The adverse effects of environmental exposures on the reproductive system have been recognized as significant threat to human health. Through the addition of new faculty and formation of collaborations among them, SWEHSC is now positioned to make significant contributions in this field. The center now counts with expertise in descriptive and mechanistic reproductive toxicology (Craig) and the reproductive and gynecological health epidemiology (Farland).
Relevance to SWEHSC:
Environmental Impacts on Reproductive and Developmental Health:
Endocrine-disrupting chemicals (EDCs) interact with signaling pathways and processes required for development and reproduction and are associated with developmental and reproductive disease. Over the past four years, RFG3 increased SWEHSC’s research capacity to address the role of EDCs in reproductive diseases of concern to the US Southwest by 1) recruiting and mentoring outstanding investigators already successful in the fields of reproductive health and disease, and 2) maximizing the use of SWEHSC Pilot Projects and FC resources to support their official entry into EHS. This effort led to the new SWEHSC expertise expanding RFG3 areas into inhaled exposures and markers of reproductive senescence and phthalate exposure impacts on female reproduction and developmental programming of adult disease.
Inhaled Exposures and Reproductive Senescence. RFG3 member Dr. Leslie Farland focuses on the influence of environmental exposures on infertility and time of menopause, as these reproductive endpoints have high burden and are associated with increased risk for other long-term health consequences later in life. Prior research has suggested that early age at menopause can adversely modify cardiometabolic disease onset, stroke, and dementia. Additionally, women suffering from infertility have a higher risk of many adverse pregnancy outcomes, and research suggests that these women may also be at increased risk of chronic diseases later in life. The time during which a woman can reproduce and when she undergoes menopause is correlated with her ovarian reserve, which is clinically assessed via anti-Müllerian hormone (AMH). As women age, AMH steadily declines to the point at which it is no longer detectable. AMH is a commonly used proxy for monitoring natural and iatrogenic declines in ovarian function over time in the infertile population. Although smoking increases risk for infertility, shifts menopause toward earlier age, and decreases AMH, little is known about the effect of wildfire, environmental smoke exposure, second-hand smoke, and air pollution on AMH. SWEHSC funded Dr. Farland to conduct a pilot project measuring AMH levels in firefighters, a high-risk group of women for these exposures.
Phthalate Exposures and Reproductive and Developmental Programming of Adult Disease. Phthalate esters are commonly used in and leach from a variety of products including food packaging, medical tubing, cosmetics, and the enteric coating of certain oral medications. Phthalate exposure is ubiquitous, as demonstrated by biomonitoring studies reporting detection of exposure markers in nearly all specimens tested. Recent publications evaluating relationships between phthalate burden and various health outcomes have demonstrated their association with adverse reproductive and metabolic health outcomes as well as increased mortality. SWEHSC’s decision to enhance research capacity in phthalate exposures stems from reports indicating that among women, non-Latinx Black and Mexican American women have higher phthalate metabolite concentrations than non-Latinx women. This observation suggests that the burden of phthalates may be disproportionate in regions with a significant Mexican American population that are near the Mexico-US border. SWEHSC’s geographical location and its history of effective partnerships with Southwest communities provides the appropriate background to foster impactful phthalate research capable of spanning NIEHS’ translational framework. Specifically, RFG3 has created momentum in three key research areas on phthalates: effects on female fertility and ovarian function, placental physiology, and developmental programming of metabolic and cardiovascular cell function. SWEHSC has invested in each of these areas through pilot funding and FC support to facilitate collaborations.
Environmentally Relevant Phthalate Exposures and Ovarian Function. Phthalates represent a significant concern for human fertility because they have been associated with early menopause, decreased hormone levels, and early pregnancy loss in women. Studies in animal models suggest that phthalates may impair fertility through their ability to disrupt ovarian function. Dr. Zelieann R. Craig’s work is aimed at identifying and characterizing the interactions between phthalates and the ovary, the main reproductive organ in the female. Her team uses environmentally relevant exposures to three model phthalates to identify which signaling pathways, ovarian follicle types and individual ovarian cell compartments are most sensitive to phthalates and establish the phenotypes (i.e., early menopause, anovulation, failed embryogenesis) that result from these relevant exposures.
Mechanistic Analysis of the Role of Phthalates in Preterm Birth. Di-2-ethylhexyl-phthalate (DEHP), a phthalate diester, is the most common plasticizer additive in various cosmetics, perfumes, shampoo, polyvinyl chloride (PVC) plastics, and many other everyday products. Recent studies have demonstrated that the metabolites of DEHP are present in significantly higher amounts in women with preterm birth and intrauterine growth-restricted fetuses (IUGR). Additionally, studies have demonstrated that maternal phthalate exposure can also affect fetal health and lead to adverse health outcomes later in offspring life. The effects of phthalate exposure on preterm birth, IUGR, and health problems in offspring demonstrate that DEHP metabolites not only affect placental function (e.g., steroidogenesis or nutrient transport) but can cross the placenta to affect fetal growth. Dr. Ravi Goyal’s work is aimed at understanding how phthalate metabolites are transferred across the placenta, accumulate in fetal tissues, and dysregulate gene expression in these tissues. This work is critical given that recent studies have demonstrated that phthalate metabolites are present in significantly higher amounts in women with preterm birth and intrauterine growth-restricted fetuses (IUGR). Additionally, studies have demonstrated that maternal phthalate exposure can also affect fetal health and lead to adverse health outcomes later in offspring life.
Role of Phthalate Exposure in Maternal Obesity-Induced Fetal Sex-specific Endothelial Dysfunction. Women at reproductive age have a significant burden of the phthalate congener, di-n-butyl phthalate (DBP). DBP exposure is associated with obesity and adverse pregnancy/fetal outcomes such as preterm birth, fetal growth retardation, and childhood obesity in humans. Although DBP is known as an obesogen, the impact of prenatal DBP exposure on fetal vascular/endothelial development and function in obese pregnancies is unclear. Dr. Chi Zhou’s work is aimed at examining the effect of DBP exposure on maternal obesity-induced female and male fetal endothelial dysfunction. Results from this study will provide important information on how phthalates exposure affects placental function as well as the fetal-sex specific programming of fetal vascular/endothelial development and function.