The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3) promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs) in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.

Pulmonary arterial hypertension (PAH) can be discovered in patients who have a loss of function mutation of activin A receptor-like type 1 (ACVRL1) gene, a bone morphogenetic protein (BMP) type 1 receptor. Additionally, ACVRL1 mutations can lead to hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, an autosomal dominant inherited disease that results in mucocutaneous telangiectasia and arteriovenous malformations (AVMs). Transcriptional regulator Inhibitor of DNA-Binding/Differentiation-3 (ID3) has been demonstrated to be involved in both PAH and HTT; however, the role of its overlapping molecular mechanistic effects has yet to be seen. This review will focus on the existing understanding of how ID3 may contribute to molecular involvement and perturbations thus altering both PAH and HHT outcomes. Improved understanding of how ID3 mediates these pathways will likely provide knowledge in the inhibition and regulation of these diseases through targeted therapies.

Vascular diseases, such as hypertension, atherosclerosis, cerebrovascular, and peripheral arterial diseases, present major clinical and public health challenges, largely due to their common underlying process: vascular remodeling. This process involves structural alterations in blood vessels, driven by a variety of molecular mechanisms. The inhibitor of DNA-binding/differentiation-3 (ID3), a crucial member of ID family of transcriptional regulators, has been identified as a key player in vascular biology, significantly impacting the progression of these diseases. This review explores the role of ID3 in vascular remodeling, emphasizing its involvement in processes such as apoptosis, cell proliferation, and extracellular matrix regulation. Furthermore, we examine how oxidative stress, intensified by exposure to estrogenic endocrine disruptors (EEDs) like polychlorinated biphenyls (PCBs) and bisphenol A (BPA), affects ID3 activity and contributes to vascular disease. Understanding the interaction between ID3 signaling and EED exposure provides critical insights into the molecular mechanisms underlying vascular remodeling and its role in the development and progression of vascular diseases.

Vascular diseases, including peripheral arterial disease (PAD), pulmonary arterial hypertension, and atherosclerosis, significantly impact global health due to their intricate relationship with vascular remodeling. This process, characterized by structural alterations in resistance vessels, is a hallmark of heightened vascular resistance seen in these disorders. The influence of environmental estrogenic endocrine disruptors (EEDs) on the vasculature suggests a potential exacerbation of these alterations. Our study employs an integrative approach, combining data mining with bioinformatics, to unravel the interactions between EEDs and vascular remodeling genes in the context of PAD. We explore the molecular dynamics by which EED exposure may alter vascular function in PAD patients. The investigation highlights the profound effect of EEDs on pivotal genes such as ID3, LY6E, FOS, PTP4A1, NAMPT, GADD45A, PDGF-BB, and NFKB, all of which play significant roles in PAD pathophysiology. The insights gained from our study enhance the understanding of genomic alterations induced by EEDs in vascular remodeling processes. Such knowledge is invaluable for developing strategies to prevent and manage vascular diseases, potentially mitigating the impact of harmful environmental pollutants like EEDs on conditions such as PAD.

The ongoing growth of the international occurrence of depression and its ability to co-occur with other serious medical disorders, such as heart disease, cancer, diabetes, and Parkinson’s disease, is a current public health problem. Inhibitor of DNA-Binding/Differentiation (ID) proteins are part of a group of transcriptional factors that have shown involvement in neurocognitive disorders and, therefore, may have influence on depressive disorders. Previously, it has been established that exposure to environmental estrogenic endocrine disruptors (EEDs), such as polychlorinated biphenyls (PCBs) and bisphenol A (BPA), have played an important role in the modulation of depressive disorders. Hence, based on many studies, we consider the impact of these environmental pollutants on the group of ID proteins and how they impact depressive outcomes. Improved knowledge of how ID proteins interact with depressive disorders, through EED exposure, will contribute essential evidence that can further benefit our public health community with innovative knowledge to prevent these types of mental illnesses.

Tumor-like proliferative vascular lesions manifest in several diseases such as peripheral arterial disease (PAD) and atherosclerosis (AS) after arterial injury. The cause of the vascular cell dysfunction in PAD patients is not known. Our recent novel discovery shows that inhibitor of differentiation 3 (ID3) is highly expressed in intimal lesions of clinical vascular disease samples. The central hypothesis of our study is: estrogenic chemical induced dysregulation of ID3 target genes is involved in the development of vascular disease. NHANES data analysis demonstrated higher geometric levels of all 6 PCB congeners in both PAD diagnosed participants and participants at risk of AS when compared to the rest of the population. Adjusted models showed association between higher exposure of PCBs, phthalates, BPA, and increased risk of PAD. Furthermore PCB153 was shown to have the highest geometric mean amongst all PCB congeners in both participants diagnosed with PAD and at risk of AS. Gene expression of ID3 & ID3 candidate targets in blood & tissue studies identified ID3 & ID3 candidate target genes as a driver of vascular disease. Overlapping ID3 & ID3 candidate target genes included: ABCB6, ACP1, BYSL, CAD, CDH15, DCBLD2, DHRS3, DNMT1, ID3, MCM4, and NDUFA7. The ID3 target genes involved in the: focal adhesion pathway were ACTN1, COL1A2, COL3A1, COL6A1, CTNNB1, IBSP, ID3, ITGA8, and MYL2; ECM-receptor interaction were COL1A2, COL3A1, COL6A1, IBSP, ID3, and ITGA8; oxidative phosphorylation pathway ATP5D, ATP5H, ATP6V0B, ATP6V0D1, ATP6V1B2, COX5A, COX7C, COX8A, CYC1, ID3, NDUFA1, NDUFA7, NDUFS4, NDUFV1, NDUFV2; and cell cycle pathway ANAPC10, ATM, CDKN2B, E2F5, MCM3, and MCM4. In summary our results showed an association between exposure to PCBs, phthalates, BPA, and increased risk of PAD and AS, and possible molecular mechanisms of interaction of ID3 target genes and estrogenic chemicals involved in PAD and AS.