Plastic pollution, though a global problem, is particularly evident in South Florida. All plastic materials share the long polymer backbone; however, additional chemicals are added to plastics to change their physical characteristics. One major group of chemicals commonly used as plasticizers is phthalates, which easily leach onto the surrounding environment during plastic degradation.
Phthalates are pervasive, bioaccumulative, and toxic to human health. They are ubiquitously present in the environment but in particular high concentrations at numerous NPL sites in Florida and the US, including the Homestead Air Force Base (HAFB) Superfund site, which is the site of interest to our UM-SRP Center. While phthalates cause significant dysfunction of the developmental, metabolic, endocrinologic, and immunologic processes, their negative impact on pregnancy is the most prominent effect. However, there is a critical gap of knowledge on the mechanisms by which environmental phthalates can negatively affect pregnancy outcomes and fetal growth, providing important obstacles in designing proper preventive and/or therapeutic interventions. Our proposal is focused on the central hypothesis that exposure to phthalates prior to and during pregnancy results in placenta-mediated pregnancy complications, consisting of pregnancy loss, fetal growth restriction, preterm birth, and preeclampsia via a process that involves circadian rhythm dysregulation. We will employ an environmentally and human-relevant phthalate mixture, which mimics phthalate contamination in the groundwater of the HAFB site.
Circadian rhythms regulate the timing of numerous physiological functions, including the responses to cellular and environmental stress. Conversely, environmental stressors have a negative impact on circadian regulation. Indeed, circadian disruption has become more prevalent in today’s society due to the increase in shift work, sleep disruption, blue light exposure, and travel via different time zones. There is increasing concern for the impact of circadian rhythm disruption on susceptibility to disease; however, this problem has not been studied in the context of exposure to environmental toxicants. Therefore, studies proposed in this application are innovative and have never been performed in literature. Our preliminary data suggests that exposure to phthalates can alter the expression of circadian rhythm genes and proteins.
Our studies will focus on the impact of phthalates on the placenta due to its fundamental role in pregnancy as the interface between the mother and the developing fetus, which is essential for gas and nutrient exchange. Mechanistically, we will evaluate the impact of phthalate exposure on circadian dysregulation in the placenta and fetoplacental vascularity, including the placenta barrier function (Aim 1). Phthalate exposure can lead to oxidative stress and inflammatory overactivation. Therefore, Aim 2 will evaluate if phthalate-induced placental mitochondrial reprogramming is involved in these events and if mitochondria-targeted therapy can offer effective protection. Aim 3 will evaluate the impact of phthalate exposure on placenta-mediated pregnancy complications, focusing on preeclampsia and fetal loss.
Specific Aims of the proposed research
- Evaluate the hypothesis that phthalate exposure leads to circadian misalignment and dysregulation of placental barrier functions.
- Evaluate the impact of placental mitochondrial dysfunction and enhanced inflammatory reactions on phthalate-induced placental dysregulation.
- Evaluate the outcomes of placenta-mediated pregnancy complications resulting from phthalate exposure.
Integration
Project 2 is closely integrated with the Overall Center by studying the same phthalate mixture and evaluating it in the context of pregnancy; i.e., the same study outcome of clinical Project 1 but on a more mechanistic level. We will inform Project 1 on the identified mechanisms of phthalate toxicity. We will employ the methodology developed by Project 3 and used by the Research Support Core. We will evaluate remediation products generated by Project 4 for any potential toxicity. Project 2 and trainees supported by Project 2 will engage in all training activities of the RETCC. We will also actively participate in translational activities of the Administrative and Research Translation Core and work with the communities via close interaction with the CEC. The study design, experimental groups, and power analysis have been prepared in collaboration with the DMAC. In addition, we will coordinate with DMAC to prepare datasets, data analysis, and depository.
Our Project responds to an important gap of knowledge related to the interactions of exposure to environmental toxicants with the disruption of circadian rhythms. The significance of this proposal is related to the high prevalence of circadian misalignment in society, the ubiquitous presence of phthalates in the environment, and their effects on women’s health. The cumulative impact of these factors has not been studied in the literature, making our proposal conceptually innovative. The planned experiments will help us to better characterize the involvement of phthalate exposure and the circadian disruption in placenta-mediated pregnancy complications, and to design novel therapies for protection against toxicity of these environmental factors.