Children’s neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD) and
Autism Spectrum Disorders (ASDs), have tremendous societal, economic, and personal consequences. The
incidence rates and behavioral presentation of these disorders vary by genetic sex, with a male bias. While
multifactorial risks have been reported for this male bias, the mechanistic origins remain unresolved.
Increasingly, epidemiological and animal studies identify a role for endocrine disrupting chemical (EDCs)
exposures in the etiology of children’s NDDs. However, translating risk is difficult because early childhood
exposures are increasingly characterized by low dose exposures to mixtures of EDCs, as exemplified by a
recent study that found 90% of newborn children had measurable serum levels of both bisphenol-a (BPA) and
perfluorooctanoic acid (PFOA) at birth. Our previous data utilizing a curated mixture (MIX) of EDCs,
representative of these infant exposures, found that a low dose EDC mixture altered testosterone (T) levels in
male mice at birth and resulted in male-specific behavioral changes, including reduced attention, impulsivity,
and reduced sociability, phenotypes seen in ADHD and ASDs. Occurring in both rodents and humans, males
experience a surge of T shortly before and after birth that is essential for nervous system development. Our
data indicate that T at birth may be a sensitive target of multiple EDC mixtures. MIX exposure also marginally
reduced DNA methyltransferase (DNMT1) levels and hypomethylated sensitive imprinted genes in male
striatum, a region essential for these behavioral domains. DNA methylation profiles are influenced by various
EDCs and suggested as a potential mechanism by which EDCs confer risk. Consequently, this proposal will
investigate a hypothesized mechanistic pathway linking EDC-induced elevated T levels at birth with DNA
hypomethylation in striatum as a mechanism of sex-dependent behavioral deficits. This hypothesis will be
examined in a series of 3 Aims that systematically manipulate endocrine and epigenetic signals and track brain
and behavioral function into adulthood. First, it will test the ability of neonatal T administration to phenocopy
both the epigenetic and behavioral consequences of MIX EDC exposure. In addition, the role of EDC-induced
DNA hypomethylation via DNMT inhibition will be tested using a genetically modified strain of mice with
reduced DNMT1 activity. Because epigenetic mechanisms of brain development are highly region and cell-type
specific, and our prior assessments used whole striatum, the proposed aims will investigate genome-wide DNA
methylation profiles in neurons from ventral striatum. As an essential step forward, this proposal will integrate
translational behavioral assays and advanced epigenetic techniques to inform our understanding of male
vulnerability. The perinatal T surge is an understudied target of EDC neurotoxicity. The proposed studies will
significantly expand our limited knowledge of how EDC mixtures alter CNS development in a sex-dependent
fashion and will provide new data that are essential for risk assessment and public health protection.