Epidemiology and animal studies suggest that a paternal history of toxicant exposure contributes to the developmental origins of health and disease. Using a mouse model, our laboratory previously reported that a paternal history of in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased his offspring’s risk of developing necrotizing enterocolitis (NEC). Additionally, our group and others have found that formula supplementation also increases the risk of NEC in both humans and mice. Our murine studies revealed that intervening with a paternal fish oil diet preconception eliminated the TCDD-associated outcomes that are risk factors for NEC (e.g., intrauterine growth restriction, delayed postnatal growth, and preterm birth). However, the efficacy of a paternal fish oil diet in eliminating the risk of disease development in his offspring was not investigated. Herein, reproductive-age male mice exposed to TCDD in utero were weaned to a standard or fish oil diet for one full cycle of spermatogenesis, then mated to age-matched unexposed females. Their offspring were randomized to a strict maternal milk diet or a supplemental formula diet from postnatal days 7–10. Offspring colon contents and intestines were collected to determine the onset of gut dysbiosis and NEC. We found that a paternal fish oil diet preconception reduced his offspring’s risk of toxicant-driven NEC, which was associated with a decrease in the relative abundance of the Firmicutes phylum, but an increase in the relative abundance of the Negativicutes class.

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.

New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunction and impaired alveolarization. Risk factors for new BPD include prematurity, delayed postnatal growth, the dysregulation of epithelial-to-mesenchymal transition (EMT), and parental exposure to toxicants. Our group previously reported that a history of paternal toxicant exposure increased the risk of prematurity and low birth weight in offspring. A history of paternal toxicant exposure also increased the offspring’s risk of new BPD and disease severity was increased in offspring who additionally received a supplemental formula diet, which has also been linked to poor lung development. Risk factors associated with new BPD are well-defined, but it is unclear whether the disease can be prevented. Herein, we assessed whether a paternal fish oil diet could attenuate the development of new BPD in the offspring of toxicant exposed mice, with and without neonatal formula feeding. We investigated the impact of a paternal fish oil diet preconception because we previously reported that this intervention reduces the risk of TCDD associated placental dysfunction, prematurity, and low birth weight. We found that a paternal fish oil diet significantly reduced the risk of new BPD in neonatal mice with a history of paternal toxicant exposure regardless of neonatal diet. Furthermore, our evidence suggests that the protective effects of a paternal fish oil diet are mediated in part by the modulation of small molecules involved in EMT.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Several factors are implicated in the pathogenesis of CVD, and efforts have been made to reduce traditional risks, yet CVD remains a complex burden. Notably, people living with HIV (PLWH) are twice as likely to develop CVD compared to persons without HIV (PWoH). Intensive statin therapy, the first-line treatment to prevent cardiovascular events, is effective at reducing morbidity and mortality. However, statin therapy has not reduced the overall prevalence of CVD. Despite antiretroviral therapy (ART), and new guidelines for statin use, PLWH have persistent elevation of inflammatory markers, which is suggested to be a bigger driver of future cardiovascular events than low-density lipoprotein. Herein, we have summarized the development of atherosclerosis and highlighted mouse models of atherosclerosis in the presence and absence of HIV. Since most mouse strains have several mechanisms that are atheroprotective, researchers have developed mouse models to study CVD using dietary and genetic manipulations. In evaluating the current methodologies for studying HIV-associated atherosclerosis, we have detailed the benefits of integrating multi-omics analyses, genetic manipulations, and immune cell profiling within mouse models. These advanced approaches significantly enhance our capacity to address critical gaps in understanding the immune mechanisms driving CVD, including in the context of HIV.

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.