Facing the Challenge of Data Transfer from Animal Models to Humans: the Case of Persistent Organohalogens

A well-documented fact for a group of persistent, bioaccumulating organohalogens contaminants, namely polychlorinated biphenyls (PCBs), is that appropriate regulation was delayed, on average, up to 50 years. Some of the delay may be attributed to the fact that the science of toxicology was in its infancy when PCBs were introduced in 1920's. Nevertheless, even following the development of modern toxicology this story repeats itself 45 years later with polybrominated diphenyl ethers (PBDEs) another compound of concern for public health. The question is why? One possible explanation may be the low coherence between experimental studies of toxic effects in animal models and human studies. To explore this further, we reviewed a total of 807 PubMed abstracts and full texts reporting studies of toxic effects of PCB and PBDE in animal models. Our analysis documents that human epidemiological studies of PBDE stand to gain little from animal studies due to the following: 1) the significant delay between the commercialisation of a substance and studies with animal models; 2) experimental exposure levels in animals are several orders of magnitude higher than exposures in the general human population; 3) the limited set of evidence-based endocrine endpoints; 4) the traditional testing sequence (adult animals – neonates – foetuses) postpones investigation of the critical developmental stages; 5) limited number of animal species with human-like toxicokinetics, physiology of development and pregnancy; 6) lack of suitable experimental outcomes for the purpose of epidemiological studies. Our comparison of published PCB and PBDE studies underscore an important shortcoming: history has, unfortunately, repeated itself. Broadening the crosstalk between the various branches of toxicology should therefore accelerate accumulation of data to enable timely and appropriate regulatory action

Astrocyte scar formation aids central nervous system axon regeneration

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration