Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer's disease.

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.

Weight and head circumference at birth in function of placental paraben load in Belgium: an ENVIRONAGE birth cohort study.

BACKGROUND: Parabens are a group of esters of para-hydroxybenzoic acid utilized as antimicrobial preservatives in many personal care products. Epidemiological studies regarding the adverse effects of parabens on fetuses are limited. The aim of this study was to determine the association between placental paraben exposure and birth outcomes. We assessed paraben concentrations in placental tissue, which potentially gives a better understanding of fetal exposure than the maternal urinary concentrations which are the current golden standard. METHODS: Placental tissue was collected immediately after birth from 142 mother-child pairs from the ENVIRONAGE birth cohort. The placental concentrations of four parabens (methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)) were determined by ultra-performance liquid chromatography coupled with tandem mass-spectrometry. Generalized linear regression models were used to determine the association between paraben exposure levels and birth outcomes. RESULTS: The geometric means of placental MeP, EtP, PrP, and BuP were 1.84, 2.16, 1.68 and 0.05 ng/g tissue, respectively. The sum of parabens (∑ parabens, including MeP, EtP and PrP) was negatively associated with birth weight in newborn girls (- 166 g, 95% CI: - 322, - 8.6, p = 0.04) after adjustment for a priori selected covariates. The sum of parabens was negatively associated with head circumference (- 0.6 cm, 95% CI: - 1.1, - 0.2, p = 0.008) and borderline associated with birth length (- 0.6 cm, 95% CI:-1.3, 0.1, p = 0.08). In newborn girls the placental concentration of EtP was negatively associated with head circumference (- 0.6 cm, 95% CI:-1.1, - 0.1, p = 0.01) and borderline significantly associated with birth weight and birth length. Lastly, placental EtP and ∑parabens were negatively associated with placental weight in newborn girls but not in newborn boys (- 45.3 g, 95% CI:-86.2, - 4.4, p = 0.03). CONCLUSION: The negative association between maternal paraben exposure and birth outcomes warrants further research and follow-up over time to determine long term effects of gestational exposure to parabens.

Prenatal particulate air pollution exposure and expression of the miR-17/92 cluster in cord blood: Findings from the ENVIRONAGE birth cohort.

BACKGROUND: Air pollution exposure during pregnancy is an important environmental health issue. Epigenetics mediate the effects of prenatal exposure and could increase disease predisposition in later life. The oncogenic miR-17/92 cluster is involved in normal development and disease. OBJECTIVES: Here, for the first time the potential prenatal effects of particulate matter with a diameter<2.5 µm (PM2.5) exposure on expression of the miR-17/92 cluster in cord blood are explored. METHODS: In 370 mother-newborn pairs from the ENVIRONAGE birth cohort, expression of three members of the miR-17/92 cluster was measured in cord blood by qRT-PCR. Expression of C-MYC and CDKN1A, a cluster activator and a target gene, respectively, was also analyzed. Multivariable linear regression models were used to associate the relative m(i)RNA expression with prenatal PM2.5 exposure. RESULTS: PM2.5 exposure averaged (10th-90th percentile) 11.7 (9.0-14.4) µg/m3 over the entire pregnancy. In cord blood, miR-17 and miR-20a showed a -45.0% (95%CI: -55.9 to -31.4, p < 0.0001) and a -33.7% (95%CI: -46.9 to -17.2, p = 0.0003), decrease in expression in association with first trimester PM2.5 exposure, and a -32.5% (95%CI: -45.6 to -16.3, p = 0.0004) and -23.3% (95%CI: -38.1 to -4.8, p = 0.02), respectively, decrease in expression in association with PM2.5 exposure during the entire pregnancy. In association with third trimester PM2.5 exposure, a reduction of -25.8% (95%CI: -40.2 to -8.0, p = 0.007) and -14.2% (95%CI: -27.7 to 1.9, p = 0.08), for miR-20a and miR-92a expression, respectively, was identified. Only miR-92a expression (-15.7%, 95%CI: -27.3 to -2.4, p = 0.02) was associated with PM2.5 exposure during the last month of pregnancy. C-MYC expression was downregulated in cord blood in association with prenatal PM2.5 exposure during the first trimester and the entire pregnancy, in the adjusted model. DISCUSSION: Lower expression levels of the miR-17/92 cluster in cord blood in association with increased prenatal PM2.5 exposure were observed. Whether this oncogenic microRNA cluster plays a role in trans-placental carcinogenesis remains to be elucidated.