High Environmental Temperature: Insights into Behavioural, Neurodevelopmental and Gut Microbiome Changes Following Gestational Exposure in Rats.

Adverse effects of changing climate have been associated with increase average global temperature resulting in environmental changes. We set out to investigate effects of environmental stress due to increased heat exposure on developmental milestones, behaviour, gut microbiota and neuroarchitecture in rat pups. Pregnant Wistar rats were held in standard temperature (ST) (26 ± 2 °C; control) or high temperature (HT) (40 ± 2 °C) housing. After parturition, a cohort of the HT group and their pups were moved to the control/ST housing (gestational-only-exposed pup [GE]) while the other subset remained in the HT housing (gestational and postnatal exposed pups [GE + PE]). At different time points, we examined neurodevelopmental milestones and behaviour in the pups. Following sacrifice changes in gut microbiota, neuroarchitecture, cytokine levels (TNF-α, IL-4, IL-10), SOD, MDA, expression of MBP, NeUN and GFAP were determined. We observed impaired positioning and placing of paws, prolonged righting reflex, delayed ear opening and significant decreased body weight gain in HT pups when compared with control. We identified Firmicutes and Proteobacteria and noted a significant difference in Firmicutes count between GE and GE + PE pups at P15. Furthermore, TNF-α, IL-4, IL-10 and MDA levels were increased in GE and GE + PE pups. There was also a reduction in MBP expression in the HT pups. Taken together, our results revealed a delay in neurodevelopmental milestones in pups exposed to high HT during gestation and post natal life. Pups whose dam were exposed to high HT during gestation also showed some set back but improved over the course of testing.

Clofibrate, a PPAR-α agonist, abrogates sodium fluoride-induced neuroinflammation, oxidative stress, and motor incoordination via modulation of GFAP/Iba-1/anti-calbindin signaling pathways.

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator-activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and cerebellar Ca2+ -binding protein calbindin-D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders.