Environmental contributors to modulation of brain estrogen signaling and male gender bias in autism: a reply to the oral contraceptive use hypothesis by Strifert (2015)

Publication date: Available online 21 June 2017
Source:Medical Hypotheses
Author(s): Keith Fluegge
Strifert has recently put forward an interesting hypothesis regarding the role of oral contraceptive (OC) use in mothers and risk of offspring autism spectrum disorder (ASD). First, the author reports that combined oral contraceptives (COCs), containing both estrogen and progesterone, were developed in the late 1950s and early 60s, which is a time-frame distinct from Leo Kanner's documentation of infantile ASD in 1943 that Strifert just briefly mentions. While this important temporal inconsistency of ASD origin does not invalidate the potential role of OC use in contributing to the rise of ASD, it does support the likely possibility of other environmental exposures at play. Second, the epigenetic basis of the hypothesis is that the endocrine-disrupting components (i.e., ethinylestradiol) of OC perturb estrogenic signaling in the fetal brain by triggering aberrant DNA methylation of the estrogen receptor β (ERβ) gene, and such methylation patterns may be imprinted to future generations and could theoretically increase subsequent ASD offspring risk. The premise of the hypothesis is challenged, however, with the recognition that MeCP2, a "reader" of DNA methylation sites, is not only associated with age-dependent alteration in ERβ in females but is also significantly reduced in ASD brain. Furthermore, Strifert does not clearly address how the OC hypothesis accounts for the male bias in ASD. Therefore, the purpose of this correspondence is to address these inconsistencies by proposing a hypothesis that challenges these points. That is, gestational exposure to the agricultural and combustion air pollutant, nitrous oxide (N2O), may be a leading contributor to the development of an ASD phenotype. The mechanism undergirding this hypothesis suggests that compensatory estrogenic activity may mitigate the effects of fetal N2O exposure and thereby confer a protective effect against ASD development in a sex-dependent manner (i.e., male bias in ASD).



http://ift.tt/2spouIk