Maternal glucose intolerance during pregnancy affects offspring POMC expression and results in adult metabolic alterations in a sex-dependent manner.

Introduction: Gestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance. Methods: To investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined. Results: As expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning. Discussion: This work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.

Characterizing the protracted neurobiological and neuroanatomical effects of paraquat in a murine model of Parkinson's disease.

The primary motor symptoms of Parkinson's disease (PD) result from the degeneration of dopamine-producing neurons of the substantia nigra pars compacta (SNc), and often, the loss is asymmetrical, resulting in unilateral tremor presentation. Notably, age is the primary risk factor for PD, and it is likely that the disease ultimately stems from the impact of environmental factors, which interact with the aging process. Recent research has focused on the role of microglia and pro-oxidative responses in dopaminergic neuronal death. In this study, we sought to examine the neurodegenerative, inflammatory, and stress effects of exposure to the etiologically relevant pesticide, paraquat, over time (up to 6 months after injections). We also were interested in whether a high-resolution, 7-Tesla animal magnetic resonance imaging would be sensitive enough to detect the degenerative impact of paraquat. We found that paraquat induced a loss of dopaminergic SNc neurons and activation of microglia that surprisingly did not change over 6 months after the last injection. A long-lasting reduction was evident for body weight, and alterations in organ (lung and heart) weight were evident, which reflect the peripheral impact of the toxicant. The microglial proinflammatory actin-remodeling factor, WAVE2, along with the inflammatory transcription factor, nuclear factor kappa B were also elevated within the brain. Remarkably, the stress hormone, corticosterone, was still significantly elevated 1 month after paraquat, whereas the inflammasome factor, caspase-1, and antigen presentation factor, MFG-E8, both displayed delayed rises after the 6-month time. Using high-resolution magnetic resonance imaging, we detected no striatal changes but modest hemispheric differences in the SNc and time-dependent volumetric enlargement of the ventricles in paraquat-treated mice. These data suggest that paraquat induces long-term nigrostriatal pathology (possibly asymmetric) and inflammatory changes and stress and trophic/apoptotic effects that appear to either increase with the passage of time or are evident for at least 1 month. In brief, paraquat may be a useful nonspecific means to model widespread stress and inflammatory changes related to PD or age-related disease in general, but not the progressive nature of such diseases.

The impact of dextran sodium sulphate and probiotic pre-treatment in a murine model of Parkinson's disease.

BACKGROUND: Recent work has established that Parkinson's disease (PD) patients have an altered gut microbiome, along with signs of intestinal inflammation. This could help explain the high degree of gastric disturbances in PD patients, as well as potentially be linked to the migration of peripheral inflammatory factors into the brain. To our knowledge, this is the first study to examine microbiome alteration prior to the induction of a PD murine model. METHODS: We presently assessed whether pre-treatment with the probiotic, VSL #3, or the inflammatory inducer, dextran sodium sulphate (DSS), would influence the PD-like pathology provoked by a dual hit toxin model using lipopolysaccharide (LPS) and paraquat exposure. RESULTS: While VSL #3 has been reported to have anti-inflammatory effects, DSS is often used as a model of colitis because of the gut inflammation and the breach of the intestinal barrier that it induces. We found that VSL#3 did not have any significant effects (beyond a blunting of LPS paraquat-induced weight loss). However, the DSS treatment caused marked changes in the gut microbiome and was also associated with augmented behavioral and inflammatory outcomes. In fact, DSS markedly increased taxa belonging to the Bacteroidaceae and Porphyromonadaceae families but reduced those from Rikencellaceae and S24-7, as well as provoking colonic pro-inflammatory cytokine expression, consistent with an inflamed gut. The DSS also increased the impact of LPS plus paraquat upon microglial morphology, along with circulating lipocalin-2 (neutrophil marker) and IL-6. Yet, neither DSS nor VSL#3 influenced the loss of substantia nigra dopamine neurons or the astrocytic and cytoskeleton remodeling protein changes that were provoked by the LPS followed by paraquat treatment. CONCLUSIONS: These data suggest that disruption of the intestinal integrity and the associated microbiome can interact with systemic inflammatory events to promote widespread brain-gut changes that could be relevant for PD and at the very least, suggestive of novel neuro-immune communication.