Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonly also exhibit adenomyosis, the growth of endometrial tissues within the uterine muscle. Each disease is associated with functional alterations in the eutopic endometrium frequently leading to pain, reduced fertility, and an increased risk of adverse pregnancy outcomes. Although the precise etiology of either disease is poorly understood, evidence suggests that the presence of endometriosis may be a contributing factor to the subsequent development of adenomyosis as a consequence of an altered, systemic inflammatory response. Herein, we will discuss the potential role of exposure to environmental toxicants with endocrine disrupting capabilities in the pathogenesis of both endometriosis and adenomyosis. Numerous epidemiology and experimental studies support a role for environmental endocrine disrupting chemicals (EDCs) in the development of endometriosis; however, only a few studies have examined the potential relationship between toxicant exposures and the risk of adenomyosis. Nevertheless, since women with endometriosis are also frequently found to have adenomyosis, discussion of EDC exposure and development of each of these diseases is relevant. We will discuss the potential mechanisms by which EDCs may act to promote the co-development of endometriosis and adenomyosis. Understanding the disease-promoting mechanisms of environmental toxicants related to endometriosis and adenomyosis is paramount to designing more effective treatment(s) and preventative strategies.

New bronchopulmonary dysplasia (BPD) is a neonatal disease that is theorized to begin in utero and manifests as reduced alveolarization due to inflammation of the lung. Risk factors for new BPD in human infants include intrauterine growth restriction (IUGR), premature birth (PTB) and formula feeding. Using a mouse model, our group recently reported that a paternal history of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure increased his offspring’s risk of IUGR, PTB, and new BPD. Additionally, formula supplementation of these neonates worsened the severity of pulmonary disease. In a separate study, we reported that a paternal preconception fish oil diet prevented TCDD-driven IUGR and PTB. Not surprisingly, eliminating these two major risk factors for new BPD also significantly reduced development of neonatal lung disease. However, this prior study did not examine the potential mechanism for fish oil’s protective effect. Herein, we sought to determine whether a paternal preconception fish oil diet attenuated toxicant-associated lung inflammation, which is an important contributor to the pathogenesis of new BPD. Compared to offspring of standard diet TCDD-exposed males, offspring of TCDD-exposed males provided a fish oil diet prior to conception exhibited a significant reduction in pulmonary expression of multiple pro-inflammatory mediators (Tlr4, Cxcr2, Il-1 alpha). Additionally, neonatal lungs of pups born to fish oil treated fathers exhibited minimal hemorrhaging or edema. Currently, prevention of BPD is largely focused on maternal strategies to improve health (e.g., smoking cessation) or reduce risk of PTB (e.g., progesterone supplementation). Our studies in mice support a role for also targeting paternal factors to improve pregnancy outcomes and child health.

Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anemia, induces hypogonadism in males. However, the impact of HU on testicular architecture and function, as well as its effects on the resumption of male fertility following treatment withdrawal, remain poorly understood. We used adult male mice to determine whether HU-induced hypogonadism is reversible. Fertility indices of mice treated with HU daily for ~1 sperm cycle (2 months) were compared with those of their control counterparts. All indices of fertility were significantly reduced among mice treated with HU compared to controls. Interestingly, significant improvements in fertility indices were apparent after a 4-month withdrawal from HU treatment (testis weight: month 1 post-HU withdrawal (M1): HU, 0.09 ± 0.01 vs. control, 0.33 ± 0.03; M4: HU, 0.26 ± 0.03 vs. control, 0.37 ± 0.04 g); sperm motility (M1: HU,12 vs. 59; M4: HU, 45 vs. control, 61%; sperm density (M1: HU, 1.3 ± 0.3 vs. control, 15.7 ± 0.9; M4: HU, 8.1 ± 2.5 vs. control, 16.8 ± 1.9 million). Further, circulating testosterone increased in the 4th month following HU withdrawal and was comparable to that of controls. When a mating experiment was conducted, recovering males sired viable offspring with untreated females albeit at a lower rate than control males (p < 0.05); therefore, qualifying HU as a potential candidate for male contraception.

Corrigendum: The potential relationship between environmental endocrine disruptor exposure and the development of endometriosis and adenomyosis

Exposure to endocrine-disrupting chemicals (EDCs) has been linked to several pathologies in human health, especially those involving the immune system. The vast majority of studies have focused on cells and functions of the adaptive immune system with little investigation of the impact of EDCs on innate immunity. While EDC exposure remains a threat throughout the lifetime of an individual, the most detrimental effects on human health occur during critical stages of development, such as in utero. Fetal development is not only associated with growth and tissue remodeling but also with the establishment of key processes, including those of the immune system. Unfortunately, due to fetal plasticity, developmental exposure to certain EDCs, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), can affect mammalian health well into adulthood by altering fetal programming. Herein, we hypothesize that in utero exposure to TCDD induces developmental reprogramming of the innate immune system that subsequently impacts the adult response to infection. To interrogate our hypothesis, we challenged adult mice with and without a history of in utero TCDD exposure with 1 × 10⁸ CFU Pseudomonas aeruginosa via intraperitoneal injection. Results revealed a significant decrease in the number of innate leukocytes at the site of infection six hours after inoculation in toxicant-exposed mice compared to unexposed mice. The reduction in the number of phagocytes correlated with a reduction in bacterial clearance in toxicant-exposed mice. We also noted a decreased ability of peritoneal immune cells from toxicant-exposed mice to produce chemokines necessary for immune cell recruitment. Taken together, our results indicate that in utero EDC exposure impairs the innate immune response to a bacterial infection in adult offspring, particularly in males.