definition of maternal toxicity is very poor.…”

Monomethylarsonic acid and dimethylarsinic acid: developmental toxicity studies with risk assessment

“…Kavlock et al (1985) found a similar increase in supernumerary ribs with DMA V treatment in mice after maternal exposure on GD 8, and correlated these to the treatment-related retardation of maternal weight gain. In the rats at the lower DMA V dose levels, there were statistically significant intergroup differences in the incidences of some fetal skeletal variants but, due to lack of dose-relationship, none was considered indicative of a treatment effect.…”

“…The authors found the latter effect to be correlated with the magnitude of the effect on maternal weight gain. The results reported by Kavlock et al (1985) are inappropriate for evaluating the risks of developmental effects in humans because (1) clearly maternally toxic, sometimes lethal doses were used, and (2) the numbers of dosage groups were not sufficient to enable evaluation of the dose-response relationship for DMA V (DeSesso et al, 1998;Jacobson et al, 1999;Holson et al, 2000). In a later study, Chernoff et al (1990) assessed a group of 16 pregnant Sprague-Dawley rats at term after oral administration of 40 mg/kg/day DMA V once daily during organogenesis (GD 6-15).…”

“…Hood (1998b) independently confirmed the greater sensitivity of rat embryos. Kavlock et al (1985) tested DMA V as one of a number of chemicals in a study investigating the relationship between maternal and developmental toxicity. These studies were of lesser value for assessing the potential for direct developmental effects of DMA V , because only maternally toxic doses were administered.…”

Developmental Toxicity of Nitrophenolic Herbicide Dinoseb, 2-Sec-Butyl-4,6-Dinitrophenol

“…An increased incidence of supernumerary ribs was observed in both dinoseb-treated groups. The authors noted that increased incidence of supernumerary ribs may be a response to a non-specific disruption in maternal status (Kavlock et al, 1985). Administration of dinoseb to pregnant CD-1 mice by gavage on GDs 7-8 at 50 mg/kg bw/day in NaOH produced reduced fetal weight and increased incidence of fetuses with supernumerary ribs (71% in litters) without maternal death.…”