Journal of the Pancreas Open Access

Environmental Chemical, Pancreatic Toxicity and Metabolic Disorder Review

Yue Ge^* Department of Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, USA
^*Correspondence: Yue Ge, Department of Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, USA, Email:

Received: 29-Jul-2024, Manuscript No. IPP-24-21018; Editor assigned: 01-Aug-2024, Pre QC No. IPP-24-21018 (PQ); Reviewed: 15-Aug-2024, QC No. IPP-24-21018; Revised: 15-Jan-2025, Manuscript No. IPP-24-21018 (R); Published: 13-Jan-2025, DOI: 10.35841/1590-8577-26.1.903

Introduction

The pancreas plays a pivotal role in the onset, development and progression of metabolic syndrome, which is characterized by obesity, insulin resistance, hypertension and dyslipidemia and a precursor to severe health conditions such as steatosis, Type 2 Diabetes (T2D), cardiovascular diseases and various cancers [1].

The surge in metabolic disorders parallels the significant increase in environmental chemical production and exposure over the past four decades, such as Vinyl Chloride (VC) [2], Bisphenol A (BPA) [3], Phthalates [4], arsenic [5] and nutritional factors such as High-Fat Diets (HFD) [6]. These studies also demonstrated the crucial role of the pancreas in regulating metabolic processes, making it a critical organ for studying the impact of environmental chemical on metabolic syndrome and disease.

Pancreas as a target organ for toxicity testing of environmental chemicals of concern for metabolic syndrome and disease

Evidence of environmental chemical disrupting the pancreas functions dates back to the early 1940s when alloxan, a glucose analogue, was found to induce type 1 diabetes in rabbits by destroying insulin-producing cells [7]. Workers in a Swedish Vinyl Chloride (VC) plant also showed an excess of pancreas tumors [2]. Table 1 summarizes 16 key studies on the effects of environmental chemicals on pancreas-mediated metabolic syndromes and diseases from 1976 to 2018.

Table 1. Table 1 summarizes 16 key studies on the effects of environmental chemicals on pancreas-mediated metabolic syndromes and diseases from 1976 to 2018. These studies were identified based on relevance to pancreatic toxicity, scientific rigor and impact and years of publications.

Pesticides and metals were prominently represented, with 3 pesticides and 4 metals examined. Studying a wide range of chemicals helped identify multiple pathways through which environmental chemicals can impact pancreatic function, leading to a broader understanding of environmental health risks. Traditional endpoints, such as insulin secretion, glucose metabolism and tumor incidence, were the primary focus of these studies, providing reliable indicators of pancreatic dysfunction and metabolic health impacts. The majority of studies utilized traditional toxicology approaches with an emphasis on toxicity endpoints or adverse health outcomes obtained from in vivo animal models or human epidemiological data, which offered a holistic view of the toxic effects on the pancreas, considering the complexities of whole-organism interactions and real-life exposure scenarios.

Efficiently screening chemicals for toxicity using the pancreas as the target required appropriate animal models, in which the phenotypes and pathogeneses of the animal's condition resembled the human disease under investigation. Overall, these studies that were conducted before 2018 highlighted the early stages of research on the relationships between environmental chemical exposure and pancreatic function and a need for more research using New Approach Methods (NAMs) and advanced in vitro systems to complement the existing approaches.

Utilizing integrated modern methodologies to provide mechanistic insides into pancreatic toxicity

To address limitations of traditional endpoints and in vivo studies, integrating modern methodologies, such as NAMs and developing effective in vitro models, have been extensively applied in the past decade to provide mechanistic insights on environmental chemical mediated pancreatic toxicity. Table 2 is a summary of some key studies using High-Throughput Screening (HTS), Omics technologies, computational modeling, and advanced in vitro systems for enhancing our understanding of how environmental chemicals impact pancreatic function, toxicity and adverse health outcome. For instances, studies conducted by Xu et al. demonstrated the potential of HTS in screening a broad range of compounds, including pesticides, industrial chemicals, and metals [8], identifying several that impaired insulin secretion and β-cell viability. The development and application of computational models [9], was crucial in predicting the effects of various chemicals on pancreatic β-cell function. These models integrated data from multiple sources, allowing for the simulation of β-cell responses and identification of potential toxicants without extensive in vitro or in vivo testing. The study on maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets [10], investigated the effects of toxicants on insulin secretion and β-cell. In addition, the co-culture models of pancreatic β-cells and α-cells was developed to study their interactions in the presence of toxicants such as phthalates and organochlorine pesticides [11]. The advanced in vitro models provided valuable information on cellular interactions and collective responses to environmental chemicals, highlighting the complexity of pancreatic responses to toxic insults. In a recent transcriptomics study [12], cell viability was found to be moderately affected after BPA, Bisphenol-F (BPF) and Perfluorooctanesulfonic acid (PFOS) exposure, indicating most of the selected chemicals studied caused functional alterations in pancreatic α-cells for the first time. These studies demonstrated that HTS is an efficient tool for identifying harmful chemicals affecting pancreatic function and Omics profiling can provide detailed insights into molecular expression and pathway changes due to chemical exposure, which is essential for understanding mechanisms of pancreatic toxicity. In addition, computational modeling of NAMs and pathway-based data offer a promising approach to predict chemical toxicity, reducing the reliance on extensive in vitro or in vivo testing. Advanced in vitro models are valuable for identifying environmental chemicals, documenting their toxicity and allowing biochemical and toxicological investigations into the underlying mechanisms, such as pancreatic β-cells for testing of chemical toxicity relevant with certain types of diabetes mellitus in both humans and experimental animals. Current in vitro differentiation protocols can efficiently generate glucose-responsive insulin-secreting β-like cells that are not fully mature but are valuable for high-throughput toxicity screening. Human pluripotent stem cell (hPSC) culture has proven to be a powerful tool for in vitro toxicity testing, overcoming many limitations of other β-cell models. In summary, integrating modern methodologies, such as NAMs and advanced in vitro models, enable more accurate characterization of environmental chemical mediated pancreatic toxicity and metabolic syndromes for improving early detection of toxic effects and ultimately contributing to better protection of human health from environmental exposures.

Table 2. List of some key studies using NAMs and in vitro systems for enhancing the understanding of how environmental chemicals impact pancreatic function, toxicity and adverse health outcomes.

Impacts of the interplay between environmental chemical and nutritional factor on metabolic dysfunction

HFD is well-established as a significant factor promoting metabolic dysfunction and is even considered a major contributor to the development of metabolic syndrome [6]. Numerous examples demonstrate that developmental exposures to metabolically disrupting chemicals can be exacerbated by high-fat diets later in life, underscoring the increased susceptibility to obesity and other metabolic diseases resulting from exposures to environmental chemicals [13]. For instance, developmental exposure to Polycyclic Aromatic Hydrocarbons (PAH) leads to obesity, insulin resistance, and inflammation, particularly when followed by a high-fat diet in adulthood [14].

The insulin resistance induced by BPA may be additive with a HFD [15]. These emerging data support the idea that developmental exposures to environmental chemicals alter the susceptibility set point for metabolic diseases by HFD and the interplay between HFD and chemicals might potentiate the development of metabolic syndromes. In a recent proteomic study, the pancreas proteome of mice exposed to occupational chemical of VC and HFD, singly and in combinations, was compared to that of normal mice fed a Low-Fat Diet (LFD) on a global scale. This comparison aimed to identify differentially expressed cytokines, enzymes and phosphorylated AKT kinases, focusing on a subset of proteins crucial to metabolic dysfunctions mediated by the pancreas. This comparative approach in protein profiling greatly facilitated the identification of dysregulated proteins associated with specific biological conditions, including metabolic syndromes. The quantitative measurement and comparison of proteins that provide mechanistic insights were essential for uncovering and distinguishing the roles of altered proteins in the pathogenesis of metabolic syndrome induced by VC and HFD.

This study provided novel insights into VC toxicity mechanisms and characterized the interactive health effects of VC and HFD on pancreas-mediated metabolic disorder for the first time. To comprehend the molecular basis and toxicity pathways underpinning the development of metabolic syndrome and disease in the pancreas, it's essential to collectively investigate both nutritional and environmental chemical exposures, such as HFD and various chemicals. Additionally, the research necessitated a reevaluation of occupational safety guidelines for the occupational toxicant of VC to protect occupational worker safety, which directly impacted human health risk assessments and regulatory contexts.

Conclusion

The pancreas is a valuable but complex target for environmental toxicity testing. Current research has provided robust but sometimes limited insights. To gain a deeper mechanistic understanding and more detailed data on the impacts of environmental chemicals on pancreatic function, it is necessary to expand the use of modern techniques such as New Approach Methodologies (NAMs) and in vitro model. Future investigations should delve into the molecular targets and pathways within the AOP framework for effective screening of environmental chemicals for their potential to disrupt metabolism and enabling earlier diagnosis and treatment of metabolic syndromes and associated diseases.

The connections between high-fat diet consumption and occupational exposures are only beginning to be elucidated. It is generally accepted that the risk of metabolic syndromes and diseases may be increased by occupational exposures to chemicals such as Vinyl Chloride (VC). In-depth studies are warranted to explore interactive health effects of occupational toxicants and lifestyle factors, such as HFD, on the pancreas pathways, function and physiology between occupational toxicants and lifestyle factors, such as HFD, for directly impacting human health risk assessments and regulatory contexts and protecting occupational worker safety.

The endocrine system consists of not only the pancreas, but alo liver, and adipose tissue which are also frequently affected simultaneously by environmental chemicals. The system, collectively rather than as individual tissues or organs, regulate overall metabolism. Therefore, for a systematic understanding of metabolic syndromes and diseases mediated by the pancreas, it is essential to integrate environmental exposure data linked to metabolic disruptions originating from the liver and adipose tissues. Translating findings from the pancreas to other metabolically active tissues, especially the liver and adipose tissue is critical to validate data and findings obtained from the pancreas to achieve a systematic understanding of how environmental factors mediate metabolic syndromes and diseases at the systematic level. A comprehensive examination of multiple endpoints and tissues is essential for defining the actions, mechanisms and toxicities of suspected environmental chemicals.

Acknowledgements

The author would like to acknowledge Dr. Arun Pandiri for his valuable comments and suggestions on the mini review manuscript and Dr. Witold Winnik and Dr. Dave Heer for their very helpful comments on this manuscript. The information in this document has been funded wholly by the US Environmental Protection Agency.

It has been subjected to review by the center for computational toxicology and exposure and has been approved for publication. Approval does not signify that the contents reflect the views of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Conflict of Interest

The authors declare no conflict of interest.

References

1. Tsai HJ, Chang JS. Environmental risk factors of pancreatic cancer. J Clin Med. 2019;8(9):1427.

   [Crossref] [Google Scholar] [PubMed]

2. Lenzen S. The mechanisms of alloxan-and streptozotocin-induced diabetes. Diabetologia. 2008;51(2):216-226.

   [Crossref] [Google Scholar] [PubMed]

3. Alonso-Magdalena P, Ropero AB, Soriano S, García-Arévalo M, Ripoll C. Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways. Mol Cell Endocrinol. 2012;355(2):201-207.

   [Crossref] [Google Scholar] [PubMed]

4. Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult US males. Environ Health Perspect. 2007;115(6):876-882.

   [Crossref] [Google Scholar] [PubMed]

5. Paul DS, Walton FS, Saunders RJ, Stýblo M. Arsenic-induced diabetes and pancreatitis in animal models. Toxicol Appl Pharmacol. 2011;257:372-381.
6. Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev. 2010;23:270-299.

   [Crossref] [Google Scholar] [PubMed]

7. Byren D, Engholm G, Englund A, Westerholm P. Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers. Environ Health Perspect. 1976;17:167-170.

   [Crossref] [Google Scholar] [PubMed]

8. Fisher RA. Advances in biokinetic models and computational toxicology. Toxicol Res. 2018;7:821-830.
9. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121-1133.

   [Crossref] [Google Scholar] [PubMed]

10. Kim SM,  Lee EJ,  Jung HS,  Han N,  Kim YJ. Co-culture of α TC-6 cells and β TC-1 cells: Morphology and function. Endocrinol Metab. 2015;30:92–97.

    [Crossref] [Google Scholar] [PubMed]

11. Al-Abdulla R, Ferrero H, Boronat-Belda T,  Soriano S,  Quesada I. Exploring the effects of metabolism-disrupting chemicals on pancreatic α-cell viability, gene expression and function: A screening testing approach. Int J Mol Sci. 2023;24:1044.

    [Crossref] [Google Scholar] [PubMed]

12. Wei J, Li Y, Ying C, Chen J, Song L. Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. Endocrinology. 2011;152:3049-3061.

    [Crossref] [Google Scholar] [PubMed]

13. Khalil A, Villard PH, Dao MA, Burcelin R, Champion S. Polycyclic aromatic hydrocarbons potentiate high-fat diet effects on intestinal inflammation. Toxicol Lett. 2010;196:161-167.

    [Crossref] [Google Scholar] [PubMed]

14. Moon MK,  Jeong IK, Oh TJ,  Ahn HK,  Kim HH. Long-term oral exposure to bisphenol A induces glucose intolerance and insulin resistance. J Endocrinol. 2015;226:35-42.

    [Crossref] [Google Scholar] [PubMed]

15. Ge Y, Bruno M, Nash MS, Coates NH, Chorley BN. Vinyl chloride enhances high-fat diet-induced proteome alterations in the mouse pancreas related to metabolic dysfunction. Toxicol Sci. 2023;193:103-114.

    [Crossref] [Google Scholar] [PubMed]