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Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups.

ABSTRACT: Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum. METHODS:Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1?, IL-6, transforming growth factor-? (TGF-?), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-?B). RESULTS:In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1?, IL-6, TGF-?, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-?B expression. CONCLUSIONS:Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.

SUBMITTER: Chibowska K

PROVIDER: S-EPMC7037720 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups.

Chibowska Karina K Korbecki Jan J Gutowska Izabela I Metryka Emilia E Tarnowski Maciej M Goschorska Marta M Barczak Katarzyna K Chlubek Dariusz D Baranowska-Bosiacka Irena I

International journal of molecular sciences 20200206 3

Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum.<h4>Methods</h4>Administration of 0.1% lead acetate (PbAc) in ...[more]

PMID: 32041252

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Project description:IntroductionCerebellum cortex fractional anisotropy is a proxy of the integrity of the cerebellum cortex. However, less is known about how it is shaped by race and socioeconomic status (SES) indicators such as parental education and household income.PurposeIn a national sample of American pre-adolescents, this study had two aims: to test the effects of two SES indicators, namely parental education and household income, on cerebellum cortex fractional anisotropy, and to explore racial differences in these effects.MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) study, we analyzed the diffusion Magnetic Resonance Imaging (dMRI) data of 9565, 9-10-year-old pre-adolescents. The main outcomes were cerebellum cortex fractional anisotropy separately calculated for right and left hemispheres using dMRI. The independent variables were parental education and household income; both treated as categorical variables. Age, sex, ethnicity, and family marital status were the covariates. Race was the moderator. To analyze the data, we used mixed-effects regression models without and with interaction terms. We controlled for propensity score and MRI device.ResultsHigh parental education and household income were associated with lower right and left cerebellum cortex fractional anisotropy. In the pooled sample, we found significant interactions between race and parental education and household income, suggesting that the effects of parental education and household income on the right and left cerebellum cortex fractional anisotropy are all significantly larger for White than for Black pre-adolescents.ConclusionsThe effects of SES indicators, namely parental education and household income, on pre-adolescents' cerebellum cortex microstructure and integrity are weaker in Black than in White families. This finding is in line with the Marginalization-related Diminished Returns (MDRs), defined as weaker effects of SES indicators for Blacks and other racial and minority groups than for Whites.

Project description:Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children, yet specific therapies to treat TBI are lacking. Therapies that decrease the inflammatory response and enhance a reparative immune action may decrease oxidative damage and improve outcomes after TBI. Docosahexaenoic acid (DHA) modulates the immune response to injury in many organs. DHA given in the diet before injury decreased rat pup cognitive impairment, oxidative stress and white matter injury in our developmental TBI model using controlled cortical impact (CCI). Little is known about DHA effects on neuroinflammation in the developing brain. Further, it is not known if DHA given after developmental TBI exerts neuroprotective effects. We hypothesized that acute DHA treatment would decrease oxidative stress and improve cognitive outcome, associated with decreased pro-inflammatory activation of microglia, the brain's resident macrophages. METHODS:17-day-old rat pups received intraperitoneal DHA or vehicle after CCI or SHAM surgery followed by DHA diet or continuation of REG diet to create DHACCI, REGCCI, SHAMDHA and SHAMREG groups. We measured brain nitrates/nitrites (NOx) at post injury day (PID) 1 to assess oxidative stress. We tested memory using Novel Object Recognition (NOR) at PID14. At PID 3 and 7, we measured reactivity of microglial activation markers Iba1, CD68 and CD206 and astrocyte marker GFAP in the injured cortex. At PID3, 7 and 30 we measured mRNA levels of inflammation-related genes and transcription factors in flow-sorted brain cells. RESULTS:DHA decreased oxidative stress at PID1 and pro-inflammatory microglial activation at PID3. CCI increased mRNA levels of two interferon regulatory family transcription factors, blunted by DHA, particularly in microglia-enriched cell populations at PID7. CCI increased mRNA levels of genes associated with "pro- " and "anti-" inflammatory activity at PID3, 7 and 30. Most notably within the microglia-enriched population, DHA blunted increased mRNA levels of pro-inflammatory genes at PID 3 and 7 and of anti-inflammatory genes at PID 30. Particularly in microglia, we observed parallel activation of pro-inflammatory and anti-inflammatory genes. DHA improved performance on NOR at PID14 after CCI. CONCLUSIONS:DHA decreased oxidative stress and histologic and mRNA markers of microglial pro-inflammatory activation in rat pup brain acutely after CCI associated with improved short term cognitive function. DHA administration after CCI has neuroprotective effects, which may result in part from modulation of microglial activation toward a less inflammatory profile in the first week after CCI. Future and ongoing studies will focus on phagocytic function and reactive oxygen species production in microglia and macrophages to test functional effects of DHA on neuroinflammation in our model. Given its favorable safety profile in children, DHA is a promising candidate therapy for pediatric TBI.

Dataset Information

Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups.

Publications

Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups.

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