Paternal exposures, sperm epigenetic marks, and autism spectrum disorder in offspring - Abstract
Research on environmental risk factors for autism spectrum disorder (ASD) has largely focused on maternal
gestational exposures and on exposures in the early postnatal period. The possibility that paternal
preconception factors play important etiological roles in the disorder has not been extensively studied. A
possible role for paternal factors in ASD is suggested based on the consistently robust associations observed
between ASD and paternal age. In addition, ASD has been associated with alterations in epigenetic marks and
related gene expression across several somatic tissues, suggesting that one possible etiologic mechanism
could be through effects on sperm epigenetic imprinting. Exposure to ambient air pollution has been
associated in animal studies with alteration in sperm epigenetic marks that can be transmitted to offspring and
affect phenotype. Human data has also linked exposure to air pollution, certain comorbidities, and use of some
medications with reduced sperm quality parameters, possibly due to inheritable epigenetic effects. My aim in
the proposed work is to evaluate the role of paternal factors in the etiology of ASD. Specifically, I will evaluate
whether exposure to air pollution during the spermatogenesis period preceding a conception is associated with
an increased risk of autism in the offspring (aim 1); whether paternal comorbidities and their pharmacologic
treatments have additive or synergistic effects with air pollution on ASD risk given that similar biologic
pathways have been implicated in these different sets of exposures (aim 2); and whether exposure to air
pollution causes DNA methylation changes in sperm overall and specifically in ASD related loci, which will
inform mechanistic pathways (aim 3). For these goals, I will use data from a large Israeli birth cohort of nearly
half a million children with detailed demographic and clinical information, and will also collect semen
biospecimens from subgroup of men attending a large IVF clinic. Air pollution exposure will be estimated using
state-of-the-art satellite-derived air pollution exposure models based on geocoded residential addresses. The
proposed work will make novel translational and mechanistic contributions to ASD through identification of
specific paternal factors and biological pathways that cause, exacerbate, or mediate ASD risk. Findings
stemming from the proposed work will help guide interventions to reduce exposure to harmful environmental
toxicants or attenuate their downstream effects. In addition to the research goals, the proposed work has a
strong training component in epigenetic and pharmacologic epidemiology and in statistical genomics that
would substantially advance my skillset in using innovative study designs and analytic approaches in
exposomic research of heterogenous risk factors for neurodevelopmental disorders using observational data.
The proposed training and mentoring will be instrumental for advancing my goal of becoming an independent
researcher in the field of environmental neuroepidemiology and precision environmental health.
