Toxicology seminars

T-cell engagers can be developed for both cancer and autoimmune disease, but differences in target cells, disease biology and therapeutic goals require different preclinical strategies. Wanjun Yuan and Haiqiao Sun compare model selection and evaluation endpoints, from T-cell engagement and tumour killing to B-cell depletion, immune reconstitution and safety. A case-based exchange examines how the same target may call for different studies across indications, including assessment of cytokine-release signals and the effects of dose and exposure on experimental design.

Caroline J. Smith examines how prenatal environmental exposures affect the development of social brain circuits through immune and gut–brain mechanisms. In a mouse model, gestational exposure to air pollution combined with maternal psychosocial stress produces persistent social-behaviour impairments alongside changes in neuroimmune signalling and gut microbial composition. The talk considers evidence that microglia and microbiota are points of convergence for these exposures, and discusses future experiments and their potential relevance as therapeutic targets.

Traditional testing can miss central-nervous-system safety problems until late drug development. Alastair J. King presents an integrated early-assessment strategy combining secondary pharmacology profiling, targeted screening for safety liabilities, and translational in-vitro neuronal models. Case studies explore off-target effects, seizure risk, abuse potential, and neurotoxicity, alongside emerging regulatory perspectives on New Approach Methodologies. The talk explains how combining these data can improve candidate selection and confidence in the safety of both CNS-targeted and other therapeutics.

NOAA's Mussel Watch records are examined as a unified framework for coastal contamination. The study combines sediment chemistry, toxicity, benthic condition and tissue measurements, using AMBI and M-AMBI scores at 732 national assessment sites and 33 Hudson–Raritan stations. Random-forest and Bayesian models associate urbanization with benthic condition in the New York region (ρ=0.62), but not nationally (ρ=0.05). A Delft3D estuary model reproduces observed tides and predicts increased deep-channel bed shear under sea-level rise. The work asks whether sediment contaminants mediate urbanization impacts and whether legacy cleanup remains effective as sea level changes. It was conducted through a NOAA NERTO graduate internship with Kimani Kimbrough and Erik Davenport at NCCOS.

Liver toxicity can emerge late in drug development when early assays fail to capture human biology, exposure or injury mechanisms. This webinar introduces Axiom’s hepatic profiling approach, combining multicellular liver systems, high-content imaging, transcriptomics, proteomics and ADME measurements. Its reasoning agent integrates those results with partner assays, chemical-series context, exposure estimates and clinical evidence to assess mechanistic liver-safety risks. Rather than using a single cell-toxicity score, the approach develops interpretable, series-specific structure–toxicity hypotheses, compares analogues, ranks compounds and suggests follow-up experiments or structural changes. Performance on established liver-injury reference compounds and newer molecules is examined through case studies, showing how multimodal evidence can inform medicinal-chemistry decisions and predicted therapeutic index.

Cancer-related fatigue is a prominent and debilitating side effect of cancer and its treatment. It can develop prior to diagnosis, generally peaks during cancer treatment, and can persist long after treatment completion. Its mechanisms are multifactorial, and its expression is highly variable. Unfortunately, treatment options are limited. Our research uses syngeneic murine models of cancer and cisplatin-based chemotherapy to better understand these mechanisms. Our data indicate that both peripherally and centrally processes may contribute to the developmental of fatigue. These processes include metabolic alterations, mitochondrial dysfunction, pre-cachexia, and inflammation. However, our data has revealed that behavioral fatigue can persist even after the toxicity associated with cancer and its treatment recover. For example, running during cancer treatment attenuates kidney toxicity while also delaying recovery from fatigue-like behavior. Additionally, administration of anesthetics known to disrupt memory consolidation at the time treatment can promote recovery, and treatment-related cues can re-instate fatigue after recovery. Cancer-related fatigue can also promote habitual behavioral patterns, as observed using a devaluation task. We interpret this data to suggest that limit metabolic resources during cancer promote the utilization of habit-based behavioral strategies that serve to maintain fatigue behavior into survivorship. This line of work is exciting as it points us toward novel interventional targets for the treatment of persistent cancer-related fatigue.

Proper development of the nervous system depends not only on the inherited DNA sequence, but also on proper regulation of gene expression, as controlled in part by epigenetic mechanisms present in the parental gametes. In this presentation an internationally recognized research advocate explains why researchers concerned about the origins of increasingly prevalent neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder should look beyond genetics in probing the origins of dysregulated transcription of brain-related genes. The culprit for a subset of cases, she contends, may lie in the exposure history of the parents, and thus their germ cells. To illustrate how environmentally informed, nongenetic dysfunction may occur, she focuses on the example of parents' histories of exposure to common agents of modern inhalational anesthesia, a highly toxic exposure that in mammalian models has been seen to induce heritable neurodevelopmental abnormality in offspring born of exposed germline.

In this talk I will discuss our recent findings that sensory signals from the brain adjust the physiology and behavior of the nematode C. elegans, enabling this animal to deal with the lethal threat of hydrogen peroxide. Hydrogen peroxide (H2O2) is the most common chemical threat in the microbial battlefield. Prevention and repair of the damage that hydrogen peroxide inflicts on macromolecules are critical for health and survival. In the first part of the talk, I will discuss our findings that C. elegans represses their own H2O2 defenses in response to sensory perception of Escherichia coli, the nematode’s food source, because E. coli can deplete H2O2 from the local environment and thereby protect the nematodes. Thus, the E. coli self-defense mechanisms create a public good, an environment safe from the threat of H2O2, that benefits C. elegans. In the second part of the talk, I will discuss how the modulation of C. elegans’ sensory perception by the interplay of hydrogen peroxide and bacteria adjusts the nematode’s behavior to improve the nematode’s chances of finding a niche that provides both food and protection from hydrogen peroxide.

Gestational exposure to environmental toxins, infections, and stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism spectrum disorder. We modeled some of these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly dysregulated the maternal immune system. Male but not female offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions, along with disruptions of gut structure and microbiome composition. Cellularly, prenatal stressors impaired microglial synaptic pruning in males during early postnatal development. Precise inhibition of microglial phagocytosis during the same critical period mimicked the impact of prenatal stressors on the male-specific social deficits. Conversely, modifying the gut microbiome rescued the social and cellular deficits, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development, perhaps via a gut-brain disruption.

The risks of in utero and early exposure to environmental contaminants, such as heavy metals and persistent organic pollutants, on child neurodevelopment is now established, however our understanding of how these contaminants alter the human brain is very limited. To address this issue, more effort must be made to integrate brain imaging tools with epidemiological studies. In this seminar, I will be presenting EEG and MRI data collected in birth-cohort studies where impairments of cognitive and sensory functions were observed in association with prenatal exposure to mercury, lead, PCB or organophosphate insecticides. Results obtained in children and adolescents suggest that each pollutant might affect different levels of brain processing and that frontal regions are particularly vulnerable.

Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.

Chemotherapeutic drugs (used for treating cancer), HIV infection and antiretroviral therapy (ART) can independently cause difficult-to-manage painful neuropathy. Paclitaxel, a chemotherapeutic drug, for example is associated with high incidence of peripheral neuropathy, around 71% of the patients of which 27% of these develop neuropathic pain. Use of cannabis or phytocannabinoids has been reported to improve pain measures in patients with neuropathic pain, including painful HIV-associated sensory neuropathy and cancer pain. Phytocannabinoids and endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), produce their effects via cannabinoid (CB) receptors, which are present both in the periphery and central nervous system. Endocannabinoids are synthesized in an “on demand” fashion and are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Various studies, including those from our group, suggest that there are changes in gene and protein expression of endocannabinoid molecules during chemotherapy-induced neuropathic pain (CINP), HIV and antiretroviral-induced neuropathic pain. Analysis of endocannabinoid molecule expression in the brain, spinal cord and paw skin using LC-MS/MS show that there is a specific deficiency of the endocannabinoids 2-AG and/or anandamide in the periphery during CINP. Various drugs including endocannabinoids, cannabidiol, inhibitors of FAAH and MGL, CB receptor agonists, desipramine and coadministered indomethacin plus minocycline have been found to either prevent the development and/or attenuate established CINP, HIV and antiretroviral-induced neuropathic pain in a CB receptor-dependent manner. The results available suggest that targeting the endocannabinoid system for prevention and treatment of CINP, HIV-associated neuropathic pain and antiretroviral-induced neuropathic pain is a plausible therapeutic option.