Maternal factors in developmental toxicity

Abstract

The maternal organism provides the developing embryo with its physical environment, nutrients, and a mechanism for eliminating metabolic wastes. Since the physiological state of the pregnant female affects her ability to provide those requirements for the developing embryo, it is not surprising that there are maternal factors that can affect the wellbeing of the embryo. Extremes of maternal age in both humans and animals have been implicated in growth retardation, as well as autosomal trisomies. The influence of maternal size on fetal size is more pronounced among larger species with longer gestation periods such as humans and domestic animals. A clear relationship between the parity of the mother and potential developmental toxicity in humans has not been established due to the confounding influences of maternal age. Among laboratory rodents, however, it appears that offspring of multiparous animals are at increased risk of developmental toxicity. A variety of infectious agents, particularly viruses, have either been demonstrated or implicated as causes of developmental toxicity. In addition, hyperthermia is a possible confounding factor inherent with maternal infection. Although under experimental conditions hyperthermia is teratogenic in laboratory animals, a causative role for transient hyperthermia, which occurs during febrile states concomitant with infections, cannot be clearly established. Chronic maternal vascular disease states including essential hypertension, heart disease, or diabetes mellitus are likely to contribute to uteroplacental insufficiency and developmental toxicity. Poor maternal nutrition among humans contributes to growth retardation, but not to malformations. The production of "abnormal" maternal antibodies, such as are present in Rh incompatibility, can cause fetal wastage. An important maternal factor in humans is uteroplacental insufficiency, which can occur in normal states like twinning, as well as in abnormal conditions including reduced placental size, chronic maternal hypoxia, or uterine ischemia. Although all these maternal factors can contribute to developmental toxicity, they do not necessarily occur as isolated events. Some developmental toxicants exert deleterious effects within both the embryo and the maternal system.

Mammalian stress proteins HSP70 and HSP28 coinduced by nicotine and either ethanol or heat.

“…Exposure of mice to elevated temperatures at specific times during pregnancy leads to specific birth defects, usually involving the central nervous system. Similar results have been reported for other species (5,7). No direct evidence links HSP to these teratogenic events, but their involvement has been hypothesized by several investigators (7,34).…”

“…In the absence of stress, HSP appear at precisely timed points during the flies' developmental cycle. The induction of HSP by exposure of the insect to nonlethal thermal shock at the wrong time during morphogenesis leads to specific malformations in the newborn fly (phenocopy errors); analogous effects are seen in higher eukaryotes (5,7). Exposure of mice to elevated temperatures at specific times during pregnancy leads to specific birth defects, usually involving the central nervous system.…”

“…No direct evidence links HSP to these teratogenic events, but their involvement has been hypothesized by several investigators (7,34). In humans, epidemiological studies have linked birth defects to hyperthermic episodes experienced by the mother during pregnancy (5,9,33). The role of ethanol in inducing birth defects is currently under careful scrutiny, and a series of central nervous system defects (fetal alcohol syndrome) closely resemble many of the characteristics seen in offspring from mice heated during pregnancy.…”

Analysis and Integration of Developmental Neurotoxicity and Ancillary Data into Risk Assessment: A Case Study of Dimethoate

“…Several studies (e.g., Khera, 1987Khera, , 1991Keen et al, 2003a;DeSesso & Goeringer, 1990;Carey et al, 2000Carey et al, , 2003DeSesso, 1987;Daston, 1994;Taubeneck et al, 1994;Duffy et al, 1997) illustrate the necessity to consider maternal toxicity as a common contributing cause to abnormal fetal development or death. Similarly, maternal toxicity can, and does, influence the development of the young during the postnatal period (Keen et al, 2003b;Weaver et al, 2004).…”

“…Further, she controls homeostatic mechanisms regulating fluids and temperature, and provides means for the elimination of metabolic wastes. If a pregnant animal is exposed to an environmental insult at such a level that it results in overt maternal toxicity (e.g., reductions in food intake, reductions in body weight, increases in body core temperature, the induction of an acute-phase response), changes in maternal metabolism secondary to maternal toxicity can contribute to fetal or pup toxicity (DeSesso, 1987), even when the insult itself exerts minimal, if any, direct effects on the fetus or pup (Keen et al, 2003a(Keen et al, , 2003b. The use of the litter as the appropriate unit of analysis has been reflected in U.S. Environmental Protection Agency (EPA) guidance from the Office of Research and Development (ORD) as well as in a key report by the International Life Sciences Institute (ILSI, 1999).…”