Phthalate Exposure and Long-Term Epigenomic Consequences: A Review

Abstract

Phthalates are esters of phthalic acid which are used in cosmetics and other daily personal care products. They are also used in polyvinyl chloride (PVC) plastics to increase durability and plasticity. Phthalates are not present in plastics by covalent bonds and thus can easily leach into the environment and enter the human body by dermal absorption, ingestion, or inhalation. Several in vitro and in vivo studies suggest that phthalates can act as endocrine disruptors and cause moderate reproductive and developmental toxicities. Furthermore, phthalates can pass through the placental barrier and affect the developing fetus. Thus, phthalates have ubiquitous presence in food and environment with potential adverse health effects in humans. This review focusses on studies conducted in the field of toxicogenomics of phthalates and discusses possible transgenerational and multigenerational effects caused by phthalate exposure during any point of the life-cycle.

Keywords: DNA methylation; DOHAD; epigenomics; gestational exposure; phthalates.

Figure 1

Potential Sources of Phthalate Exposure in daily life. Phthalates have widespread applications in consumer products- they are used in a wide range of daily use household and personal care items starting from soaps, body lotions, and plastic containers to blood transfusion units. They can enter the human body through different routes like ingestion of foods, air inhalation, dust ingestion or dermal absorption. Phthalates can also cross the placenta and affect the developing fetus in a pregnant woman. Infants and neonates are also subjected to phthalate exposure via breast milk and from infant toys like pacifiers, bottle nipples, teethers, and neonatal medical care units.

Figure 2

Pathway of phthalate metabolism in human body. LMW phthalates are mainly excreted in urine and feces as a monoester, no further metabolism is required. During phase I hydrolysis, diester phthalates are hydrolyzed by the enzymes like esterases and lipases in the intestine and parenchyma to their respective monoesters. High molecular weight (HMW) phthalates such as diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), and dipropylheptyl phthalate (DPHP) have 9–13 carbon atoms in their chemical backbone and undergo further metabolism from monoesters via hydroxylation or oxidation and produce several oxidative metabolites which are excreted in urine within 24 h of exposure. Oxidative metabolites can also undergo phase II conjugation to form hydrophilic glucuronide conjugates which are excreted. Urinary phthalate metabolite is the most important biomarker for phthalate exposure [Adapted from the article, Metabolism of phthalates in humans by (Frederiksen et al., 2007)].

Figure 3

Chemical structures of the top 10 major phthalates and their corresponding metabolites [adapted from the article, A Review of Biomonitoring of Phthalate Exposures by (Wang et al., 2019)].