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

Abstract

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.

Looking at Developmental Neurotoxicity Testing from the Perspective of an Invertebrate Embryo

“…Toxicant exposure is possible for the fly embryo and developing larvae. Dose-dependent larval exposure to methyl mercury, mercury chloride, lead acetate, and sodium arsenite induced larval lethality and reduced the time-delayed pupariation, metamorphosis, and eclosion, with methyl mercury as the most toxic metal compound [41]. This model also proved insightful for the study of metal mixtures.…”

Untitled

“…The upregulation of serotonin and downregulation of norepinephrine in the midbrain and diencephalon leads to lower gonadotrophin synthesis and secretion (Kaminski et al 1997). The toxic effect of Arsenic in a timedependent manner on flies' development had been reported earlier by (Beamish et al 2021), but there has been no mention of the Arsenic effect on fecundity of female flies. The present study revealed that female flies' fecundity decreased by increasing the Arsenite concentration in media, which corroborated with the findings of Quansah et al (2015).…”

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

“…A salient example of this is seen with an examination of lead, arsenic, and two mercury isoforms, where all of these metals can delay time to pupariation. However, methylmercury selectively inhibits eclosion at lower doses (Beamish et al., 2021). Other toxic effects can alter wings, eyes, bristles, and body size.…”

“…Since there is no single assay capable of measuring all metabolites within biological systems, the metabolomic approach used to study exposed flies must be thoughtfully selected to examine metabolites that will provide the most insight as to how a toxicant alters metabolism and physiology. For instance, metabolomics analysis of flies exposed to a heavy metal such as arsenic would use targeted methods to quantify metal ions, small polar metabolites, and lipids (for examples see Beamish et al., 2021; Carvalho et al, 2012; Li & Tennessen, 2018). Individual studies must also choose whether to employ a targeted approach designed to quantify a predetermined set of metabolites, an untargeted approach, which aims to measure as many metabolites as possible, or a hybrid method.…”