Maternal toxicity: A possible etiological factor in embryo‐fetal deaths and fetal malformations of rodent‐rabbit species

Abstract

Data from animal teratology studies were surveyed to determine whether embryo-fetal mortality and fetal malformations result from a primary action of the agent on the conceptus or if they are secondary to maternal toxicity--a consequence of administration with high dose levels of test chemicals. A fairly strong association between embryo-fetal mortality and maternal toxicity was revealed by analysis of data from hamsters, mice, rats, and rabbits in 234 studies of chemical and physical agents, of which 83 were conducted at both maternotoxic and nonmaternotoxic doses, 94 only at maternotoxic doses, and 49 at nonmaternotoxic doses. In the above studies, only nine chemicals (four each in hamsters and rabbits and one in rats) were reported to induce embryo-fetal deaths at apparently nonmaternotoxic doses. These findings tend to suggest a contributory role for maternal toxicity in the induction of embryo-fetal deaths. The previously reported hypothesis that certain fetal defects in mice may perhaps be caused by maternal toxicity was also found to be true in a review of data on hamsters, rats, and rabbits. Salient maternal toxicity-associated fetal malformations were exencephaly, encephalocele, micro- or anophalmia, and fused ribs in hamsters and defective (fused, missing, or extra) ribs, vertebrae, and sternebrae, ex-, an-, or microphthalmia, and cleft palate in rats and rabbits. These malformations occurred at low frequencies, generally with no readily apparent dose-response relationship. Presumptive evidence indicates that embryo-fetal deaths, and the above-mentioned fetal malformations in experimental animals, which in published literature are presently attributed to chemical induction for a large number of chemicals, may be a consequence of maternal toxicity per se.

Embryo development alteration in rats treated with lapachol

“…**p<0.01 in relation to other groups. Khera (1985) correlated the low frequency of fetal malformations to the maternal weight reduction and later defined maternal toxicity as transient, or permanent alterations in the maternal physiology with potential to cause adverse effects in the offspring during the embryo-fetal and post-natal development (Khera, 1987). Maternal toxicity can be observed through different approaches such as the clinical observation of body weight loss, locomotor alteration, diarrhea, piloerection, food intake reduction and maternal deaths (Khera, 1984;.…”

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.…”

Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits

“…anomaly, misalignment, was evident in rat fetuses of the high dose group, but the increased incidence of this aberration was not significant on a litter basis. Khera (1985) has reviewed a number of teratology studies to examine the contributory role of maternal toxicity in the induction of fetal deaths and malformations. He concluded that certain malformations, including sternebra!…”