Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation

Abstract

SUMMARYEndocrine disruptors (ED) are environmental pollutants that mimic endogenous hormonal signals. Exposure to EDs during fetal and early life is a public health concern because these are periods characterized by high cellular plasticity that influence the physiology and development of disease later in life. Phthalates are plasticizers used in the industry to manufacture polyvinyl chloride products and several consumer products. Di(2-ethylhexyl) phthalate (DEHP) is one of the most produced plasticizers; it is ubiquitously found contaminating the environment, and has been shown to be an ED. Human exposure to phthalates starts during fetal development and continues after birth through contact of the newborn with the environment and contaminated food sources. We used a rat model in which pregnant dams are gavaged with DEHP from gestational day 14 until birth to study the long-term effects of DEHP. This window of fetal exposure results in decreased circulating testosterone and aldosterone levels in adult male offspring and estradiol in the female. The observed steroid changes are likely of an epigenetic origin as DEHP is rapidly cleared after birth. Here, we review the long-term effects of fetal exposure to DEHP with a focus on the molecular and epigenetic changes, including DNA methylation, which may mediate long-term endocrine dysfunction.

Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

“…The negative relationship observed between PPARA methylation and SDEHP is particularly notable. In addition to being one of the most commonly identified EDCs in the US population [45], observed changes in DNA methylation and expression in adult rats resulting from in utero SDEHP exposure have raised speculation that the PPAR pathway, and specifically PPARA, may participate in epigenetic disruption [46]. The findings from the present study support this hypothesis, as human PPARA promoter was inversely associated with SDEHP levels.…”

Phthalate exposure and reproductive hormones and sex-hormone binding globulin before puberty – Phthalate contaminated-foodstuff episode in Taiwan

“…However, the results were consistent with previous studies that showed that DEHP had antiandrogenic and estrogenic effect in children [15, 40]. These children should be followed to investigate the effects of exposure to phthalate-tainted foodstuffs on children’s health [41]. Second, the range of the children’s age was wide (mean = 5.48 years; range = 1 to approximately 11.6 years) in the present study.…”

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls

“…In males, adrenal androgens are far surpassed by androgens produced by the testes, so effects on the adrenal gland may not be evident. Animal studies have demonstrated that the adrenal gland is indeed a target for in utero DEHP exposure, with females being more sensitive to exposure than males and effects that last into adulthood (Martinez-Arguelles and Papadopoulos 2016). One hypothesis for how this may occur is through changes in fetal epigenetic programming (Martinez-Arguelles and Papadopoulos 2016).…”