Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder

Bilder, Deborah A.; Esplin, M. Sean; Coon, Hilary; Burghardt, Paul; Clark, Erin A.S.; Fraser, Alison; Smith, Ken R.; Worsham, Whitney; Chappelle, Katlin; Rayner, Thomas; Bakian, Amanda V.

doi:10.1007/s10803-019-04162-2

Cited by 25 publications

(36 citation statements)

References 67 publications

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“…4), were reflected in clinical hirsutism differences (Fig. 2), and are in accordance with those observed in other studies of clinical autism [10,13]. The high degree of correlation between many of the assessed hormones (Fig.…”

Section: Limitationssupporting

confidence: 90%

“…Autistic males also have higher levels of steroid hormones in amniotic fluid, when these were assessed in a multivariate analysis, as well as higher levels of estrogens in particular in univariate analyses of the same amniotic fluid samples [9,10]. Additionally, estradiol levels are elevated in maternal serum of pregnancies linked to a later autism diagnosis in the child [13].…”

Section: Introductionmentioning

confidence: 99%

“…The prenatal environment shows baseline sex differences in steroid production via the placenta [21], as well as in markers of placental formation and function, such as human choriogonadotropin (hCG) [1,20,38]. Atypical levels in both have been found in maternal serum of pregnancies that resulted in an autistic child, with both higher (for estradiol) and lower levels (for estriol) reported compared to controls [13,53]. However, these prenatal factors have not been studied together with fetal sex and in relation to both maternal and infant autistic traits.…”

Section: Introductionmentioning

confidence: 99%

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Maternal steroid levels and the autistic traits of the mother and infant

et al. 2021

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Background Prenatal sex steroids have been associated with autism in several clinical and epidemiological studies. It is unclear how this relates to the autistic traits of the mother and how early this can be detected during pregnancy and postnatal development. Methods Maternal serum was collected from pregnant women (n = 122) before or during their first ultrasound appointment [mean = 12.7 (SD = 0.7) weeks]. Concentrations of the following were measured via immunoassays: testosterone, estradiol, dehydroepiandrosterone sulphate, progesterone; and sex hormone-binding globulin which was used to compute the free fractions of estradiol (FEI) and testosterone (FTI). Standardised human choriogonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) values were obtained from clinical records corresponding to the same serum samples. Mothers completed the Autism Spectrum Quotient (AQ) and for their infants, the Quantitative Checklist for Autism in Toddlers (Q-CHAT) when the infants were between 18 and 20 months old. Results FEI was positively associated with maternal autistic traits in univariate (n = 108, Pearson’s r = 0.22, p = 0.019) and multiple regression models (semipartial r = 0.19, p = 0.048) controlling for maternal age and a diagnosis of PCOS. Maternal estradiol levels significantly interacted with fetal sex in predicting infant Q-CHAT scores, with a positive relationship in males but not females (n = 100, interaction term: semipartial r = 0.23, p = 0.036) after controlling for maternal AQ and other covariates. The opposite was found for standardised hCG values and Q-CHAT scores, with a positive association in females but not in males (n = 151, interaction term: r = −0.25, p = 0.005). Limitations Sample size of this cohort was small, with potential ascertainment bias given elective recruitment. Clinical covariates were controlled in multiple regression models, but additional research is needed to confirm the statistically significant findings in larger cohorts. Conclusion Maternal steroid factors during pregnancy are associated with autistic traits in mothers and their infants.

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Section: Limitationssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maternal steroid levels and the autistic traits of the mother and infant

et al. 2021

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“…In this regard, ASD pathway network analysis has demonstrated the existence of eight functional metabolism pathways and one metabolic disease pathway, constituting nearly 22.5% of the network [ 56 ]. Moreover, it has been well-established that ASD patients have a high risk of suffering from or developing metabolic problems as comorbidities, even during the prenatal stage [ 185 , 186 ]. In this respect, the “calcium-PKC-Ras-Raf-MAPK/ERK” pathway emerges as a novel relation with ASD, as this pathway is implicated in heart diseases and metabolic problems that are already related with or lead to an increased familial risk for ASD [ 56 ].…”

Section: Mapk/erk Signaling and Autism Spectrum Disordersmentioning

confidence: 99%

MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes

Albert-Gascó

Ros-Bernal

Castillo-Gómez

et al. 2020

IJMS

130

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The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space. The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns. In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially. As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood. During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway. In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors. During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis. During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation. Alterations in mechanisms related to ERK are associated with different pathological outcomes. Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders. The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, as well as prionic diseases. The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure. However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes.

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“…Similarly, because of the paucity of data on meconium, we did not analyze other steroids, including estrogens, in meconium. This may be important in understanding the correlations between fetal steroids and ASD outcomes have implicated maternal steroids and estrogens in ASD [ 42 , 43 ]. Future work including validation of bioanalytical assay of other hormones and their stability in meconium is needed.…”

Section: Limitationsmentioning

confidence: 99%

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort

et al. 2020

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Background Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. Methods To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS. Results Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium. Conclusions This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

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Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder

Cited by 25 publications

References 67 publications

Maternal steroid levels and the autistic traits of the mother and infant

Maternal steroid levels and the autistic traits of the mother and infant

MAP/ERK Signaling in Developing Cognitive and Emotional Function and Its Effect on Pathological and Neurodegenerative Processes

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort

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