Developmental toxicity chemical mediation

The effects of a chemical in a tissue frequently depend on the chemical s interaction with cell surface or cytoplasmic receptors. In some cases, a chemical interacts directly with the cell membrane and alters its permeability. The pharmacodynamic actions of drugs are usually mediated by interactions with a receptor, and a drug often competes with endogenous ligands of a receptor. The toxicity of environmental chemicals can also depend on and be mediated by interactions with receptors. In some cases, the responses are different for chemical exposures at different fetal stages of development, and it is possible to explain the different responses by the chronology of the development of fetal receptor systems. The fetus may develop receptor systems for a compound before it develops the ability to metabolize that compound thus, a low level of an active chemical can have greater and more persistent effects in the fetus than in the mother, whose metabolism limits the duration and extent of the effect. This is one mechanism for selective developmental toxicity of chemicals. 

Preconceptual and transplacental carcinogenesis are special types of developmental toxicity and can result when either parent is exposed prior to mating. Both male-mediated and female-mediated effects have been demonstrated in experimental animals for a variety of chemicals and several types of radiation (Anderson, 2000). Transplacental carcinogenesis is recognized in the female, but carcinogenesis mediated through the male germ cells is not as well appreciated or understood. 

Classification should not automatically be discounted for chemicals that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a chemical is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it may be reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification may not necessarily be the outcome in the case of minor developmental changes e.g. small reduction in foetal/pup body weight, retardation of ossification when seen in association with maternal toxicity. 

Although drugs such as acetaminophen bind to AhR, the majority of AhR agonists or antagonists are environmental chemicals. Polychlorinated diben-zodioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), dibenzofu-rans, biphenyls, and a number of other chemicals are widespread pollutants in aquatic ecosystems. These compounds cause a high reproductive and developmental toxicity, which is mediated via binding to the AhR. Thus they pose a serious threat to many populations of mammals, birds, and fish. Various adverse effects—including structural malformations, reduced fertility, tumor promotion, immunotoxicity, and skin disorders like chloracne—have been observed [139]. 

ROS, or repair the macromolecular damage (Fig. 4). If there is an imbalance favoring accumulation of the reactive intermediate and/or macromolecular damage, that individual can experience developmental toxicity at a therapeutic dose or concentration of a drug, or a normally safe level of exposure to an environmental chemical. Particularly for reactive intermediate-mediated mechanisms, most of the data are derived from animal studies, and very little has been confirmed in humans. 

A.7.2.3.5 If appropriate information is available it is important to try to determine whether developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of maternal toxicity should not be used to negate findings of embryo/fetal effects, unless it can be clearly demonstrated that the effects are secondary nonspecific effects. This is especially the case when the effects in the offspring are significant, e.g., irreversible effects such as structural malformations. In some situations it is reasonable to assume that reproductive toxicity is due to a secondary consequence of maternal toxicity and discount the effects, for example if the chemical is so toxic that dams fail to thrive and there is severe inanition they are incapable of nursing pups or they are prostrate or dying. 

Compensatory changes, which occur in response to TCDD s primary effects, can complicate the analysis of dioxin action in intact animals. For example, TCDD can produce changes in the levels of steroid hormones, peptide growth factors, and/or their cognate cellular receptors. In turn, such alterations have the potential to produce a series of subsequent biological effects, which are not directly mediated by the Ah receptor. Furthermore, the hormonal status of an animal appears to influence its susceptibility to the hepatocarcinogenic effects of TCDD [172]. Likewise, exposure to other chemicals can alter the developmental toxicity of TCDD [173] Therefore, in some cases, TCDD may act in combination with other chemicals to produce its biological effects. 

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