Windows of Sensitivity to Toxic Chemicals in the Development of Cleft Palates

Abstract

Cleft lip and cleft palate are among the most common birth defects worldwide. There is a genetic component to the development of these malformations, as well as evidence that environmental exposures and prescription drug use may exacerbate or even produce these manifestations. Thus, it is important to understand the underlying mechanisms and when these exposures affect development of the growing fetus. The purpose of this investigation was to critically review the available literature related to orofacial cleft formation following chemical exposure and identify specific time frames for windows of sensitivity. Further, an aim was to evaluate the potential for predicting effects in humans based on animal studies. Evidence indicates that chemical causes of cleft palate development are due to dose and timing of exposure, susceptibility of the species (i.e., the genetic makeup), and mechanism of action. Several studies demonstrated that dose is a crucial factor; however, some investigators argued that even more important than dose was timing of exposure. Data show that the window of sensitivity to environmental teratogens in the development of cleft palates is quite narrow and follows closely the window of palatogenesis in the fetus of any given species.

Windows of sensitivity to toxic chemicals in the development of reproductive effects: an analysis of ATSDR’s toxicological profile database

“…The Gray and Ostby (1995) experiments also show that the effects can be found across species. Previously, we have noted differences among strains of species (Buser and Pohl 2015). Differences among strains were evaluated for this review; however, there were no noteworthy patterns to report.…”

“…Principal rules of toxicology discussed in our previous papers include: (1) the dose of the chemical,(2) time of exposure (sensitive window), and (3) species differences (Buser and Pohl 2015; Ingber and Pohl 2016). These variables are also critical for determining effects that tested chemicals may have on the development of the reproductive system.…”

“…Previously, we have investigated the windows of sensitivity in the development of cleft palates (Buser and Pohl 2015) and of motor function (Ingber and Pohl 2016) using the Agency for Toxic Substances and Disease Registry’s (ATSDR’s) toxicological profiles. ATSDR publishes toxicological profiles for hazardous substances that examine, summarize, and interpret available toxicological studies in order to ascertain levels of exposure for humans that may be associated with health effects (https://www.atsdr.cdc.gov/toxprofiles/index.asp).…”

Mechanisms of Developmental Toxicity of Dioxins and Related Compounds

“…The incidence in the earlier period is low to modest (0–40%) at a TCDD dose of up to 40 μg/kg [14,16,17], whereas it is high (100%) at a dose of 80 μg/kg [17], suggesting that the higher dose cancels the apparent window of susceptibility in the earlier period. The lower or no incidence in later periods irrespective of the lower or higher dose [14,15,16,17] is considered to be related to the timing of palatogenesis completion [18].…”

Windows of sensitivity to toxic chemicals in the motor effects development

“…The windows of sensitivity to environmental toxicants in the development of neurological effects are not that well defined as compared to the window for development of cleft palates. The window of sensitivity for cleft palate coincides with development of the palate itself (Buser and Pohl, 2015). In contrast, neurological effects may develop during organogenesis, proliferation and migration of nerves, differentiation and synaptogenesis, and myelination over a much broader time period.…”