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Article ; Online: Complex Mixtures and Multiple Stressors: Evaluating Combined Chemical Exposures and Cumulative Toxicity.

Kassotis, Christopher D / Phillips, Allison L

2023 Volume 11, Issue 6

Abstract: The problem of chemical mixtures in the environment encompasses biological, analytical, logistical, and regulatory challenges, among others [ ... ]. ...

Abstract	The problem of chemical mixtures in the environment encompasses biological, analytical, logistical, and regulatory challenges, among others [...].
Language	English
Publishing date	2023-05-26
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics11060487
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Article ; Online: Molecular Assessment of Pro-Adipogenic Effects for Common-Use Contraceptives and their Mixtures.

Chiang, Yu-Ting Tiffany / Kassotis, Christopher D

Endocrinology

2024

Abstract: Hormonal contraceptives are widely prescribed due to their effectiveness and convenience and have become an integral part of family planning strategies worldwide. In the US, ∼65% of reproductive aged women are estimated to be using contraceptive options, ...

Abstract	Hormonal contraceptives are widely prescribed due to their effectiveness and convenience and have become an integral part of family planning strategies worldwide. In the US, ∼65% of reproductive aged women are estimated to be using contraceptive options, with ∼33% using one or a combination of hormonal contraceptives. While these methods have undeniably contributed to improved reproductive health, recent studies have raised concerns regarding their potential impact on metabolic health. Despite widespread anecdotal reports, epidemiological research has been mixed as to whether hormonal contraceptives contribute to metabolic health effects. As such, the goals of this study were to assess the adipogenic activity of common hormonal contraceptive chemicals and their mixtures. Five different models of adipogenesis were utilized to provide a rigorous assessment of metabolism disrupting effects. Interestingly, every individual contraceptive (both estrogens and progestins) and each mixture promoted significant adipogenesis (e.g., triglyceride accumulation and/or pre-adipocyte proliferation). These effects appeared to be mediated in part through estrogen receptor signaling, particularly for the contraceptive mixtures, as co-treatment with fulvestrant acted to inhibit contraceptive-mediated pro-adipogenic effects on triglyceride accumulation. In conclusion, this research provides valuable insights into the complex interactions between hormonal contraceptives and adipocyte development. The results suggest that both progestins and estrogens within these contraceptives can influence adipogenesis, and the specific effects may vary based on the receptor activation profiles. Further research is warranted to establish translation of these findings to in vivo models and to further assess causal mechanisms underlying these effects.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqae050
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Article ; Online: The Pediatrician's Role in Protecting Children from Environmental Hazards.

Trasande, Leonardo / Kassotis, Christopher D

Pediatric clinics of North America

2022 Volume 70, Issue 1, Page(s) 137–150

Abstract: Children suffer disproportionately from disease and disability due to environmental hazards, for reasons rooted in their biology. The contribution is substantial and increasingly recognized, particularly due to ever-increasing awareness of endocrine ... ...

Abstract	Children suffer disproportionately from disease and disability due to environmental hazards, for reasons rooted in their biology. The contribution is substantial and increasingly recognized, particularly due to ever-increasing awareness of endocrine disruption. Regulatory actions can be traced directly to reductions in toxic exposures, with tangible benefits to society. Deep flaws remain in the policy framework in industrialized countries, failing to offer sufficient protection, but are even more limited in industrializing nations where the majority of chemical production and use will occur by 2030. Evidence-based steps for reducing chemical exposures associated with adverse health outcomes exist and should be incorporated into anticipatory guidance.
MeSH term(s)	Child ; Humans ; Developed Countries ; Pediatricians
Language	English
Publishing date	2022-11-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	215711-1
ISSN	1557-8240 ; 0031-3955
ISSN (online)	1557-8240
ISSN	0031-3955
DOI	10.1016/j.pcl.2022.09.003
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Article ; Online: Endocrine disruptor global policy.

Kassotis, Christopher D / Trasande, Leonardo

Advances in pharmacology (San Diego, Calif.)

2021 Volume 92, Page(s) 1–34

Abstract: Over the past several decades, scientific consensus has grown around the concept and evidence for human health impacts from exposure to endocrine disrupting chemicals (EDCs). A series of publications have now demonstrated considerable economic costs of ... ...

Abstract	Over the past several decades, scientific consensus has grown around the concept and evidence for human health impacts from exposure to endocrine disrupting chemicals (EDCs). A series of publications have now demonstrated considerable economic costs of EDC exposure-induced adverse health outcomes. This research has suggested economic burdens in the hundreds of billions, even considering only a small subset of EDCs and health. As of yet, regulatory efforts and policies to protect and decrease human exposure to most EDCs have been insufficient and have not kept pace with the science. Given the overwhelming scientific evidence, referenced throughout this collection, as well as the economic costs of inaction, described here, regulations are clearly needed. The EU and some other countries have taken promising steps towards protective regulation of EDCs, though the response of the US and many other countries has been limited or altogether lacking. Regulatory bodies that have and continue to apply risk-based approaches to regulating EDCs have also failed to consider the complete economic impacts of EDC-related health impacts. In this chapter, we will discuss broad strategies taken to regulate EDCs, examine the approaches currently taken to regulate EDCs in a global context (discussing the strengths and weaknesses of these regulations), discuss the economic costs of EDC exposures (detailing where consideration of health and economic costs could improve regulations), and discuss next steps and novel approaches to adapting existing regulatory frameworks to this class of chemicals.
MeSH term(s)	Endocrine Disruptors/toxicity ; Humans ; Policy
Chemical Substances	Endocrine Disruptors
Language	English
Publishing date	2021-05-24
Publishing country	United States
Document type	Journal Article
ISSN	1557-8925
ISSN (online)	1557-8925
DOI	10.1016/bs.apha.2021.03.005
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Article: Endocrine-Mediated Mechanisms of Metabolic Disruption and New Approaches to Examine the Public Health Threat.

Kassotis, Christopher D / Stapleton, Heather M

Frontiers in endocrinology

2019 Volume 10, Page(s) 39

Abstract: Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative ... ...

Abstract	Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative environmental contributors. Exposure to numerous environmental contaminants have, over decades, been demonstrated to result in increased metabolic dysfunction and/or weight gain in cell and animal models, and in some cases, even in humans. There are numerous mechanisms through which environmental contaminants may contribute to metabolic dysfunction, though certain mechanisms, such as activation of the peroxisome proliferator activated receptor gamma or the retinoid x receptor, have received considerably more attention than less-studied mechanisms such as antagonism of the thyroid receptor, androgen receptor, or mitochondrial toxicity. As such, research on putative metabolic disruptors is growing rapidly, as is our understanding of molecular mechanisms underlying these effects. Concurrent with these advances, new research has evaluated current models of adipogenesis, and new models have been proposed. Only in the last several years have studies really begun to address complex mixtures of contaminants and how these mixtures may disrupt metabolic health in environmentally relevant exposure scenarios. Several studies have begun to assess environmental mixtures from various environments and study the mechanisms underlying their putative metabolic dysfunction; these studies hold real promise in highlighting crucial mechanisms driving observed organismal effects. In addition, high-throughput toxicity databases (ToxCast, etc.) may provide future benefits in prioritizing chemicals for
Language	English
Publishing date	2019-02-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2019.00039
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Article: Cetyl Alcohol Polyethoxylates Disrupt Metabolic Health in Developmentally Exposed Zebrafish.

LeFauve, Matthew K / Bérubé, Roxanne / Heldman, Samantha / Chiang, Yu-Ting Tiffany / Kassotis, Christopher D

Metabolites

2023 Volume 13, Issue 3

Abstract: Alcohol polyethoxylates (AEOs), such as cetyl alcohol ethoxylates (CetAEOs), are high-production-volume surfactants used in laundry detergents, hard-surface cleaners, pesticide formulations, textile production, oils, paints, and other products. AEOs have ...

Abstract	Alcohol polyethoxylates (AEOs), such as cetyl alcohol ethoxylates (CetAEOs), are high-production-volume surfactants used in laundry detergents, hard-surface cleaners, pesticide formulations, textile production, oils, paints, and other products. AEOs have been suggested as lower toxicity replacements for alkylphenol polyethoxylates (APEOs), such as the nonylphenol and octylphenol polyethoxylates. We previously demonstrated that nonylphenol polyethoxylates induced triglyceride accumulation in several in vitro adipogenesis models and promoted adiposity and increased body weights in developmentally exposed zebrafish. We also demonstrated that diverse APEOs and AEOs were able to increase triglyceride accumulation and/or pre-adipocyte proliferation in a murine pre-adipocyte model. As such, the goals of this study were to assess the potential of CetAEOs to promote adiposity and alter growth and/or development (toxicity, length, weight, behavior, energy expenditure) of developmentally exposed zebrafish (
Language	English
Publishing date	2023-02-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo13030359
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Article ; Online: The regulation of endocrine-disrupting chemicals to minimize their impact on health.

Duh-Leong, Carol / Maffini, Maricel V / Kassotis, Christopher D / Vandenberg, Laura N / Trasande, Leonardo

Nature reviews. Endocrinology

2023 Volume 19, Issue 10, Page(s) 600–614

Abstract: Endocrine-disrupting chemicals (EDCs) are substances generated by human industrial activities that are detrimental to human health through their effects on the endocrine system. The global societal and economic burden posed by EDCs is substantial. Poorly ...

Abstract	Endocrine-disrupting chemicals (EDCs) are substances generated by human industrial activities that are detrimental to human health through their effects on the endocrine system. The global societal and economic burden posed by EDCs is substantial. Poorly defined or unenforced policies can increase human exposure to EDCs, thereby contributing to human disease, disability and economic damage. Researchers have shown that policies and interventions implemented at both individual and government levels have the potential to reduce exposure to EDCs. This Review describes a set of evidence-based policy actions to manage, minimize or even eliminate the widespread use of these chemicals and better protect human health and society. A number of specific challenges exist: defining, identifying and prioritizing EDCs; considering the non-linear or non-monotonic properties of EDCs; accounting for EDC exposure effects that are latent and do not appear until later in life; and updating testing paradigms to reflect 'real-world' mixtures of chemicals and cumulative exposure. A sound strategy also requires partnering with health-care providers to integrate strategies to prevent EDC exposure in clinical care. Critical next steps include addressing EDCs within global policy frameworks by integrating EDC exposure prevention into emerging climate policy.
MeSH term(s)	Humans ; Endocrine Disruptors/adverse effects ; Endocrine System
Chemical Substances	Endocrine Disruptors
Language	English
Publishing date	2023-08-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2489381-X
ISSN	1759-5037 ; 1759-5029
ISSN (online)	1759-5037
ISSN	1759-5029
DOI	10.1038/s41574-023-00872-x
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Zs.A 6336: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 93: Show issues

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Article ; Online: On the Utility of ToxCast-Based Predictive Models to Evaluate Potential Metabolic Disruption by Environmental Chemicals.

Filer, Dayne L / Hoffman, Kate / Sargis, Robert M / Trasande, Leonardo / Kassotis, Christopher D

Environmental health perspectives

2022 Volume 130, Issue 5, Page(s) 57005

Abstract: Background: Research suggests environmental contaminants can impact metabolic health; however, high costs prohibit : Objectives: We sought to : Methods: Using a set of 38 chemicals with previously published results in 3T3-L1 cells, we performed a ... ...

Abstract	Background: Research suggests environmental contaminants can impact metabolic health; however, high costs prohibit Objectives: We sought to Methods: Using a set of 38 chemicals with previously published results in 3T3-L1 cells, we performed a metabolism-targeted literature review to determine consensus activity determinations. To assess ToxCast predictive utility, we used two published ToxPi models: Results: The literature review revealed relevant publications for 30 out of the 38 chemicals (the remaining 8 chemicals were only examined in our previous 3T3-L1 testing). We observed a balanced accuracy (average of sensitivity and specificity) of 0.86 comparing our previous Discussion: Using the most recent ToxCast data and an updated ToxPi model, we found ToxCast performed similarly to that of our own 3T3-L1 testing in predicting consensus calls. Furthermore, we provide the full ranked list of largely untested chemicals with ToxPi scores that predict adipogenic activity and that require further investigation. https://doi.org/10.1289/EHP6779.
MeSH term(s)	3T3-L1 Cells ; Adipogenesis ; Animals ; High-Throughput Screening Assays/methods ; In Vitro Techniques ; Mice
Language	English
Publishing date	2022-05-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP6779
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Zs.B 1360: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 379: Show issues

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Article ; Online: Exposure to a mixture of per-and polyfluoroalkyl substances modulates pulmonary expression of ACE2 and circulating hormones and cytokines.

Yang, Zhao / Roth, Katherine / Ding, Jiahui / Kassotis, Christopher D / Mor, Gil / Petriello, Michael C

Toxicology and applied pharmacology

2022 Volume 456, Page(s) 116284

Abstract: Genetic and environmental factors impact on the interindividual variability of susceptibility to communicable and non-communicable diseases. A class of ubiquitous chemicals, Per- and polyfluoroalkyl substances (PFAS) have been linked in epidemiological ... ...

Abstract	Genetic and environmental factors impact on the interindividual variability of susceptibility to communicable and non-communicable diseases. A class of ubiquitous chemicals, Per- and polyfluoroalkyl substances (PFAS) have been linked in epidemiological studies to immunosuppression and increased susceptibility to viral infections, but possible mechanisms are not well elucidated. To begin to gain insight into the role of PFAS in susceptibility to one such viral infection, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), male and female C57BL/6 J mice were exposed to control water or a mixture of 5 PFAS (PFOS, PFOA, PFNA, PFHxS, Genx) for 12 weeks and lungs were isolated for examination of expression of SARS-CoV-2-related receptors Angiotensin-Converting Enzyme 2 (ACE2) and others. Secondary analyses included circulating hormones and cytokines which have been shown to directly or indirectly impact on ACE2 expression and severity of viral infections. Changes in mRNA and protein expression were analyzed by RT-qPCR and western blotting and circulating hormones and cytokines were determined by ELISA and MESO QuickPlex. The PFAS mixture decreased Ace2 mRNA 2.5-fold in male mice (p < 0.0001), with no significant change observed in females. In addition, TMPRSS2, ANPEP, ENPEP and DPP4 (other genes implicated in COVID-19 infection) were modulated due to PFAS. Plasma testosterone, but not estrogen were strikingly decreased due to PFAS which corresponded to PFAS-mediated repression of 4 representative pulmonary AR target genes; hemoglobin, beta adult major chain (Hbb-b1), Ferrochelatase (Fech), Collagen Type XIV Alpha 1 Chain (Col14a1), 5'-Aminolevulinate Synthase 2 (Alas2). Finally, PFAS modulated circulating pro and anti-inflammatory mediators including IFN-γ (downregulated 3.0-fold in females; p = 0.0301, 2.1-fold in males; p = 0.0418) and IL-6 (upregulated 5.6-fold in males; p = 0.030, no change in females). In conclusion, our data indicate long term exposure to a PFAS mixture impacts mechanisms related to expression of ACE2 in the lung. This work provides a mechanistic rationale for important future studies of PFAS exposure and subsequent viral infection.
MeSH term(s)	Male ; Female ; Mice ; Animals ; Angiotensin-Converting Enzyme 2 ; SARS-CoV-2 ; COVID-19 ; Fluorocarbons/toxicity ; Cytokines ; Mice, Inbred C57BL ; Lung ; Hormones ; RNA, Messenger
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Fluorocarbons ; Cytokines ; Hormones ; RNA, Messenger
Language	English
Publishing date	2022-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2022.116284
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Article ; Online: Adipogenic and endocrine disrupting mixture effects of organic and inorganic pollutant mixtures.

Bérubé, Roxanne / LeFauve, Matthew K / Heldman, Samantha / Chiang, Yu-Ting Tiffany / Birbeck, Johnna / Westrick, Judy / Hoffman, Kate / Kassotis, Christopher D

The Science of the total environment

2023 Volume 876, Page(s) 162587

Abstract: Chronic health conditions are rapidly increasing in prevalence and cost to society worldwide: in the US, >42 % of adults aged 20 and older are currently classified as obese. Exposure to endocrine disrupting chemicals (EDCs) has been implicated as a ... ...

Abstract	Chronic health conditions are rapidly increasing in prevalence and cost to society worldwide: in the US, >42 % of adults aged 20 and older are currently classified as obese. Exposure to endocrine disrupting chemicals (EDCs) has been implicated as a causal factor; some EDCs, termed "obesogens", can increase weight and lipid accumulation and/or perturb metabolic homeostasis. This project aimed to assess the potential combination effects of diverse inorganic and organic contaminant mixtures, which more closely reflect environmentally realistic exposures, on nuclear receptor activation/inhibition and adipocyte differentiation. Herein, we focused on two polychlorinated biphenyls (PCB-77 and 153), two perfluoroalkyl substances (PFOA and PFOS), two brominated flame retardants (PBB-153 and BDE-47), and three inorganic contaminants (lead, arsenic, and cadmium). We examined adipogenesis using human mesenchymal stem cells and receptor bioactivities using luciferase reporter gene assays in human cell lines. We observed significantly greater effects for several receptor bioactivities by various contaminant mixtures relative to individual components. All nine contaminants promoted triglyceride accumulation and/or pre-adipocyte proliferation in human mesenchymal stem cells. Comparing simple component mixtures to individual components at 10 % and 50 % effect levels revealed putative synergistic effects for each of the mixtures for at least one of the concentrations relative to the individual component chemicals, some of which also exhibited significantly greater effects than the component contaminants. Our results support further testing of more realistic and complex contaminant mixtures that better reflect environmental exposures, in order to more conclusively define mixture responses both in vitro and in vivo.
MeSH term(s)	Adult ; Humans ; Environmental Pollutants/toxicity ; Environmental Pollutants/analysis ; Adipogenesis ; Environmental Exposure ; Cell Differentiation ; Triglycerides ; Endocrine Disruptors/toxicity
Chemical Substances	Environmental Pollutants ; Triglycerides ; Endocrine Disruptors
Language	English
Publishing date	2023-03-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2023.162587
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