A Practical Approach, Second Edition=Ronald D. Ho.pdf

102 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONand “In reality, it is of little consequence to the embryo/fetus whether it was harmed by a chemicalthat acted directly or through maternal mediation.” Thus, until we know much more about maternallymediated effects and their relation to developmental hazard, the critical factors should be thelikelihood of toxicity to the pregnant woman and the relative margin of safety between likelymaternal exposures and toxic doses.4. Potentiation of Chemical Teratogenesis by Maternal StressSeveral studies have attempted to determine if maternal stress can interact with or potentiate theeffects of teratogenic chemicals or radiation when given in combination with such agents. In anearly study, 20 Hartel and Hartel subjected pregnant rats to both intermittent loud noises and brightlights or to immobilization during midgestation, in combination with vitamin A. Only immobilizationincreased the incidence of retinoid-induced malformations, primarily cleft palate, and prenatalmortality. In contrast, Ishii and Yokobori 66 found that loud noise increased the incidence ofprenatal deaths and malformations in mice treated with trypan blue. Goldman and Yakovac 21 thencoadministered restraint stress and salicylate to pregnant rats and observed an enhancement of theteratogenic effects of the chemical. The finding that two central nervous system (CNS) depressants,chlorpromazine and pentobarbital, attenuated the ability of maternal restraint to potentiate salicylateteratogenicity in rats suggested that the restraint effect is mediated via the CNS. 85 In a later study,pregnant mice of two strains were either briefly restrained, injected with lucanthone, or both. 86Lucanthone treatment of NMRI mice caused a high incidence of malformations that was notincreased by maternal restraint, but restraint appeared to have increased the incidence of resorptions.Conversely, in the F/A strain, the chemical alone did not significantly increase the malformationrate but its teratogenic effect was potentiated by restraining the pregnant dams, with no increasein resorptions.More recently, combined exposure to cadmium and noise was assessed in mice. 87 The combinationwas said to have significantly increased the fetal malformation rate (gross plus skeletal), butthe data appeared equivocal, and the specific defects seen were not listed. In another study, femaleUje:WIST strain rats were dosed with lithium prior to and throughout pregnancy. 88 Their femaleoffspring were then mated at maturity, with no further lithium exposure, and half of them weresubjected to restraint on gestation days 6 through 20. The restrained females gained less weightduring pregnancy, and their offspring weighed less at birth than was true of the (unrestrained)controls. The lack of an appropriate food- and water-deprived control group limits the interpretationof the data because the restrained group was food and water deprived as well as restrained.Rasco and Hood exposed pregnant mice to restraint stress and low doses of teratogens todetermine if the apparent enhancement of teratogenic effects seen by others when combiningmaternal immobilization stress and chemicals was a common response or an anomaly. They foundthat maternal restraint concurrent with either sodium arsenate or all-trans retinoic acid enhancedthe teratogenicity of the chemical. 68,89 The timing of administration of the retinoid during therestraint period influenced the intensity of the potentiative effect. 90 Although Domingo’s laboratorysubsequently found relatively few apparent developmental effects of maternal restraint when combinedwith treatment with various metal salts and other chemicals, they most often used restraintperiods of only 1 to 2 h/d, repeated for several days. 91,92 Brief restraint periods may not be effective,and there is also the possibility of habituation to the repeated stress. 93The mechanisms by which maternal stress potentiates the effects of chemical teratogens remainto be investigated. A number of possibilities come to mind, including altered biotransformingcapability, 94 changes in gastrointestinal secretion and motility that may influence absorption of anorally administered compound, altered blood flow to the placenta and/or the maternal liver, alteredlevels of cell proliferation or thresholds for intracellular signaling due to effects of increasedmaternal serum hormone levels, altered target tissue receptor binding, altered gene or protein© 2006 by Taylor & Francis Group, LLC