Abstract: Mercury, cadmium, arsenic and lead are among priority metals for toxicological studies due to the frequent human exposure and to the significant burden of disease following acute and chronic intoxication. Among their common characteristics is chemical affinity to proteins and non-protein thiols and their ability to generate cellular oxidative stress by the best-known Fenton mechanism. Their health effects are however diverse: kidney and liver damage, cancer at specific sites, irreversible neurological damages with metal-specific features. Mechanisms for the induction of oxidative stress by interaction with the cell thiolome will be presented, based on literature evidence and of experimental findings.
Abstract: The C57BL/6 (B6) mouse is the background strain most frequently used for genetically-modified mice. Previous studies have found significant behavioral and genetic differences between the B6J (The Jackson Laboratory) and B6N substrains (National Institutes of Health); however, most studies employed only male mice. We performed a comprehensive battery of motor function and learning and memory tests on male and female mice from both substrains. The B6N male mice had greater improvement in the rotarod test. In contrast, B6J female mice had longer latencies to falling from the rotarod. In the Morris water maze (MWM), B6J males had significantly shorter latencies to finding the hidden platform. However, B6N females had significantly shorter path lengths in the reversal and shifted-reduced phases. In open field locomotor activity, B6J males had higher activity levels, whereas B6N females took longer to habituate. In the fear conditioning test, B6N males had a significantly longer time freezing in the new context compared with B6J males, but no significant differences were found in contextual or cued tests. In summary, our findings demonstrate the importance of testing both males and females in neurobehavioral studies. Both factors (sex and substrain) must be taken into account when designing developmental neurotoxicology studies.
Abstract: The US National Research Council recently released a report promoting sustainability assessment as the future of environmental regulation. Thirty years earlier, this organization (under the same senior author) had issued a similar report promoting risk assessment as a new method for improving the science behind regulatory decisions. Tools for risk assessment were subsequently developed and adopted in state and federal agencies throughout the US. Since then, limitations of the traditional forms of risk assessment have prompted some dramatic modifications toward cumulative assessments that combine multiple chemical and non-chemical stressors in community settings. At present, however, there is little momentum within the risk assessment community for abandoning this evolved system in favor of a new sustainability-based one. The key question is, how best to proceed? Should sustainability principles be incorporated into current risk assessment procedures, or vice versa? Widespread recognition of the importance of sustainability offers no clear guidance for the risk assessment community, especially in light of institutional commitments to sustainability tools and definitions that appear to have little in common with cumulative risk notions. The purpose of this paper is to reframe the sustainability challenge for risk assessors by offering analytical guidance to chart a way out. We adopt a decision analysis framework to overcome some conceptual barriers separating these two forms of assessment, and thereby, both escape the either/or choice and accept the inevitability of sustainability as a central regulatory concern in the U.S.
Abstract: Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4'-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'-triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND) 4–21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0 mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations.
Abstract: Developmental exposure to neurotoxic chemicals presents significant health concerns because of the vulnerability of the developing central nervous system (CNS) and the immature brain barrier. To date, a short list of chemicals including some metals have been identified as known developmental neurotoxicants; however, there are still numerous chemicals that remain to be evaluated for their potential developmental neurotoxicity (DNT). To facilitate evaluation of chemicals for DNT, the zebrafish vertebrate model system has emerged as a promising tool. The zebrafish possesses a number of strengths as a test species in DNT studies including an abundance of embryos developing ex utero presenting ease in chemical dosing and microscopic assessment at all early developmental stages. Additionally, rapid neurodevelopment via conserved molecular pathways supports the likelihood of recapitulating neurotoxic effects observed in other vertebrates. In this review, we describe the biological relevance of zebrafish as a complementary model for assessment of DNT. We then focus on a metalloid and two metals that are known developmental neurotoxicants (arsenic, methylmercury, and lead). We summarize studies in humans and traditional vertebrate models and then detail studies defining the toxicity of these substances using the zebrafish to support application of this model system in DNT studies.