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Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (A vy ) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposed A vy /a offspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs.

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Purpose of review The genetic material of every organism exists within the context of regulatory networks that govern gene expression—collectively called the epigenome. Animal models and human birth cohort studies have revealed key developmental periods that are important for epigenetic programming and vulnerable to environmental insults. Thus, epigenetics represent a potential mechanism through which sexually dimorphic effects of early-life exposures such as endocrine disrupting chemicals (EDCs) manifest. Recent findings Several animal studies, and to a lesser extent human studies, have evaluated life-course sexually dimorphic health effects following developmental toxicant exposures; many fewer studies, however, have evaluated epigenetics as a mechanism mediating developmental exposures and later outcomes. Summary To evaluate epigenetic reprogramming as a mechanistic link of sexually dimorphic early-life EDCs exposures, the following criteria should be met: 1) well characterized exposure paradigm that includes relevant windows for developmental epigenetic reprogramming; 2) evaluation of sex-specific exposure-related epigenetic change; and 3) observation of a sexually dimorphic phenotype in either childhood, adolescence, or adulthood.

Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.