Arrhenius thermodynamics and birth defects: Chemical teratogen synergy. Untested, testable, and projected relevance

Abstract

This article addresses the issue of hyperthermia-induced birth defects with an accompanying additional teratogen, be it a chemical or a physical agent (i.e., a simultaneous "combinational" exposure to two teratogens, one of which is hyperthermia). Hyperthermia per se is a recognized human and animal teratogen. An excellent example of such combinational exposures is an epileptic woman who becomes pregnant while taking valproic acid (VPA) to control seizures. VPA is a recognized chemical teratogen, and fever (hyperthermia) is not an uncommon event during pregnancy. While VPA also may occasionally induce fever as a side effect, we are concerned here with fevers arising from other, unrelated causes. There is a small but internally consistent literature on these combinational-teratogen exposures involving hyperthermia plus a chemical teratogen; in each instance, the effect level has been observed to be synergistically elevated above levels induced by the separate teratogenic components. The data were empirical. The observed synergy is, however, consistent with Arrhenius thermodynamics, a well-known chemical rate equation. The need for information about combinational teratogen exposures is acute; fever is a common occurrence during pregnancy; and there are many instances whereby there is also the simultaneous presence of some other teratogen(s). Given that the rate of autism spectrum disorders in the United States was recently presented as 1 in 88 births, it seems reasonable to suspect that such combinational regimens are much more prevalent than previously thought. Our hypothesis is that synergistic birth defect levels from combinational regimens are consistent with Arrhenius thermodynamics.

Elevated temperature fatally disrupts nuclear divisions in the earlyDrosophilaembryo

“…Temperature is a key factor determining the fidelity of embryonic development. Studies have shown occurrence of birth defects due to hyperthermia during pregnancy (Edwards 2006; Miller and Church 2013; Graham 2020), in spite of active regulation of core temperature. Here, the cell biological basis for the developmental defects due to an exposure to high temperature, remains elusive.…”

“…Previous studies suggest that such gradal departure could, under certain circumstances, impact animal suvival. For instance, studies have shown the occurrence of birth defects due to high fever during pregnancy in humans [2][3][4] , indicating that the same temperature condition is more detrimental to the embryo than it is to the adult. This raises the possibility that specific characteristics of embryo development renders it more vulnerable to temperature increase.…”

Biomechanics and the Thermotolerance of Development

“…They may be exposed to environmental toxins, limited nutrients, extreme temperatures, etc. We are particularly interested in one of these environmental factors, temperature, since temperature extremes can result in a diverse set of birth defects [1] – [4] . High fever is one of the largest risk factors leading to birth defects.…”