Foetal oestrogens and autism.

Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n = 98 cases, n = 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function.

Is the association between mothers' autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

BACKGROUND: Previous studies showed that there is a positive association between mothers' and children's autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). METHOD: The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). RESULT: Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; ßadjusted = 0.20, p < 0.01), in early childhood (Generation R; ßadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; ßadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (ßadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. CONCLUSION: We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.

Medical symptoms and conditions in autistic women.

LAY ABSTRACT: Sex-steroids, such as testosterone, are thought to be one of the biological factors implicated in autism. This relies on the sex bias in the diagnosis of autism (boys are approximately four times more likely to be diagnosed than girls) and findings of associations with fetal testosterone levels in traits and abilities related to autism. The current study aimed to examine the association between medical conditions and physical symptoms, which tend to manifest in adulthood, and autism in females. Moreover, we examined their association with autistic traits throughout the spectrum. We focused on autistic women because there is little research focusing on the healthcare needs of autistic women, but those that exist suggest heightened vulnerability, and lower access to medical care. We find that conditions related to steroid hormones function are more frequent in autistic women and that they correlate with autistic traits. Specifically, we found that body mass index, reproductive system diagnoses, prediabetes symptoms, irregular puberty onset, and menstrual irregularities were significantly more frequent in autistic women and were significantly correlated with autistic traits in neurotypical women. The findings have important implications for raising awareness in autistic women of the possibility of medical conditions which might need medical attention. In addition, healthcare providers should consider these associations when performing healthcare maintenance checks and/or screening for autism.

Is there an association between prenatal testosterone and autistic traits in adolescents?

Prenatal testosterone (pT) is a crucial component in physiological masculinization in humans. In line with the Prenatal Sex Steroid Theory of autism, some studies have found a positive correlation between pT and autistic traits in childhood. However, effects in adolescence have not been explored. Hormonal and environmental changes occurring during puberty may alter the strength or the nature of prenatal effects on autistic traits. The current study examines if pT relates to autistic traits in a non-clinical sample of adolescents and young adults (N = 97, 170 observations; age 13-21 years old). It also explores pT interactions with pubertal stage and timing. PT concentrations were measured from amniotic fluid extracted in the 2nd trimester of gestation via amniocentesis conducted for clinical purposes. Autistic traits were measured by self- and parent-reports on the Autism Spectrum Quotient (AQ) which provides a total score and 5 sub-scores (social skills, communication, imagination, attention switching and attention to detail). Self-reported pubertal stage was regressed on age to provide a measure of relative timing. We found no statistical evidence for a direct association between pT and autistic traits in this adolescent sample (males, females or full sample). Exploratory analyses suggested that pT correlated positively with autistic traits in adolescents with earlier puberty-onset, but statistical robustness of this finding was limited. Further exploratory post-hoc tests suggested the pT-by-pubertal timing interaction was stronger in males relative to females, in self-reported compared to parent-reported AQ and specifically for social traits. These findings require replication in larger samples. Findings have implications for understanding the effects of pT on human behavior, specifically existence of effects in adolescence.

Ciliary neurotrophic factor upregulates follistatin and Pak1, causes overexpression of muscle differentiation related genes and downregulation of established atrophy mediators in skeletal muscle.

INTRODUCTION: The Ciliary Neurotrophic Factor (CNTF) is a pluripotent cytokine with anorexigenic actions in the hypothalamus that improves insulin sensitivity, increases energy expenditure and induces weight loss. Since CNTF also has an established myotrophic role, we sought to examine whether skeletal muscle contributes to the CNTF-induced metabolic improvement and identify the molecular mechanisms mediating these effects. METHODS: We used a mouse model of diet-induced obesity, to which high or low CNTF doses were administered for 7days. Whole transcriptome expression levels were analyzed in dissected soleus muscles using microarrays and data were then confirmed using qRT-PCR. RESULTS: We demonstrate that CNTF administration significantly downregulates leptin, while it upregulates follistatin and Pak1; a molecule associated with insulin sensitization in skeletal muscle. A significant overexpression of muscle differentiation related genes and downregulation of established atrophy mediators was observed. CONCLUSIONS: The overall gene expression changes suggest an indirect, beneficial effect of CNTF on metabolism, energy expenditure and insulin sensitivity, exerted by the pronounced stimulation of muscle growth, with similarities to the described effect of follistatin and the activation of the Akt pathway in skeletal muscle.

Pharmacogenomics in the development and characterization of atheroprotective drugs.

Atherosclerosis is the main cause of cardiovascular disease (CVD) and can lead to stroke, myocardial infarction, and death. The clinically available atheroprotective drugs aim mainly at reducing the levels of circulating low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and attenuating inflammation. However, the cardiovascular risk remains high, along with morbidity, mortality, and incidence of adverse drug events. Pharmacogenomics is increasingly contributing towards the characterization of existing atheroprotective drugs, the evaluation of novel ones, and the identification of promising, unexplored therapeutic targets, at the global molecular pathway level. This chapter presents highlights of pharmacogenomics investigations and discoveries that have contributed towards the elucidation of pharmacological atheroprotection, while opening the way to new therapeutic approaches.