Sex differences in associations between white matter microstructure and gonadal hormones in children and adolescents with prenatal alcohol exposure

Abstract

Despite accumulating evidence from animal models demonstrating that prenatal alcohol exposure (PAE) results in life-long neuroendocrine dysregulation, very little is known on this topic among humans with fetal alcohol spectrum disorders (FASD). We expected that alterations in gonadal hormones might interfere with the typical development of white matter (WM) myelination, and in a sex-dependent manner, in human adolescents with FASD. In order to investigate this hypothesis, we used diffusion tensor imaging (DTI) to assess: 1) whether or not sex moderates the impact of PAE on WM microstructure; and 2) how gonadal hormones relate to alterations in WM microstructure in children and adolescents affected by PAE. Methods 61 youth (9 to 16 yrs.; 49% girls; 50% PAE) participated as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). DTI scans and passive drool samples were obtained to examine neurodevelopmental associations with testosterone (T) and dehydroepiandrosterone (DHEA) levels in boys and girls, and estradiol (E2) and progesterone (P) levels in girls. Tract-based spatial statistics were utilized to generate fractional anisotropy (FA) and mean diffusivity (MD) for 9 a priori WM regions of interest (ROIs). Results As predicted, alterations in FA were observed in adolescents with PAE relative to controls, and these differences varied by sex. Girls with PAE exhibited lower FA (Inferior fronto-occipital and Uncinate fasciculi) while boys with PAE exhibited higher FA (Callosal body, Cingulum, Corticospinal tract, Optic radiation, Superior longitudinal fasciculus) relative to age-matched controls. When gonadal hormone levels were examined in relation to DTI measures, additional group differences in FA were revealed, demonstrating that neuroendocrine factors are associated with PAE-related brain alterations. Conclusions These findings provide human evidence that PAE relates to sex-specific differences in WM microstructure, and underlying alterations in gonadal hormone function may, in part, contribute to these effects. Determining PAE-effects on neuroendocrine function among humans is an essential first step towards developing novel clinical (e.g., assessment or intervention) tools that target hormone systems to improve on-going brain development among children and adolescents with FASD.

White matter microstructure in fetal alcohol spectrum disorders: A systematic review of diffusion tensor imaging studies

“…The results of Treit et al might, therefore, stem from the effect of PAE on testosterone neurophysiological functioning. This hypothesis is well addressed in another fresh DTI study by Uban et al on adolescents using TBSS method(Uban et al, 2017). They surprisingly showed lower FA in white matter tracts in girls with PAE compared with healthy controls, while boys with PAE had higher FA relative to control boys; with no association between age and FA only in PAE boys.…”

An interaction between fetal sex and placental weight and efficiency predicts intrauterine growth in response to maternal protein insufficiency and gestational exposure window in a mouse model of FASD

“…Likewise, May and colleagues [ 23 ] recently reported that maternal drinking increases the males’ risk of mortality prior to birth but causes more growth impairments in females compared to their surviving male counterparts. The sex-specific effects of gestational alcohol exposure are also evidenced in the children’s dysregulated activation of the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes as well as altered production of reproductive hormones and inflammatory markers [ 24 – 26 ].…”

Alcohol Modulates the Biogenesis and Composition of Microglia-Derived Exosomes

“…It has been documented that the abuse of alcohol impairs glial and astrocytic function [16]. Of important note, prenatal alcohol exposure alters the development of several brain regions, leading to structural and functional modifications in areas such as the cerebellum, cortex, and hippocampus [17], as well as white matter [18,19]. Alcohol-associated brain neuropathology can lead to behavior changes and impairments in learning, attention, executive functioning, and emotional regulation, which can seriously impact daily activities [20,21,22].…”