Phthalates and Alternative Plasticizers in Female Reproductive Health and Pregnancy: From Epidemiological Evidence to Nuclear Receptor-Mediated Mechanisms: A State-of-the-Art Review
Phthalate esters (PAEs), which are widely used as plasticizers in various products, are recognized as endocrine-disrupting chemicals (EDCs) that can affect female reproductive health. Numerous studies linked PAE exposure to several health hazards, including disruption of folliculogenesis, steroidogenesis, implantation, and pregnancy maintenance, contributing to complications such as miscarriage, preeclampsia, and preterm birth. In response to growing concerns regarding their toxicity, alternative plasticizers (APs) have been introduced, with particular attention given to the commonly used compounds, including di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH), tris(2-ethylhexyl) trimellitate (TOTM), di(2-ethylhexyl) adipate (DEHA), and acetyl tributyl citrate (ATBC). While these alternatives are often presented as safer, recent studies have suggested that these compounds can also disrupt hormonal pathways and fertility regulation mechanisms. Both PAEs and APs have been shown to interact with key nuclear receptor systems, especially with peroxisome proliferator-activated receptors (PPARs) and steroid hormone receptors. These receptors are essential regulators of ovarian function, placental development, and pregnancy maintenance. Disruption of these signaling pathways, particularly in the placenta and fetal membranes, may contribute to altered inflammatory responses, impaired endocrine regulation, and increased risk of adverse pregnancy outcomes. This review provides a state-of-the-art synthesis of the current literature on PAEs and APs, focusing on exposure patterns, associations with female reproductive health and pregnancy outcomes, and the identification of dysregulated biological pathways. This review emphasizes the urgent need to limit plasticizer exposure, especially among women of reproductive age, in order to preserve reproductive health and prevent associated complications.