Although all developmental toxicity must ultimately result from an insult to the conceptus at the cellular level, the insult may occur through a direct effect on the embryo/fetus, indirectly through toxicity of the agent to the mother and/or the placenta, or a combination of direct and indirect effects. Some conditions that may adversely affect the fetus are depicted in Figure 10–2.
The distinction between direct and indirect developmental toxicity is important for interpreting safety assessment results in pregnant animals, as the highest dosage level in these experiments is chosen based on its ability to produce some maternal toxicity (e.g., decreased food or water intake, weight loss, and clinical signs). However, maternal toxicity defined only by such crude manifestations gives little insight to the toxic actions of a xenobiotic. When developmental toxicity is observed only in the presence of maternal toxicity, the developmental effects may be indirect (i.e., caused by an inappropriate growing condition because of an altered maternal environment rather than by a direct interaction of the fetus with the toxin). Greater understanding of the physiologic changes underlying the observed maternal toxicity and elucidation of the association with developmental effects is needed before one can begin to address the relevance of the observations to human safety assessment.
Maternal Factors Affecting Development
The genetic makeup of the pregnant female has been well documented as a determinant of developmental outcome. The incidence of cleft lip and/or palate [CL(P)], which occurs more frequently in whites than in blacks, has been investigated in offspring of interracial couples in the United States. Offspring of white mothers had a higher incidence of CL(P) than offspring of black mothers after correcting for paternal race, whereas offspring of white fathers did not have a higher incidence of CL(P) than offspring of black fathers after correcting for maternal race.
Chronic hypertension in the mother, uncontrolled maternal diabetes mellitus, and certain infections in the mother (i.e., cytomegalovirus and Toxoplasma gondii) are leading causes of several types of defects in the fetus. Exposure to hyperthermia (such as febrile illness in the mother) is also implicated in neural defects in the fetus.
A wide spectrum of dietary insufficiencies ranging from protein-calorie malnutrition to deficiencies of vitamins, trace elements, and/or enzyme cofactors is known to adversely affect pregnancy. In fact, folate supplementation by pregnant women can reduce neural tube defect recurrence by over 70 percent.
Diverse forms of maternal toxicity may have in common the induction of a physiologic stress response. Various forms of physical stress have been applied to pregnant animals in attempts to isolate the developmental effects of stress. Noise stress of pregnant rats or mice throughout gestation can produce developmental toxicity. Restraint stress produces increased fetal death in rats, and malformations of cleft palate, fused and supernumerary ribs, and encephaloceles in mice. There is a positive correlation in humans between stress and adverse developmental effects, including low birth weight and congenital malformations.
The placenta is the interface between the mother and the conceptus, providing attachment, nutrition, gas exchange, and waste removal. The placenta also produces hormones critical to the maintenance of pregnancy, and it can metabolize and/or store xenobiotics. Placental toxicity may compromise these functions. Known placental toxicants include cadmium, arsenic or mercury, cigarette smoke, ethanol, cocaine, endotoxin, and sodium salicylate.
A retrospective analysis of relationships between maternal toxicity and specific types of prenatal effects found species-specific associations between maternal toxicity and specific adverse developmental effects. Various adverse developmental outcomes include increased intrauterine death, decreased fetal weight, supernumerary ribs, and enlarged renal pelvises.
A number of studies directly relate specific forms of maternal toxicity to developmental toxicity, including those in which the test chemical causes maternal effects that exacerbate the agent's developmental toxicity. However, clear delineation of the relative role(s) of indirect maternal and direct embryo/fetal toxicity is difficult.
Diflunisal, an analgesic and anti-inflammatory drug, causes axial skeletal defects in rabbits. Developmentally toxic dosages resulted in severe maternal anemia and depletion of erythrocyte ATP levels. Teratogenicity, anemia, and ATP depletion were unique to the rabbit. The teratogenicity of diflunisal in the rabbit was probably due to hypoxia resulting from maternal anemia.
Phenytoin, an anticonvulsant, can affect maternal folate metabolism in experimental animals, and these alterations may play a role in the teratogenicity of this drug. A mechanism of teratogenesis was proposed relating depressed maternal heart rate and embryonic hypoxia. Supporting studies have demonstrated that hyperoxia reduces the teratogenicity of phenytoin in mice.