Biology subjects

Cirillo, P. M.

Publications and source records attributed to Cirillo, P. M..

3 recordsLinked to original sources

bioRxiv2026

Prenatal Maternal Inflammation Is Associated with Altered Offspring Mesolimbic White Matter Circuitry Observed in Late Midlife

BackgroundExposure to prenatal maternal inflammation (PNMI) has been linked to neurodevelopmental alterations in human offspring. Preclinical studies suggest that PNMI disrupts reward circuitry, particularly within mesolimbic circuits. However, the effects of PNMI on mesolimbic circuits (i.e, ventral tegmental area (VTA) projections to the hippocampus (VTA-H) and limbic striatum (VTA-LS)) in humans are not yet known. MethodsData for PNMI biomarkers [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor-II (sTNF-RII)] from first trimester (T1) and second trimester (T2) maternal sera, and offspring MRI brain scans in late midlife (aged 57-63 years), were available for 89 mother-offspring dyads. Probabilistic tractography delineated bilateral VTA-H and VTA-LS tracts. Macrostructural tract measures were examined using hierarchical linear regressions. Microstructural integrity was assessed using neurite orientation dispersion and density imaging, and permutation-based cluster analyses. ResultsHigher T2 IL-1ra was associated with increased macrostructure (left VTA-H tract), whereas higher T2 sTNF-RII was associated with reduced macrostructure (right VTA-H and VTA-LS tracts) and higher T2 IL-8 (bilateral VTA-LS tracts). Microstructurally, higher T2 IL-6 was associated with increased neurite density (distal cluster, right VTA-H tract), while higher T1 IL-8 was associated with reduced neurite density (near the hippocampus in the left VTA-H tract, near the VTA in bilateral VTA-LS tracts). ConclusionsPNMI was associated with altered mesolimbic reward circuitry in offspring. This suggests that prenatal inflammation may contribute to affective and motivational disorders in offspring via alterations in mesolimbic circuitry.

neuroscience↗

bioRxiv2024

Decreased hippocampal neurite density in middle-aged/aging adults following prenatal exposure to higher levels of maternal inflammation

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interests neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes. Significance StatementThe contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early mid-gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of prenatal insults in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.

immunology↗

bioRxiv2024

Females with autism spectrum disorders show stronger DNA methylation signatures than males in perinatal tissues

BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental conditions currently diagnosed by behavioral assessment in childhood, although neuropathology begins during gestation. A poorly understood male bias for ASD diagnosis is thought to be due to both biological sex differences and cultural biases against female diagnosis of ASD. Identification of molecular biomarkers of ASD likelihood in newborns would provide more objective screening and early intervention. Epigenetic dysregulation has been reported in multiple tissues from newborns who are later diagnosed with ASD, but this is the first study to investigate sex-specific DNA methylation signatures for ASD in newborn blood, an accessible and widely banked tissue. MethodsDNA methylation was assayed from ASD and typically developing (TD) newborn blood (discovery set n = 196, replication set n = 90) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed for replication, comparisons by sex, overlaps with DMRs from other tissues, and enrichment for biological processes and SFARI ASD-risk genes. ResultsWe found that newborn blood ASD DMRs from both sexes significantly replicated in an independent cohort and were enriched for hypomethylation in ASD compared to TD samples, as well as location in promoters, CpG islands and CpG shores. Comparing females and males, we found that most DMRs with sex differences amongst TD individuals were also found in ASD individuals, plus many additional DMRs with sex differences that were only found in those with ASD. Newborn blood DMRs from females were enriched for the X chromosome and both sexes showed significant overlap with DMRs from umbilical cord blood and placenta but not post-mortem cortex. DMRs from all tissues were enriched for neurodevelopmental processes (females) and SFARI ASD-risk genes (females and males). LimitationsThis study is primarily limited by sample sizes, particularly amongst females. ConclusionsOverall, we found a highly replicated sex-specific DNA methylation signature of ASD in newborn blood that showed support for the female protective effect and convergence with epigenetic and genetic signatures of ASD in newborns. These results demonstrate the utility of newborn blood in ASD screening and emphasizes the importance of sex-stratification in future studies.

genomics↗