Associations between prenatal exposure to chemicals like endocrine disruptors found in plastics and the development of neurological diseases later in life have been well described (1). Although mechanisms have been proposed for how endocrine disruptors affect human health (2), those mediating the development of neurological conditions like autism and dementia have been difficult to elucidate because of the multifactorial nature of these diseases. Researchers, therefore, considered the issue through a new lens: inherited DNA methylation patterns.
Bisphenols and phthalates are among the most common plasticizers. These chemicals are useful in food packaging because they make plastics flexible. Both are problematic, however, because of their endocrine-disrupting effects. Bisphenols, for example, mimic the effects of hormones like estrogen and have been linked to hypertension, cardiovascular disease, and type 2 diabetes (3).
Recently, di-(2-ethylhexyl) phthalate (DEHP), a type of phthalate that was introduced in the 1930s, has gained attention due to its increasing prevalence in plastics and high rate of leaching (4). Contamination with DEHP was first reported in the 1970s in blood samples that were stored in plastic bags (5, 6). DEHP was later found in the tissues of patients who had received blood transfusions from these samples.
DEHP is thought to act as an endocrine disruptor, but the mechanism mediating its effects has not been described. Researchers, therefore, explored a novel epigenetic link between prenatal exposure to DEHP and neurological disease by measuring exposure and correlating it with methylation patterns in placental tissue (7). Importantly, they also examined the identities of genes with abnormal DNA methylation patterns in placentas exposed to DEHP.
Placentas with high DEHP exhibited both hyper- and hypomethylation patterns. Genes that were hypermethylated were mostly associated with gene expression regulation. Notably, the Wnt family of genes was affected, suggesting a possible role for early embryonic patterning in the development of autism and dementia. Downregulation of Wnt genes has been previously implicated in the development of autism and dementia (8, 9).
Hypomethylated genes were mostly involved in the development of neural networks and cell adhesion. Cadherins, for example, which are important for normal neuronal differentiation and cell communication, are dysregulated in the presence of DEHP (10, 11). In fact, similar DNA hypomethylation patterns are observed in animal models where DEHP exposure has been shown to exacerbate autism-like behaviors (12).
Methylation patterns are well-known to affect transgenerational genetics, likely through modification of genes expressed early in development. Although this process has implications for normal inheritance of gene expression patterns, methylation can be altered by exposure to environmental toxins. Examination of the link between plastics and neurological diseases contributes to our understanding of complex diseases like autism and dementia that together affect more than 100 million people worldwide. The data in the current study emphasize the wide-ranging effects environmental endocrine disruptors like DEHP have on human physiology.
Source: Tran MTMT, Kuo F-C, Low J-T, et al. Prenatal DEHP exposure predicts neurological disorders via transgenerational epigenetics. Sci Rep 2023;13(7399).
- Rahman Kabir E, Sharfin Rahman M, Rahman I. A review on endocrine disruptors and their possible impacts on human health. Environ Toxicol Pharmacol 2015;40(1):241-258.
- Diamanti-Dandarakis E, Bourguignon J-P, Guidice LC, et al. Endocrine-disrupting chemicals: An endocrine society scientific statement. Endocr Rev 2009:30(4):293-342
- Bauer BA. What is BPA, and what are the concerns about BPA? Mayo Clinic 2023.
- di(2-ethylhexyl) phthalate in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 101. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon (FR): International Agency for Research on Cancer; 2013.
- Jaeger RJ, Rubin RJ. Plasticizers from plastic devices extraction, metabolism, and accumulation by biological systems. Science. 1970;170:460–462.
- Jaeger RJ, Rubin RJ. Migration of a phthalate ester plasticizer from polyvinyl chloride blood bags into stored human blood and its localization in human tissues. N Engl J Med. 1972;287:1114–1118.
- Liu J, Wu Y, Sun H, et al. Placental DNA methylation abnormalities in prenatal conotruncal heart defects. Front Genet. 2022;13(878063).
- Zhang Y, Yan S, Wang F, Wang Z, Peng Y, Li R. Downregulating the canonical Wnt/β-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes by decreasing oxidative stress. Neurochem Res. 2012;37:1409–1419.
- Palomer E, Martin-Flores N, Jolly S, et al. Epigenetic repression of Wnt receptors in AD: A role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters. Mol Psychiatry. 2022(27): 3024–3033.
- Punovuori K, Malaguti M, Lowell S. Cadherins in early neural development. Cell Mol Life Sci. 2021;78(9):4435-4450.
- Wei Z, Liquiong S, Wei J, et al. Maternal exposure to di-(2-ethylhexyl)phthalate alters kidney development through the renin-angiotensin system in offspring. Toxicol Lett. 2012;212:212–221.
- Nadeem, A. et al. Exposure to the plasticizer, Di-(2-ethylhexyl) phthalate during juvenile period exacerbates autism-like behavior in adult BTBR T + tf/J mice due to DNA hypomethylation and enhanced inflammation in brain and systemic immune cells. Prog Neuropsychopharmacol Biol Psychiatry 2021;109:110249.