Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.

BACKGROUND: The association between childhood cancer risk and maternal prenatal substance use/abuse remains uncertain due to modest sample sizes and heterogeneous study designs. METHODS: We surveyed parents of children with cancer regarding maternal gestational use of tobacco, alcohol, and illicit drugs, using a Likert-type scale, and demographic, perinatal, and clinical variables. Multivariable log-Poisson regression assessed differences in frequency of prenatal substance use across fifteen childhood cancer subtypes, adjusting for birthweight, gestational age, and demographic factors. RESULTS: Respondents from 3,145 unique families completed the survey (92% biological mothers). A minority reported gestational use of tobacco products (14%), illicit drugs including marijuana or cocaine (4%), or more than a moderate amount of alcohol (2%). Prenatal illicit drug use was associated with increased prevalence of intracranial embryonal tumors [prevalence ratio (PR) = 1.94; confidence interval [CI], 1.05-3.58], including medulloblastoma (PR = 1.82) and supratentorial primitive neuroectodermal tumors (PNET; PR = 2.66), and was also associated with retinoblastoma (PR = 3.11; CI, 1.20-8.08). Moderate to heavy alcohol consumption was strongly associated with elevated prevalence of non-Hodgkin lymphoma (PR = 5.94; CI, 1.84-19.21). Prenatal smoking was not associated with elevated prevalence of any childhood cancer subtype. CONCLUSIONS: We identify novel associations between illicit drug use during pregnancy and increased prevalence of nonglioma central nervous system tumors, including medulloblastoma, supratentorial PNETs, and retinoblastoma. Gestational exposure to alcohol was positively associated with non-Hodgkin lymphoma. IMPACT: Although alcohol and tobacco use during pregnancy has declined, gestational cannabis use has risen. Investigating its impact on neurodevelopment and brain tumorigenesis is vital, with important implications for childhood cancer research and public health education.

Misexpression of ptf1a in cortical pyramidal cells in vivo promotes an inhibitory peptidergic identity.

The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al., 2008), retina (Fujitani et al., 2006; Dullin et al., 2007; Nakhai et al., 2007; Lelièvre et al., 2011), and cerebellum (Hoshino et al., 2005; Pascual et al., 2007; Yamada et al., 2014), where it promotes an inhibitory over an excitatory neuronal identity. In this study, we investigate the potency of Ptf1a to cell autonomously confer a specific neuronal identity outside of its endogenous environment, using mouse in utero electroporation and a conditional genetic strategy to misexpress Ptf1a exclusively in developing cortical pyramidal cells. Transcriptome profiling of Ptf1a-misexpressing cells using RNA-seq reveals that Ptf1a significantly alters pyramidal cell gene expression, upregulating numerous Ptf1a-dependent inhibitory interneuron markers and ultimately generating a gene expression profile that resembles the transcriptomes of both Ptf1a-expressing spinal interneurons and endogenous cortical interneurons. Using RNA-seq and in situ hybridization analyses, we also show that Ptf1a induces expression of the peptidergic neurotransmitter nociceptin, while minimally affecting the expression of genes linked to other neurotransmitter systems. Moreover, Ptf1a alters neuronal morphology, inducing the radial redistribution and branching of neurites in cortical pyramidal cells. Thus Ptf1a is sufficient, even in a dramatically different neuronal precursor, to cell autonomously promote characteristics of an inhibitory peptidergic identity, providing the first example of a single transcription factor that can direct an inhibitory peptidergic fate.

Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord.

During perinatal development, corticospinal tract (CST) projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit. We found that putative GABApre interneurons receive CST input and, using an established mouse model of perinatal stroke, that cortical ischemic injury results in a reduction of CST density within the intermediate region of the spinal cord, where these interneurons reside. Importantly, CST alterations were restricted to the side contralateral to the injury. Within the synaptic terminals of the GABApre interneurons, we observed a dramatic upregulation of the 65-isoform of the GABA synthetic enzyme glutamic acid decarboxylase (GAD65). In accordance with the CST density reduction, GAD65 was elevated on the side of the spinal cord contralateral to cortical injury. This effect was not seen for other GABApre synaptic markers or in animals that received sham surgery. Our data reveal a novel effect of perinatal stroke that involves severe deficits in the architecture of a descending spinal pathway, which in turn appear to promote molecular alterations in a specific spinal GABAergic circuit.