Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism
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.
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.
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.
KeywordsLead (Pb) Bisphenol A (BPA) Epigenetics Sexually dimorphic effects Developmental origins of health and disease (DOHaD)
Kari Neier was supported by training grant T32 079342 from the National Institute of Child Health and Human Development (NICHD) while preparing this manuscript, and Luke Montrose was supported by T32 ES007062 from the National Institute of Environmental Health Sciences (NIEHS). This work was also supported by the University of Michigan (UM) NIEHS/EPA Children’s Environmental Health and Disease Prevention Center P01 ES022844/RD83543601, the Michigan Lifestage Environmental Exposures and Disease (M-LEEaD) NIEHS Core Center (P30 ES017885),
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 9.Dolinoy DC. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev. 2008; https://doi.org/10.1111/j.1753-4887.2008.00056.x.
- 14.•• Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509:282–3. This piece highlights the recent recognition of the importance of including both sexes in laboratory studies in order to understand sex-specific effects, and describes a policy recently implemented by the National Institutes of Health with the aim to increase the number of studies that examine outcomes in both sexes CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Strakovsky RS, Wang H, Engeseth NJ, Flaws JA, Helferich WG, Pan Y-X, et al. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicol Appl Pharmacol. 2015;284:101–12.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.(2010) Bisphenol A (BPA): use in food contact application.Google Scholar
- 36.•• Anderson OS, Kim JH, Peterson KE, Sanchez BN, Sant KE, Sartor MA, et al. Novel epigenetic biomarkers mediating bisphenol A exposure and metabolic phenotypes in female mice. Endocrinology. 2016;158:en.2016–1441. This study includes an epigenome-wide approach followed by candidate gene validation. It links exposure to phenotype by statistically modeling DNA methylation (at the candidate genes) as a mediating variable Google Scholar
- 40.Chen Z, Myers R, Wei T, Bind E, Kassim P, Wang G, et al. Placental transfer and concentrations of cadmium, mercury, lead, and selenium in mothers, newborns, and young children. J Expo Sci Environ Epidemiol [Internet]. 2014;24(5):537–44. https://www.ncbi.nlm.nih.gov/pubmed/24756102
- 41.Stein J, Schettler T, Wallinga D, Valenti M. In Harm’s Way: Toxic Threats to Child Development. J Dev Behav Pediatr [Internet]. 2002 (Supplement):S13–22. http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00004703-200202001-00004
- 50.Leasure JL, Giddabasappa A, Chaney S, Johnson JE, Pothakos K, Lau YS, et al. Low-level human equivalent gestational lead exposure produces sex-specific motor and coordination abnormalities and late-onset obesity in year-old mice. Environ Health Perspect. 2007;116:355–61.CrossRefPubMedCentralGoogle Scholar
- 52.• Sánchez-Martín FJ, Lindquist DM, Landero-Figueroa J, Zhang X, Chen J, Cecil KM, et al. Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead. Neurotoxicology. 2015;46:92–100; https://www.ncbi.nlm.nih.gov/pubmed/25530354 This manuscript is of importance because the authors show that, in their model of developmental Pb exposure, the brains of female but not male mice are the targets of epigenetic modification and these sex-specific impacts are functionally relevant for gene expression
- 54.Montrose L, Faulk C, Francis J, Dolinoy DC. Perinatal lead (Pb) exposure results in sex and tissue-dependent adult DNA methylation alterations in murine IAP transposons. Environ Mol Mutagen [Internet]. 2017. https://www.ncbi.nlm.nih.gov/pubmed/28833526
- 63.Nigg JT, Nikolas M, Mark Knottnerus G, Cavanagh K, Friderici K. Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure levels. J Child Psychol Psychiatry Allied Discip. 2010;51:58–65.CrossRefGoogle Scholar
- 66.Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, et al. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect [Internet]. 2016 ;124(5):666–73. https://www.ncbi.nlm.nih.gov/pubmed/26115033
- 67.Hunter AA, Smit-McBride Z, Anderson R, et al. (2015) GSTM1 and GSTM5 genetic polymorphisms and expression in age-related macular degeneration. Curr Eye Res 1–7.Google Scholar