Publisher Summary This chapter discusses the effects of heat and chemical stress on development. The chapter presents common features of environmental induced morphological defects during mammalian and Drosophila development. Cellular response to heat is the prototype system for this analysis. Heat is easy to apply and withdraw, and the effects of heat on cells have been extensively studied in a wide variety of experimental systems. Evidence that several teratogenic chemicals cause defects by a mechanism similar to heat is also presented in the chapter. It is suggested to make several reviews on teratology and on the heat-shock response for more general treatments of these subjects. Similarities in the means by which developmental defects are induced in vertebrates and Drosophila suggest that some kinds of defects may be induced by similar mechanisms. The similarities include the fact that heat and a group of chemicals that induce synthesis of heat-shock proteins induce defects in mammals, chickens, and flies. Different kinds of defects are even produced in one type of animal, depending on the precise timing of the environmental insult. Developmental defects induced by heat in mice, rats, and flies can all be prevented by thermotolerance-inducing treatments.

Effects of heat and chemical stress on development.

We have tested the potential of a single dose of ethanol (0.20ml 50% ethanol in chick Ringer's saline (CRS) administered into the air sac) to produce ventricular septal defect (VSD) in three distinct commercially available strains of White Leghorn chick embryo: stress-resistant Dekalb Delta strain, Hy-Vac SPF type V, and Hy-Vac SPF type L. Eggs were controlled for both size and developmental stage (Hamburger-Hamilton stage 18–19) at time of injection. The frequency of VSD in Dekalb Delta embryos was 4.0% (1/25), in Hy-Vac SPF type L embryos 9.1% (3/33), and in Hy-Vac SPF type V embryos 38.9% (14/36). Statistical analysis with the two-tailed Fisher Exact Test indicated that frequencies were not significantly different (P = 0.3215) when Dekalb Delta and Hy-Vac type L embryos were compared. However, the frequency of VSD for Hy-Vac type V embryos was significantly greater than that for either the Dekalb Delta or the Hy-Vac type L embryos (P <0.005). All VSDs observed were located within the crista supraventricularis. When Hy-Vac SPF type V embryos were exposed to either 0.20 ml 50% ethanol in CRS or to 0.20 ml CRS (controls), ethanol-treated embryos showed a VSD incidence of 34.1% compared with a 3.6% incidence in the controls (P = 0.0017). These data suggest that ethanol is the cause of VSD in this strain. From the results of this study, we are led to conclude that different commercial strains of White Leghorn chick embryo show different susceptibilities to the induction of VSD by ethanol. © 1993 Wiley-Liss, Inc.

Strain-dependent effect of ethanol on ventricular septal defect frequency in white leghorn chick embryos

Effects of caffeine administration to Hamburger-Hamilton stage 19 chick embryos (3 days of incubation) were investigated. A morphologic study of the effect of caffeine on cardiogenesis showed that caffeine produced total cardiac malformations in the chick in a dose-related fashion. A maximum frequency of 70.6% was observed with 4.7 mg caffeine. Major malformations included common aorticopulmonary trunk and dextroposition of the aorta accompanied by ventricular septal defect with/without pulmonary stenosis. Qualitative analysis of cinegraphs following exposure of embryos to a single teratogenic dose of caffeine (3.5 mg/egg) produced marked alterations in cardiac function when compared with chick Ringer's controls. Within 3 minutes after exposure to caffeine, dilation of the common ventricle and weak ventricular contractility were observed and persisted for 1 hour. Dose-response data and microcinematographic observations suggest that caffeine induced cardiac anomalies by a direct toxic effect on the embryo rather than by altering cardiac cell function. Our data also suggest that pathophysiologic changes in cardiac function may play an important role in the pathogenesis of caffeine-induced cardiac anomalies in the chick embryo.

Pulmonary stenosis with ventricular septal defect, common aorticopulmonary trunk, and dextroposition of the aorta: morphologic and qualitative physiologic effects in caffeine-treated chick embryos.

Treatment of gravid rats (days 6-15 of gestation) with the beta-sympathomimetic doxaminol resulted in wavy ribs and bent limbs in the offspring. The fetuses also exhibited defective mineralization. These anomalies were produced by pharmacologically effective doses of the drug. Prior treatment with the beta-receptor blocker carazolol prevented their formation, so that the beta-sympathomimetic action of doxaminol is evidently a causative factor. Various hypotensive agents whose activity is not mediated by beta-receptors failed to produce abnormalities. This eliminates the possibility of a non-specific etiology such as diminished placental perfusion. The cyclooxygenase inhibitor indomethacin lowered the incidence of wavy ribs. Furosemide, a loop diuretic that stimulates renal prostaglandin synthesis, increased the incidence of abnormalities when combined with doxaminol. The nature of the anomalies found suggests that 1) fetal compression by the myometrium and 2) defective mineralization are prerequisites for their development. The first condition could be produced via the complex mechanism of beta-sympathomimetic-induced stimulation of prostaglandin synthesis. Defective mineralization can result directly from cAMP-mediated activation of osteoclasts and possibly be further promoted by beta-sympathomimetic-mediated prostaglandin action on the osteoclast. The pathological findings in the fetal rat skeleton cannot be correlated with corresponding findings in human neonates whose mothers were subjected to prolonged therapeutic uterine relaxation with beta 2-sympathomimetics, for example. Since the anomalies in the rat disappear spontaneously in the post-natal period, their clinical relevance appears to be slight.

A postulated mechanism of β‐sympathomimetic induction of rib and limb anomalies in rat fetuses

Adverse hemodynamic changes during cardiogenesis and vascular development predispose to abnormal morphogenesis of the cardiovascular system. It has been demonstrated that the embryonic chick circulation is pharmacologically responsive to drugs that we have shown induce cardiovascular defects in the chick embryo. These include, in particular, p-adrenergic stimulants and methylxanthines.'-' Previous techniques are, however, invasive, and embryos have not survived the trauma produced by the methodology. Our approach to determination of pathophysiologic mechanisms of teratogenesis is unique in that embryos subjected to microcinephotoanalysis survive to an age when cardiac development is complete and hearts and vessels are large enough to determine structural defects by gross examination. In this study, embryos were noninvasively examined using microcinephotoanalysis (Hamburger-Hamilton stages 18-21). Cardiac function determinations may be conducted during a major period within the interval of early heart morphogenesis.Cardiovascular malformations can be related to alterations in hemodynamic function as shown by decrease in end-diastolic volume, end-systolic volume, stroke volume, heart rate, cardiac output, and a rapid and sustained increase in ejection fraction. Alterations in hemodynamic function have been correlated with abnormalities in cardiac embryogenesis (FIG. 1 ). Clinically significant cardiovascular anomalies have been induced with exposure of chick embryos to cardioactive drugs. Malformations have included tetralogy of Fallot (FIG. 2A), truncus arteriosus (FIG. 2B), double outlet right ventricle, isolated ventricular septal defect, interruption of the aortic arch with subpulmonic ventricular septal defect and posterior deviation of the subpulmonic conus, and dextroposition of the aorta. We have further shown that p-1 receptor activity plays an important role in the teratogenic process.' Pretreatment with &receptor blocking agents significantly reduces the incidence of malformations.'

Hemodynamic Mechanisms in Cardiovascular Teratogenesis

Prenalterol (levo-1-[4-hydroxyphenoxy]-3-isopropyl-amino-2-propanol), a new stimulant of cardiac beta-adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2 1/2- through 5 1/2-day chick embryos (Hamburger-Hamilton stages 17-27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched-out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger-Hamilton stages 17 and 26-27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50-1/20) epinephrine (P = .035 at concentrations of 8-10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5-1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac beta-adrenergic receptors in the chick embryo produces cardiovascular malformations.

Cardiovascular malformations associated with administration of prenalterol to young chick embryos

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Cardiovascular malformations associated with administration of prenalterol to young chick embryos