Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring
Disruption of endocrine pathways at critical stages in development may differentially affect non-reproductive behaviors in male and female offspring.
Sexually-dimorphic responses to sex steroids could potentially occur in human brain regions such as the hippocampus, prefrontal cortex, striatum and amygdala, regions that are associated with attention, working memory and emotional regulation.
Attention-deficit/hyperactivity disorder (ADHD) is a sexually-dimorphic clinical disorder that appears to be influenced by hormone-sensitive neural pathways.
We therefore examined sex interactions for behavior outcomes that characterize ADHD: attention, hyperactivity, adaptability (including leadership and social skills), aggression, conduct problems, and externalizing behaviors .
We hypothesized that maternal polymorphisms in the sex steroid pathway may influence these sexually-dimorphic behaviors in offspring.
Sex steroids are major modulators of mammalian brain function, regulating neurotransmitters and influencing neuronal differentiation, growth, and synapse formation
Exposure to varying levels of sex steroids early in development can lead to permanent changes in behavior.
Slight perturbations in maternal sex steroid production and metabolism may interfere with normal fetal neurodevelopment. The balance of maternal estrogens and androgens may have direct fetal effects, may influence the fetal hypothalamic-pituitary-gonadal axis or may alter local hormonal activity within the fetal brain. We investigated maternal functional polymorphisms of CYP17, CYP19 and CYP1B1, which control three major enzymatic steps in sex steroid biosynthesis and metabolism, in relation to childhood behaviors.
The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic urban pregnancy cohort from 1998–2002 (n = 404). DNA was obtained from maternal blood (n=149) and from neonatal cord blood (n=53). At each visit, mothers completed the Behavior Assessment System for Children (BASC), a parent-reported questionnaire used to evaluate children for behavior problems. We focused on problem behaviors more commonly associated with ADHD (hyperactivity, attention problems, externalizing behaviors, conduct disorder, poor adaptability) to see if maternal genetic variants in sex steroid production and metabolism influence sexually-dimorphic behaviors in offspring.
The more active gene variants were significantly associated with Attention Problems and poorer Adaptive Skills in male compared to female offspring. The CYP19 variant allele was also significantly associated with worse scores for boys on the Hyperactivity, Externalizing Problems Composite and Adaptive Skills Composite scales (p < 0.05).
We found significant associations for maternal polymorphisms known to affect sex steroid synthesis and metabolism with several problem behaviors in male children. These gene-sex interactions appear to be driven by the maternal genotype and not the child genotype. Epidemiologic studies of environmental toxins such as bisphenol A (BPA), polychlorinated biphenyls (PCB), and diethylstilbestrol (DES) demonstrate that low-level exposures to estrogenic compounds during pregnancy can induce abnormal neurodevelopment in offspring. We, therefore, posit that alterations in endogenous levels of estrogens and androgens during vulnerable windows of brain development may tip the estrogen to androgen balance or achieve a threshold level for hormonal effect on fetal tissues including the brain. Future studies should address whether these CYPs have additive effects, non-hormonal effects, or linkage disequilibrium to unidentified functional polymorphisms that may influence behavior. As an exploratory study, ours would be the first to examine behavioral outcomes in offspring in relation to maternal sex steroid polymorphisms. While the effects may be modest, even a 5-point shift in the distribution of BASC scores for all males could significantly increase the proportion of boys that fall beyond the cut-off for clinical disorders such as ADHD.
- Read and download the full study (free access) Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring, on the NCBI, PubMed, PMC3335953, 2013 Jun 1.
- Image credit NASA gsfc.