Developmental Toxicology of Metal Mixtures in Drosophila: Unique Properties of Potency and Interactions of Mercury Isoforms

Mercury ranks third on the U.S. Agency of Toxic Substances and Disease Registry priority list of hazardous substances, behind only arsenic and lead. We have undertaken uncovering the mechanisms underlying the developmental toxicity of methylmercury (MeHg), inorganic mercury (HgCl2), lead acetate (Pb), and sodium arsenite (As). To probe these differences, we used the Drosophila model, taking advantage of three developmental transitions—pupariation, metamorphosis, and eclosion—to differentiate potentially unique windows of toxicity. We elaborated dose response profiles for each individual metal administered in food and accounted for internal body burden, also extending analyses to evaluate combinatorial metal mixture effects. We observed all four metals producing larval lethality and delayed pupariation, with MeHg being most potent. Compared to other metals, MeHg’s potency is caused by a higher body burden with respect to dose. MeHg uniquely caused dose-dependent failure in eclosion that was unexpectedly rescued by titrating in HgCl2. Our results highlight a unique developmental window and toxicokinetic properties where MeHg acts with specificity relative to HgCl2, Pb, and As. These findings will serve to refine future studies aimed at revealing tissue morphogenesis events and cell signaling pathways, potentially conserved in higher organisms, that selectively mediate MeHg toxicity and its antagonism by HgCl2.

Reliability Simulation of Two Component Warm-Standby System with Repair, Switching, and Back-Switching Failures under Three Aging Assumptions

We analyze the influence of repair on a two-component warm-standby system with switching and back-switching failures. The repair of the primary component follows a minimal process, i.e., it experiences full aging during the repair. The backup component operates only while the primary component is being repaired, but it can also fail in standby, in which case there will be no repair for the backup component (as there is no indication of the failure). Four types of system failures are investigated: both components fail to operate in a different order or one of two types of switching failures occur. The reliability behavior of the system is investigated under three different aging assumptions for the backup component during warm-standby: full aging, no aging, and partial aging. Four failure and repair distributions determine the reliability behavior of the system. We analyzed two cases—in the First Case, we utilized constant failure rate distributions. In the Second Case, we applied the more realistic time-dependent failure rates. We used three methods to identify the reliability characteristics of the system: analytical, numerical, and simulational. The analytical approach is limited and only viable for constant failure rate distributions i.e., the First Case. The numerical method integrates simultaneous Algebraic Differential Equations. It produces a solution in the First Case under any type of aging, and in the Second Case but only under the assumption of full aging in warm-standby. On the other hand, the developed simulation algorithms produce solutions for any set of distributions (i.e., the First Case and the Second Case) under any of the three aging assumptions for the backup component in standby. The simulation solution is quantitively verified by comparison with the other two methods, and qualitatively verified by comparing the solutions under the three aging assumptions. It is numerically proven that the full aging and no aging solutions could serve as bounds of the partial aging case even when the precise mechanism of partial aging is unknown.