Heart developmental defects

In animals, both vitamin A deficiency and an excess of dietary vitamin A or retinoid analogs, at specific critical periods of development, can result in severe developmental defects, and may be lethal to the embryo. The differentiation of cells in the neural crest and the development of the head and sensory organs, nervous system, heart, limbs, and skeleto-muscular system are often affected. Birth defects of a similar nature have occurred in women exposed to excessive dietary vitamin A, or to pharmacologic retinoids for treatment of skin diseases, in early pregnancy. 

Developmental effects of trichloroethylene exposure have been demonstrated with the FETAX (Frog Embryo Teratogenesis Assay Xenopus) bioassay, an in vitro method using whole frog embryos (Fort et al. 1991, 1993 Rayburn et al. 1991). Observed defects included gut miscoding, skeletal kinking, and heart malformations heart malformations have also been observed in rat developmental assays (Dawson et al. 1993). 

Mirex has considerable potential for chronic toxicity because it is only partly metabolized, is eliminated very slowly, and is accumulated in the fat, liver, and brain. The most common effects observed in small laboratory mammals fed mirex included weight loss, enlarged livers, altered liver enzyme metabolism, and reproductive failure. Mirex reportedly crossed placental membranes and accumulated in fetal tissues. Among the progeny of mirex-treated mammals, developmental abnormalities included cataracts, heart defects, scoliosis, and cleft palates (NAS 1978 Blus 1995). 

Muscle, whose structure and function are discussed in Chapter 19, develops in response to four members of the myoD family. These include myoD, myogenin, myf5, and MRF4.417-419 All are muscle-specific transcription factors of the basic helix -loop -helix class. An unusual aspect of muscle development is formation of multinucleate myotubes (muscle fibers p. 1096)420 Apoptosis plays an important role in muscle development and can present significant complications in damaged cardiac muscle.421 Defects in several developmental control genes are responsible for congenital heart diseases.422... 

Developmental toxicity has also been observed in animals exposed to other CDDs. These effects include heart defects in rats exposed to 2,7-DCDD (Schwetz et al. 1973) decreased thymic weight in rats exposed to 1,2,3,7,8-PCDD (Madsen and Larsen 1989) subcutaneous edema, decreased fetal growth, delayed ossification, dilated renal pelvis, and cleft palate in rats exposed to HxCDD (Schwetz et al. 

As indicated previously, adverse health outcomes from early exposures may become apparent at any point in the lifespan. In some instances, they may be apparent only after long latency periods. Chapter 6 addresses the various methodologies that can be used to assess health outcomes. Studies have shown that the effects of toxic exposures on developmental processes may result from different mechanisms of action, and the toxic exposures may produce different health outcomes compared with the same exposures in adults. Some examples of health effects resulting from developmental exposures include those observed prenatally and at birth (e.g. miscarriage, stillbirth, low birth weight, birth defects), in young children (e.g. asthma, neurobehavioural and immune impairment), in adolescents (e.g. precocious or delayed puberty), and in adults (e.g. diabetes and heart disease). 

Perhaps the most striking illustration of the pervasive developmental effects of thyroid hormones is provided by children with severe thyroid hormone deficiency from early childhood, a condition termed cretinism. This may either be endemic in regions of severe iodine deficiency or sporadic due to failure of the thyroid to develop normally or defects in the synthesis of thyroid hormone. Affected children are dwarfed with short extremities, have mental retardation, and are inactive and listless. Other manifestations include facial puffiness, enlarged tongue, dry and doughy skin, slow heart rate, and decreased body temperature. Eor full recovery, treatment of patients with cretinism must be initiated before these florid features are apparent. Thus, pregnant women in areas of endemic cretinism due to iodine deficiency are supplemented with iodine and aU newborns are screened for thyroid hormone deficiency in many developed nations. 

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