Cumulative Exposure to Phthalates and Their Alternatives and Associated Female Reproductive Health: Body Burdens, Adverse Outcomes, and Underlying Mechanisms

Abstract

The global birth rate has recently shown a decreasing trend, and exposure to environmental pollutants has been identified as a potential factor affecting female reproductive health. Phthalates have been widely used as plasticizers in plastic containers, children's toys, and medical devices, and their ubiquitous presence and endocrine-disrupting potential have already raised particular concerns. Phthalate exposure has been linked to various adverse health outcomes, including reproductive diseases. Given that many phthalates are gradually being banned, a growing number of phthalate alternatives are becoming popular, such as di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) adipate (DEHA), and di(2-ethylhexyl) terephthalate (DEHTP), and they are beginning to have a wide range of environmental effects. Studies have shown that many phthalate alternatives may disrupt female reproductive function by altering the estrous cycle, causing ovarian follicular atresia, and prolonging the gestational cycle, which raises growing concerns about their potential health risks. Herein, we summarize the effects of phthalates and their common alternatives in different female models, the exposure levels that influence the reproductive system, and the effects on female reproductive impairment, adverse pregnancy outcomes, and offspring development. Additionally, we scrutinize the effects of phthalates and their alternatives on hormone signaling, oxidative stress, and intracellular signaling to explore the underlying mechanisms of action on female reproductive health, because these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption. Given the declining global trends of female reproductive capacity and the potential ability of phthalates and their alternatives to negatively impact female reproductive health, a more comprehensive study is needed to understand their effects on the human body and their underlying mechanisms. These findings may have an important role in improving female reproductive health and in turn decreasing the number of complications during pregnancy.

Global environmental and toxicological data of emerging plasticizers: current knowledge, regrettable substitution dilemma, green solution and future perspectives

“…Notably, DINCH does not influence the activity of human nuclear receptors, including ERα, ERβ, AR, PPARα, and PPARγ, in HEK293 cell lines. 100 On the other hand, DINCH metabolites like M2NCH, MINCH, OH-MINCH, oxo-MINCH, and cx-MINCH have been shown to activate these receptors. The review also noted that limited studies hinder the complete understanding of the impact of emerging plasticizers on female reproductive health.…”

First Insight into Fetal Exposure to Legacy and Emerging Plasticizers Revealed by Infant Hair and Meconium: Occurrence, Biotransformation, and Accumulation

“…Pregnant women’s exposure to pollutants from various environmental matrices can have a negative impact on the fetus due to maternal–fetal transmission. In utero exposure to environmental pollutants and their health effects have received substantial attention. , Both extensive experimental animal studies as well as epidemiological findings have demonstrated that early-life environmental factors are associated with an increased risk of developing a variety of chronic illnesses in later life . Recent epidemiological and toxicological studies demonstrated that widely used plasticizers, including organic phosphate esters (OPEs) and phthalate acid esters (PAEs), are commonly present in utero and may exhibit strong embryonic and developmental toxicity early in life. − However, most environmental epidemiologic studies have focused on monitoring parental exposure, and little is known about cumulative exposure in the intrauterine environment.…”

Mitochondrial DNA Stress-Mediated Health Risk to Dibutyl Phthalate Contamination on Zebrafish (Danio rerio) at Early Life Stage

“…DBP is classified as an endocrine-disrupting chemical and potentially causes teratogenicity, mutagenicity, and carcinogenicity. Several studies have reviewed the association between DBP exposure and reproductive diseases, cardiovascular diseases, thyroid diseases, and other adverse effects that were confirmed by some cohort studies and animal model experiments. − Previous works suggest that the potential mechanisms underlying toxicity of DBP may result from oxidative stress, inflammation, and epigenetic modifications, as well as further raising concerns at the subcellular level . Due to the hydrophobic nature of DBP with a high K ow (octanol–water partition coefficients: 3.74) and low vapor pressure, it is not unexpected that DBP tends to be attracted to lipid-rich organelles inside the cell such as mitochondria, the well-known predictive targets of chemical agents.…”