Alterations in Sensitivity to Estrogen, Dihydrotestosterone, and Xenogens in B-Lymphocytes from Children with Autism Spectrum Disorder and Their Unaffected Twins/Siblings

Abstract

It has been postulated that androgen overexposure in a susceptible person leads to excessive brain masculinization and the autism spectrum disorder (ASD) phenotype. In this study, the responses to estradiol (E2), dihydrotestosterone (DHT), and dichlorodiphenyldichloroethylene (DDE) on B-lymphocytes from ASD subjects and controls are compared. B cells were obtained from 11 ASD subjects, their unaffected fraternal twins, and nontwin siblings. Controls were obtained from a different cell bank. Lactate dehydrogenase (LDH) and sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction levels were measured after incubation with different concentrations of E2, DHT, and DDE. XTT/LDH ratio, representative of mitochondria number per cell, was calculated. E2, DHT, and DDE all cause “U”-shaped growth curves, as measured by LDH levels. ASD B cells show less growth depression compared to siblings and controls (P < 0.01). They also have reduced XTT/LDH ratios (P < 0.01) when compared to external controls, whereas siblings had values of XTT/LDH between ASD and external controls. B-lymphocytes from people with ASD exhibit a differential response to E2, DHT, and hormone disruptors in regard to cell growth and mitochondrial upregulation when compared to non-ASD siblings and external controls. Specifically, ASD B-lymphocytes show significantly less growth depression and less mitochondrial upregulation when exposed to these effectors. A mitochondrial deficit in ASD individuals is implied.

Immune dysfunction and neuroinflammation in autism spectrum disorder

“…It is intriguing to note that both CD38 and CD157 modulate the innate and adaptive immune response in T and B cells (Malavasi et al 2006). Probably, in subjects with ASD, a mitochondrial dysfunction in B-cells may explain why B lymphocytes in ASD exhibit a differential immune response to estrogens, dihydrotestosterone, and hormone disrupters, which were associated with ASD onset (Sharpe et al 2013a). B-cell sensitivity to external stimuli has also been reported for thimerosal (Sharpe et al 2013b).…”

Association Between HLA-B Polymorphisms and Autism Spectrum Disorder in Chinese Population

“…However, the phenomenon of altered immune function and immune dysregulation in individuals with ASD was observed. The elevated level of inflammatory cytokines (TNF, IL) (22,23), along with abnormal expression of chemokines (MCP-1, MIP-1α, RANTES) in plasma (24) as well as altered levels of multiple immune cells (T cells, B cells, NK cells) were found in ASD (25,26). It is worth noting that such immune responses will eventually account for inflammations, especially in brain.…”

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

“…Consistent with this idea, Baron-Cohen proposed that fetal exposure to sex steroids, specifically fetal androgens, might contribute to the sex bias in ASD (57). A number of clinical studies, many of which are from Baron-Cohen's group, have directly investigated associations between prenatal exposure to sex steroid hormones, including androgens and estrogens, and ASD (reviewed in Table 1) (58)(59)(60)(61)(62)(63)(64). In support of this theory, Baron-Cohen's research group identified a positive correlation between fetal testosterone levels measured in amniotic fluid by amniocentesis and the development of ASD traits in typically developing male (n = 118) and female (n = 117) children at ages 6-10 years in a longitudinal cohort study (58).…”