Target tissue specificity of retinoic acid‐induced stress proteins and malformations in mice

Abstract

Retinoic acid (RA) is teratogenic in rodents and also induces the synthesis of stress proteins in fetal mouse limb buds. To determine if the RA induction of stress proteins is target tissue specific, pregnant CD-1 mice were gavaged with 100 mg/kg RA on day 11 of gestation, and nuclei isolated from tissues susceptible to RA-induced malformations (target tissues) as well as nuclei isolated from nontarget tissues were examined for stress protein synthesis and malformations. Forelimb and hindlimb (target tissues), as well as heart and tail (nontarget tissues), were removed from embryos 2.5 hours after RA treatment (1.5 hr after [3H]leucine labeling). Cell nuclei were isolated, stained with a DNA specific fluorochrome, propidium iodide, and sorted from the G0 + G1 and G2 + M phases of the cell cycle. Forelimb and hindlimb target tissues showed the synthesis in these embryonic nuclear proteins of an 84,000 relative molecular mass (Mr) protein and a 90,000 Mr protein following RA treatment. Two 20,000-25,000 Mr stress proteins were also labeled both in forelimb and hindlimb. Forelimb and hindlimb from untreated dams showed no stress protein labeling. Neither heart nor tail, nontarget tissues, showed any stress protein labeling following RA treatment. Classical teratological evaluation of embryos treated on GD 11 and sacrificed on GD 17 showed that 100% of the fetuses had forelimb and/or hindlimb malformations, while no malformations were observed in either the heart or tail. Based on the correlation of teratological anomalies with the identification of stress proteins in target tissue only, we postulate that stress proteins may be involved in the teratogenic process. Further work is necessary to establish whether a causal relationship exists.

Inotropic Effect of Increasing Concentration of Ca2+ in the Fetal Rat Heart with Retinoic Acid-Induced Malformations

“…20). Our results have, however, clearly shown that the administration of RA significantly influenced the growth of rat fetuses, supporting the view that its effect is more complex and the heart is not the only target tissue (21). Furthermore, Ruberte et al (22,23) and Dolle et al (24) have shown that cellular RA-binding protein adjacent mesenchyme, and neural crest cells.…”

Mercury, cadmium, and arsenite enhance heat shock protein synthesis in chick embryos prior to embryotoxicity

“…In GD13 mice, maternal exposure to retinoic acid resulted in cleft palate and stress proteins of 34-, 84-, and 90-kD accumulated in craniofacial tissue. In GD11 mice, hindlimbs and forelimbs are the only tissues malformed by retinoic acid treatment, and accumulation of stress proteins of 25-, 84-, and 90-kD were specific to those tissues (Anson et al, 1991). The above studies suggest that stressors increase hsp synthesis in the affected tissues.…”

Alpha-B-Crystallin in Neuropathology

“…However, both proteins contain the so-called α-crystallin domain that is shared by all members of the sHSP family [10]and that presumably is responsible for the chaperone-like activity. sHSPs as well as αB-crystallin appeared to be involved in intracellular changes during disease progression [11, 12]. Besides, in disease progression, αB-crystallin is also involved in reactive processes of astrocytes and oligodendrocytes in the central nervous system [13], development of astrocytic tumors [14]and in the development of benign tumors associated with tuberous sclerosis.…”