Detection of vulnerable neurons damaged by environmental insults in utero

Abstract

Development of prognostic biomarkers for the detection of prenatally damaged neurons before manifestations of postnatal disorders is an essential step for prevention and treatment of susceptible individuals. We have developed a versatile fluorescence reporter system in mice enabling detection of Heat Shock Factor 1 activation in response to prenatal cellular damage caused by exposure to various harmful chemical or physical agents. Using an intrautero electroporation-mediated reporter assay and transgenic reporter mice, we are able to identify neurons that survive prenatal exposure to harmful agents but remain vulnerable in postnatal life. This system may provide a powerful tool for exploring the pathogenesis and treatment of multiple disorders caused by exposure to environmental stress before symptoms become manifested, exacerbated, and/or irreversible.

Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling

“…5). Similar heterogeneous reporter expression patterns across embryos, as well as among cells within the brain and other tissues in each embryo, have been observed by prenatal exposure to other environmental factors including sodium arsenite, Pentylenetetrazol (PTZ)-induced maternal seizure, and lipopolysaccharide (LPS)-induced maternal inflammation22.…”

“…3a). No significant differences were detected between the founder lines22. Given that the electroporation-based reporter assay shows higher sensitivity in general23, this indicates that the transgenic reporter detects only cells in which Hsf1–Hsp signalling is activated at high levels.…”

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

“…Moreover, nursing mothers often use cannabis without realizing that delta-9-tetrahydrocannabinol (THC; the psychoactive cannabinoid) is transferred into breast milk and therefore poses risks to infants (Baker et al, 2018). Indeed, exposure to cannabis during critical windows of neurodevelopment has the potential to alter the endogenous cannabinoid (endocannabinoid [eCB]) system that is critical for hardwiring the developing brain (Harkany et al, 2007;Wu et al, 2011;Torii et al, 2017). This can predispose children to psychiatric disorders, many of which have a developmental etiology.…”

Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system

“…All animals were handled according to protocols approved by the Institutional Animal Care and Use Committees of the Children’s National Medical Center, the VA Connecticut Healthcare System, and Yale University. Generation of the HSE-RFP transgenic mice has been described previously ( Torii et al, 2017 ). Briefly, the sequence of the Hsp70 promoter region conserved across mammalian species was amplified by polymerase chain reaction (PCR).…”

“…Heat stress and many other stimuli can activate HSF1 through sequential protein modification events including phosphorylation, sumoylation, trimerization and nuclear translocation, triggering the transcription of HSPs and other downstream gene targets. Utilizing this cellular stress-inducible mechanism, we have recently reported the generation of a Heat Shock-response Element-Red Fluorescent Protein (HSE-RFP) reporter transgenic mouse line ( Torii et al, 2017 ). The reporter expression in these mice enables early identification of cells that exhibit altered molecular, morphological, and behavioral properties due to the damage by prenatal or postnatal exposure to a spectrum of chemical and physical environmental insults including alcohol, methyl mercury and x-ray ( Torii et al, 2017 ).…”