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Results of Proof-of-concept study indicate that hsCRP may be valid indicator of Bisphenol A contamination, but finds that ubiquitous co-confounding factors may invalidate most dietary interventions

NOTE: This is a draft in progress (May 22, 2020). Edits and citations are actively being added.


Results of investigation: Revised Protocol: UCSF IRB/CHR Number: 15-17703

Clinical blood profile assays as biomarkers to directly assess potential health effects resulting from the controlled elimination of suspected dietary and environmental chemical toxins.

Co-principal investigators Dr. Victor Reus and Lewis Perdue

SUMMARY

This proof-of-concept trial was designed to explore a potential causal relationship between the ubiquitous low levels of Bisphenol A and other  plastic-derived chemicals  (PDCs) in the food chain and the effects of their reduction in a precisely controlled diet

This study is the first to use an easily accessed and medically accepted clinical laboratory test to directly measure human health effects of the PDC reduction rather than simply measuring human serum and urine concentrations of the subject chemicals and extrapolating those effects from animal models.

This is a revised version of the study’s original protocol which called for testing of 20 subjects, and was approved by UCSF-IRB/CHR on Nov. 15, 2014. The study revisions, approved by UCSF IRB/CHR, November 14, 2018 were based upon 2.5 years of intensive research that determined  that the original protocol would be be impractical, too expensive for allocated resources, and could not be replicated by other investigators.

The serious issues discovered during those 2.5 years of research mandated that — before conducting a larger study — the revised protocol called for an n-of-1, proof-of-concept investigation to determine the feasibility of implementing the new techniques which were designed to circumvent the serious and ubiquitous replicability issues inherent to standard dietary interventions.

The protocols in the revised version were further refined with the development of best practices and the imposition of specific, rigorous scientific practices common to bench laboratory investigations, but which have been universally absent from dietary interventions.

Additional research and experience resulting from that experience and the outcomes from this study indicate that no dietary intervention study to date, including this one, can propose a valid causal relationship because it is impossible to separate the health effects from PDCs from the same health effects connected with ultra-processed foods, micronutrients, and other confounding factors.

Objectives

Objective 1: Determine if hsCRP — a well-regarded human clinical blood indicator of inflammation — could be a direct human marker for levels of BPA, phthalates and other environmental chemicals. Specifically, could intensive efforts to avoid plastic-derived chemicals (using BPA levels as a marker) “move the needle” on C-Reactive Protein?

Outcomes: The sourcing, preparation and serving protocols used in the intervention phase indicated that hsCRP levels were affected by the trial legs and can serve as a valid indicator.

Objective 2: Is a short — six-day trial — of sufficient duration to affect hsCRP clinical outcome measurements?

Outcomes: The study protocol’s projections of the metabolic pharmacokinetics of Bisphenol A and hsCRP confirmed the usefulness of the trial length.

Objective 3: Determine if it is possible to increase the causality, accuracy and replicability of dietary intervention trials by developing methods (including best practices)  to bring the discipline of standard laboratory practices to the sourcing, preparation, and serving of human food and their complete data capture and reporting.

Outcomes: Useful information and techniques were successfully developed that can improve the replicability and accuracy of dietary intervention trials involving Plastic-Derived Chemicals. However, the trial revealed a pattern of hsCRP behavior consistent with a major, 28-day dietary intervention study which measured hsCRP as an indicator of inflammation in a trial of Ultra-Processed Foods.

Further investigation indicates that any causality conclusions are invalid in that study and this one because of the unexpectedly similar clinical effects resulting from co-contamination by both PDCs and the additives and ingredients in UPFs.

Conclusions

This investigation of hsCRP as a possible direct clinical human indicator for BPA health effects in food revealed fundamental flaws in current accepted methods of dietary intervention studies. Disciplined protocols and record keeping can improve human dietary intervention replicability. Further, the length of the human trial may retain that replicability during relatively short periods of time.

However, replication does not assure causality when co-contaminants produce nearly identical clinical manifestations.

Conversely, causality and replicability of a human dietary intervention trial are possible only by:

  • the application of basic scientific principles and record-keeping
  • the measured dosing of foods using a single compound as an independent variable,
  • conducting the study with human subjects, and
  • conducting the trial in a disciplined  but human-centered dormitory environment to eliminate non-food exposures and other confounding environmental and stress-related psychological confounders.

For more information on those issues, please see: Significant changes necessary in order for dietary intervention studies to be causal and replicable

BACKGROUND

Exposure to environmental chemicals in the U.S. is widespread20.

More than 84,000 chemicals are approved for use in the United States today1, and at least 4,000 of those are Plastic-Derived Chemicals present in food contact materials2,3,4.

The health effects of most of those chemicals is unknown and/or incomplete5..

While controversial by some, many of these PDCs in low-level concentrations are increasingly classified as endocrine disruptors22,23.

Bisphenol A (BPA), phthalates, and other PDCs are present in approximately 97% of the U.S. population.6,8 Public concern over the risks from these chemicals have resulted in the reduction of concentrations of some7, but also increases in concentrations of substitutes which are also of concern. 39

While there is no current census of the PDCs found in food, two ubiquitous compounds serve as markers for the category. Bisphenol A is used to strengthen and offer heat resistance to common plastics such as polycarbonate. Phthalates are added to plastics for flexibility. Those two compounds are among the most common and widely studied chemicals of emerging concern and can serve as markers (proxies) for overall chemical contamination.

Exposure

BPA and phthalates have become nearly ubiquitous in our environment and can be found in many different products, including the plastic in water bottles and baby bottles, thermal paper for printers, and even in dental sealants and medical devices including intravenous fluid and chemotherapy bags and tubing 8,9,10,1,12,13,14.

In addition, food and beverage packaging are substantial contributors to the PDC burden8,15,16,17,25,26.

Consumers are exposed to many PDCs from leaching and migration of chemicals from plastics and other food contact materials.8,14,15,16, 30-37

Other PDCs are deliberately added to consumer and household products such as detergents, cosmetics, lotions, and fragrances38.

Still other contamination may result from the harvest and processing of food products17.

One important reason for revising this study’s original protocol was the realization that plastic contact from equipment and transfer operations during food production and processing could be a significant source of PDC even in minimally processed foods.

Further, the additional research conducted for this revised study show that PDCs are extremely common in ultra-processed foods because of the extensive use of plastics in the forming, processing and manufacturing stages.

Much of the additional effort resulting from the revision of the original protocol was directed at developing best practices including sourcing and preparation methods to avoid PDCs in both legs of the study. Ultra-processed foods were included in the “contamination” leg of the intervention study given their increased PDC levels.

Causes For Concern

Human and animal studies have identified low levels of PDCs compounds as contributors to cancer24,40-52,, cardiovascular disorders53-61, obesity62-68, type 2 diabetes69-72, metabolic syndrome73-77, neurological and behavioral disorders including Alzheimer’s Disease78-84, as well as reproductive85-94, and developmental95-102 disorders and allergies103-110.

Specific Exposure Routes

Exposure routes for all products include:

  1. Migration/leaching of chemicals from packaging materials,
  2. Deliberate addition of chemicals used as preservatives, flavorings, scents, texture enhancers, coloring agents etc.4,
  3. Contamination by unknown compounds formed by chemical reactions among multiple intentionally used constituent chemicals18.

Exposure routes for food and beverages specifically include:

  1. Incidental contamination via migration/leaching of chemicals from harvesting and processing17.
  2. Home food-handling can also accelerate migration through heating, microwaving, ultraviolet light exposure (including fluorescent lighting) and the contact of oils and alcohols with plastics.

Previous PDC Studies

A literature search reveals that studies evaluating potential adverse health effects of PDCs by controlled chemical exposure have been done in vitro or in vivo using murine PDC or other non-human models.

Despite the fact that all of the PDCs in question are nearly ubiquitous in the human environment, ethical concerns have discouraged controlled human exposure studies. Those studies which have been conducted have not focused on clinical or other health effects, but on administered doses of BPA and its metabolism rate.

Practical concerns also complicate controlled human exposure studies because ethical concerns, costs and ubiquitous exposure to mixtures of PDCs make it impossible to create an adequate control population.

Because of that, only a small number of interventional dietary studies have been done. Recent dietary interventionsRecent dietary interventions for BPA/Phthalates  have found significant reductions in the targeted chemicals measured concurrent with study designs to replace pre-prepared meals and other foods with known levels of endocrine disruptors with a fresh, home-prepared diet. However, no direct or causal health effects have been measured.

Plastic-Derived Chemical Health Effects

The human health effects of low-level concentrations of plastic-derived chemicals  — most notably Bisphenol A and its analogues as well as phthalates — have stirred immense controversy between traditional toxicologists and endocrinologists and other scientists grounded in the most current disciplines including epigenetics and molecular-level effects.<<cite>> Traditional toxicologists insist that current risk evaluations at high concentration levels can be monotonically extrapolated to low concentrations and that a firm No Observed Adverse Effects Level (NOAEL) of safety can be established.

On the other hand, a more recent and growing body of peer-reviewed, published data indicates that many PDCs exhibit non-monotonic behavior and present risks to humans at low concentrations. That controversy continues partly because of the lack of controlled human studies and the almost complete absence of investigations into effects of combinations of PDCs.

PDCs are a subset of chemical compounds also known as endocrine disruptors and chemicals of emerging concern.

Relevant Dietary Intervention Studies on Ultra-Processed Foods

Ultra-processed foods have numerous  avenues of contamination from PDCs that are due to the residual contamination in additives, contamination from PDCs from additional contacts with plastic components, and the addition of fats which facilitate the transfer of  lipid-soluble polymer components into the UPFs. For a detailed analysis, see: How food processing adds plastic-derived chemical contamination.
An examination of ultra-processed foods was prompted by research conducted for the revised protocol. That research revealed that ultra-processed foods shared the same health effects and clinical indicators as plastic derived chemicals.
As with PDCs, ultra-processed foods have  been associated with a number of non-communicable diseases and syndromes such as obesity <cite below: UPF1-9>, diabetes<cite below: UPF10-12>, cardiovascular disease<cite below: UPF13-15>, cancer<cite below: UPF16-19>, among others.

As a result, our revised study protocol prioritized UPF’s in its contamination leg given the substantial contact with plastic and other known PDC sources like the linings of food and soft drink cans.

In general, the results from lifestyle and dietary intervention studies have been of limited value in clinical practice.

The lack of direct human data on the health effects of low-level, plastic-derived environmental chemicals such as Bisphenol A (BPA) has contributed to an internationally divisive scientific controversy that has prevented health professionals and consumers from making scientifically valid health decisions.

On one side of the controversy are university and independent scientists who contend that hundreds of published studies prove that micro- and pico-molar concentrations of BPA are unhealthy. On the other side, corporate and some federal regulatory scientists point to the recent CLARITY-BPA study whose results, they contend show that low levels are safe.

CLARITY-BPA and most other published studies have been based upon an in vivo murine model. As a result, the current debate centers on protocol flaws, confounding factors, sources of contamination and the finer points of how the murine studies were conducted

All of the arguments on both sides are unlikely to sway opinion one way or another because:

(1) There are no direct human studies measuring health effects.

(2) The murine model results almost always fail to translate accurately to humans.

(3) The human dietary intervention studies published so far have focused only on reducing subject levels of marker chemicals such as BPA and have not measured any direct health outcome indicators. That means that conclusions of possible causality rest on extrapolating from animal studies such as CLARITY-BPA.

Please see this link for a deeper discussion of this issue with citations.

A possible solution waiting in clinical blood tests?

Significantly, a source of ethical, respected and clinically valuable direct human data may lurk in standard laboratory blood profiles.

One potential blood profile candidate is High-Sensitivity C-Reactive Protein (hsCRP) which offers valuable clinical insights into numerous inflammation-linked conditions including cardiovascular disease, Type 2 Diabetes, cancer, Alzheimer’s Disease, depression, suicide, and auto-immune diseases including IBD, rheumatoid arthritis, and lupus.

Further, hsCRP is a likely candidate for assessing the human health effects of Bisphenol A because that chemical (and its analogs) has been clinically shown to increase inflammation and also has been credibly associated with those conditions.

Given that the use of clinical blood tests as possible direct human health effects indicators of environmental chemical contamination is an unknown field, investigators felt that a small (N=1) proof-of-concept trial was warranted to test the validity of the concept and protocols before beginning a larger, far more expensive study.

METHODS

This n=1, proof-of-concept, six-day study was approved by the Committee on Human Research/IRB at the University of California San Francisco School of Medicine (UCSF). The intervention consisted of a three-day “typical” American diet with known sources of plastic contamination followed by a three-day intervention in which food sourcing, preparation, and serving were subjected to extreme scrutiny and methods to reduce BPA contamination from source to the subject’s mouth. An extensive protocol for this strict regime was also approved by CHR/UCSF.

Two blood samples — one to determine hsCRP levels and the second to determine BPA concentrations — were taken each day at baseline, the second on the morning of the “typical” menu leg and the third on the morning after the extreme decontamination intervention leg. All blood draws were taken at Sonoma Valley Hospital (an affiliate of UCSF) in light-green-topped tubes with standard concentrations of Li-heparin. The hsCRP sample was centrifuged by SVH and the test was run by the UCSF Parnassus laboratory.

The samples for BPA analysis were hand-delivered as whole blood to a UCSF lab where they were centrifuged and frozen for LC-MS/MS analysis. All samples were drawn using a vacutainer kit supplied by the lab and composed of polymers known not to leach BPA or other contaminants into the blood samples. As directed by the lab, samples were hand-delivered within four hours of blood draws. Results have been delayed because of an administrative complication with the lab.

Menu

The menu for the two legs of the study was as close to identical as possible.

Food items for the “typical” leg of the study were selected because they:

  • appeared on the USDA’s list of frequently consumed items and  national food frequency consumption surveys,
  • were readily available as top-selling items in supermarket chains , and
  • were likely to provide typical levels of PDCs because of their high degree of processing.,

Choosing popular national-branded items that are widely available in supermarket chains makes facilitated replication because the items are easier for future investigators to obtain. These items also provided a nutritional composition table which are likely to have consistent compositions due to rigidly controlled corporate processes for food sourcing and production.

Once the menu was set for the “typical” leg, we then “reverse-engineered” the typical food choices to use in the intervention menu by substituting identical or highly similar items which were minimally processed, organic and (when possible) were not packed in plastic. Reverse engineering involved best efforts to sort and weigh components of all the measurable ingredients in the pre-packaged foods.

Foods for the intervention study were also selected for transparency of the producer and because they were either available in national distribution or came from a source who would ship nationwide.

Dairy posed a unique problem because milk is sourced locally or regionally even by large chains. For that reason, we had milk samples analyzed via LC-MS/MS which offers future investigators the advantage of choosing milk with the same or similar BPA quantification. This testing was also performed because our original protocol called for using the least contaminated milk to produce our own cheese. Time constraints and other issues of practicality make that unfeasible. We elected to select cheese from a nationally available dairy brand whose milk scored below LOQ in the LC-MS/MS tests.

Beyond sourcing foods with transparency and replication, we extended the discipline to preparation and serving.

Recipes were considered formulae and cooking methods and times as experimental protocols.

All main ingredients were measured to the nearest gram. Spices and other items were measured to the nearest tenth of a gram. Culinary assistants were trained and monitored for compliance.

Items with known plastic contamination (such as micro-plastic contamination of table salt) were replaced where possible with reagents from Sigma-Aldrich.

A 400-square-foot professional kitchen with stainless steel countertops and carbon-filtered water was cleared of all plastic and polymer items utensils, containers, and cookware. Only glass, stainless steel, aluminum foil, and maple cutting boards were allowed. Vinyl gloves were used in food preparation for sanitary control in both legs of the trial, but actual food contact with the gloves was minimal and incidental.

Efforts were made to Reduce Non-Food Exposures

RESULTS

Levels of hsCRP decreased 21.4% from baseline to end of the minimally contaminated leg: 1.1 mg/L from 1.4 mg/L. In addition, our study results demonstrated a final reduction in hsCRP that was approximately half of that reposted by a major NIH-funded dietary intervention by Hall, et. al. published in 2019 approximately four months prior to our trial.

NIH/Hall data from: “Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake”

The lower overall decrease in hsCRP in 0ur study was reasonably attributable to:

The shorter length of our trial:  Stahlhut, R.W., Welshons, W.V., and Swan, S.H. 2009. indicated that BPA may a longer half life than previously thought. The methodology of that study suggests that the lower decline in hsCRP levels in our study versus NIH/Hill could be caused by our shorter trial duration (six days rather than 28) which affects for the release of BPA from adipose stores and/or its metabolism.

In addition, our trial was interrupted by Northern California wildfires that dramatically increased PM2.5 particulate pollution which is a notorious promoter of inflammation

The public safety power shutoffs by Pacific Gas & Electric occurred during the start of the trial which forced investigators to cancel the trial and dispose of much of the fresh, minimally processed foods for the intervention leg. Auxilliary generator power allowed limited use of electricity including the operation of two HEPA air filters which maintained interior air quality at satisfactory (50 ppb or less).

Replacement foods purchased after the power had been restored and fires had somewhat abated may have been contaminated despite efforts to clean it thoroughly.

The trial was re-started after power was restored because the kitchen facility had been prepared for the trial in such a manner that left it unsuitable for usual operation. In addition, we were constrained by the culinary assistants available for a limited time.

A final confounding factor was the need of the n-of-1 test subject to be exposed to environmental PM2.5 pollution  in order to deliver blood draw samples to two UCSF laboratories at the Parnassus and Mt. Zion campuses. Those exposures lasted for a minimum of 2.5 hours on three occasion. That level of exposure was substantial and may account for the overall smaller decrease in hsCRP in our study versus NIH/Hall.

This experience validates the value of using a controlled dormitory setting such as that employed by NIH/Hall.

Investigating An Unexpected Anomaly of the Intervention Legs

Despite expectations that inflammation would increase with foods projected to contain higher levels of BPA, hsCRP  actually declined at the end of the “typical/contaminated” diet leg. Significantly,  NIH/Hall independently exhibited this same anomaly.

Efforts to explain this anomaly led investigators to consider possible causes.

NIH/Hall’s primary outcome focused on obesity and investigated weight gain from the ad libitum consumption of UPFs versus less processed foods. The results confirmed weight gain from the UPF leg of the study.

Investigators of this study were aware that Bisphenol A has been termed as an “obesegen” and associated with unhealthy body weight, diabetes, insulin dependence as well as cancer, cardiovascular disease. All of those are associated with chronic inflammation which prompted us to use hsCRP as a marker for PDC concentrations. Likewise hsCRP and a vastly expanded blood panel were chosen by NIH/Hall.

Because that expanded panel included “appetite peptides” ghrelin, leptin, and adiponectin which are associated with eating behavior, we searched the literature for relevant BPA health outcome associations.  We found parallel associations not only between diseases and syndromes, but also the associated clinical effects including ghrelin, leptin, and adiponectin.

Typical examples of unavoidable mutual co-contaminants that confound dietary interventions and thwart causal conclusions

CONCLUSIONS

A primary objective of our study was to determine if it was possible to increase the causality, accuracy and replicability of dietary intervention trials by developing methods (including best practices)  to bring the discipline of standard laboratory practices to the sourcing, preparation, and serving of human food and their complete data capture and reporting.

While accomplishing those stated goals, our study — and that conducted by NIH/Hall — we failed at the study protocol design stage to recognize the similar (and confounding) effects of Plastic-Derived Chemicals and Ultra-Processed Foods.

Indeed, that mutual confounding factor means that the results of both our study, and that of NIH/Hall can only conclude that the observed outcomes are a result of both PDCs and UPFs. Conversely, neither study can credibly claim that observed outcomes are due to the single factor focused upon.

As noted in the results, above, inflammation levels are measurably affected by two different dietary interventions — one for Plastic-Derived Chemicals and and the other for Ultra-Processed Foods. Most notably, it confirms our thesis that a short intervention trial can “move the needle” on inflammation.

However, it is still unknown whether the lowered hsCRP level in our study can be a valid health indicator of human BPA contamination not only because of confounding UPF factors, but also because the blood samples to be measured for BPA levels were misplaced by the LC/MS lab of a UCSF researcher who had agreed to analyze them. It is unknown whether that researcher can locate the samples and test them. However, those samples are irrelevant because both PDCs and food additives are most prevalent in ultra-processed foods. Conversely NIH/Hall cannot say UPF ingrediets are causal because of the PDC co-contaminants.

Conclusions with relevance beyond the results of this study

 

Causality and replicability of a human dietary intervention trial are possible only by:

  • the application of basic scientific principles and record-keeping
  • the measured dosing of foods using a single compound as an independent variable,
  • conducting the study with human subjects, and
  • conducting the trial in a disciplined  but human-centered dormitory environment to eliminate non-food exposures and other confounding environmental and stress-related psychological confounders.

A deeper examination of these issues can be found at: Accounting for unknown interactions of co-confounding factors prohibit valid causality conclusions

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34. Hayasaka, Y. 2014. Analysis of phthalates in wine using liquid chromatography tandem mass spectrometry combined with a hold-back column: Chromatographic strategy to avoid the influence of pre-existing phthalate contamination in a liquid chromatography system. Journal of Chromatography A 1372: 120-127. **

35. Wagner, M., and Oehlmann, J. 2009. Endocrine disruptors in bottled mineral water: Total estrogenic burden and migration from plastic bottles. Environmental Science and Pollution Research 16(3): 278-286.

36. Bittner, G.D., Denison, M.S., Yang, C.Z., Stoner, M.A., and He, G. 2014. Chemicals having estrogenic activity can be released from some bisphenol a-free, hard and clear, thermoplastic resins. Environmental Health 13(1): 103.

37. Vandermeersch, G., Lourenço, H.M., Alvarez-Muñoz, D., Cunha, S., Diogène, J., Cano-Sancho, G., Kwadijk, C., Barcelo, D., Allegaert, W., Bekaert, K., Fernandes, J.O., Marques, A., and Robbens, J. 2015. Environmental contaminants of emerging concern in seafood–European database on contaminant levels. Environmental Research 143(B): 29-45.**

38. Myers, SlL., Yang, C.Z., Bittner, G.D., Witt, K.L., Tice, R.R., and Baird, D.D. 2014. Estrogenic and anti-estrogenic activity of off-the-shelf hair and skin care products. Journal of Exposure Science and Environmental Epidemiology 25(3): 271-277.

39. Rochester, J.R., and Bolden, A.L. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environmental Health Perspectives 123(7): 643-650.

CANCER

40. Keri, R.A., Ho, S.M., Hunt, P.A., Knudsen, K.E., Soto, A.M., and Prins, G.S. 2007. An evaluation of the evidence for the carcinogenic activity of bisphenol A. Reproductive Toxicology 24: 240-252.

41. Fang, L., Wuptra, K., Chen, D., Li, H., Huang, S.-K., Jin, C., and Yokoyama, K. K. 2014. Environmental-stress-induced Chromatin Regulation and its Heritability. Journal of Carcinogenesis & Mutagenesis 5(1), 22058.

42. Fang, L., Wuptra, K., Chen, D., Li, H., Huang, S.-K., Jin, C., and Yokoyama, K. K. 2014. Environmental-stress-induced Chromatin Regulation and its Heritability. Journal of Carcinogenesis & Mutagenesis 5(1), 22058.

43. Vega, A., Baptissart, M., Caira, F., Brugnon, F., Lobaccaro, J.-M. A., and Volle, D. H. 2012. Epigenetic: a molecular link between testicular cancer and environmental exposures. Frontiers in Endocrinology 3: 150.

44. Tarapore, P., Ying, J., Ouyang, B., Burke, B., Bracken, B., and Ho, S-M. 2014. Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PloS ONE 9(3): e90332.

45. Wong, R.L., Wang, Q., Treviño, L.S., Bosland, M.C., Chen, J., Medvedovic, M., Prins, G.S., Kurunthachalan, K., Ho, S-M., and Walker, C.L. 2015. Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate. Epigenetics 10(2): 127-134.

46. Ferguson, L.R., Chen, H., Collins, A.R., Connell, M., Damia, G., Dasgupta, S., Malhotra, M., Meeker, A.K., Amedei, A., Amin, A. et al. 2015. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Seminars in Cancer Biology 35: S5-24.

47. Zhang, Z., Chen, S., Feng, Z., and Su, L.J. 2015. Pregnancy Exposures Determine Risk of Breast Cancer in Multiple Generations of Offspring. In: Environmental Epigenetics. Springer London. pp. 75-103.

48. Gassman, N.R., Coskun, E., Stefanick, D.F., Horton, J.K., Jaruga, P., Dizdaroglu, M., and Wilson, S.H. 2015. Bisphenol A promotes cell survival following oxidative DNA damage in mouse fibroblasts. PloS ONE 10(2): e0118819. **

49. Bishop, K.S., and Ferguson, L.R. 2015. The Interaction between Epigenetics, Nutrition and the Development of Cancer. Nutrients 7(2): 922-947.

50. Kim, Y-S., Hwang, K-A., Hyun, S-H., Nam, K-H., Lee, C-K., and Choi, K-C. 2015. Bisphenol A and Nonylphenol Have the Potential to Stimulate the Migration of Ovarian Cancer Cells by Inducing Epithelial–Mesenchymal Transition via an Estrogen Receptor Dependent Pathway. Chemical Research In Toxicology 28(4): 662-671.

51. Nahta, R., Al-Mulla, F., Al-Temaimi, R., Amedei, A., Andrade-Vieira, R., Bay, S., Brown, D.G., Calaf, G.M., Castellino, R.C., Cohen-Solal, K.A. et al. 2015. Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression. Carcinogenesis 36(S1): S2-S18.

52. Hajjari, M., and Salavaty, A. 2015. HOTAIR: An oncogenic long non-coding RNA in different cancers. Cancer Biology & Medicine 12(1): 1.

CARDIOVASCULAR

53. Fang, L., Wuptra, K., Chen, D., Li, H., Huang, S.-K., Jin, C., and Yokoyama, K. K. 2014. Environmental-stress-induced Chromatin Regulation and its Heritability. Journal of Carcinogenesis & Mutagenesis 5(1), 22058.

54. Gao, X., and Wang, H-S.. 2014. Impact of bisphenol A on the cardiovascular system—epidemiological and experimental evidence and molecular mechanisms. International Journal of Environmental Research and Public Health 11(8): 8399-8413.

CARDIAC

55. Rancière, F., Lyons, J.G., Loh, V.H, Botton, J., Galloway, T., Wang, T., Shaw, J.E., and Magliano, D.J. 2015. Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence. Environmental Health 14(1): 46.

56. Bae, S., and Hong, Y-C. 2015. Exposure to Bisphenol A From Drinking Canned Beverages Increases Blood Pressure Randomized Crossover Trial. Hypertension 65(2): 313-319.

57. Belcher S.M., Chen Y., Yan S., and Wang H.S. 2012. Rapid estrogen receptor-mediated mechanisms determine the sexually dimorphic sensitivity of ventricular myocytes to 17β-estradiol and the environmental endocrine disruptor bisphenol A. Endocrinology 153: 712–720.

58. Gao X., Liang Q., Chen Y., and Wang H.S. 2013. Molecular mechanisms underlying the rapid arrhythmogenic action of bisphenol A in female rat hearts. Endocrinology 154: 4607–4617.

59. Liang Q., Gao X., Chen Y., Hong K., and Wang H.S. 2014. Cellular mechanism of the nonmonotonic dose response of bisphenol A in rat cardiac myocytes. Environmental Health Perspectives 122 :601–608.

60. Melzer D., Osborne N.J., Henley W.E., Cipelli R., Young A., Money C., McCormack, P., Luben, R., Khaw, K.T., Wareham, N.J., and Galloway, T.S. 2012. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation 125: 1482–1490.

61. Yan S., Song W., Chen Y., Hong K., Rubinstein J., and Wang H.S. 2013. Low-dose bisphenol A and estrogen increase ventricular arrhythmias following ischemia–reperfusion in female rat hearts. Food and Chemical Toxicology 56: 75–80.

OBESITY

62. Regnier, S.M. and Sargis, R.M. 2014. Adipocytes under assault: Environmental disruption of adipose physiology. Biochimica et Biophysica Acta 1842(3): 520-533.

63. Ellero-Simatos, S., Claus, S.P., Benelli, C., Forest, C., Letourneur, F., Cagnard, N., Beaune, P.H. and de Waziers, I. 2011. Combined Transcriptomic–1H NMR Metabonomic Study Reveals That Monoethylhexyl Phthalate Stimulates Adipogenesis and Glyceroneogenesis in Human Adipocytes. Journal of Proteome Research 10(12): 5493-5502.

64. Marmugi, A., Ducheix, S., Lasserre, F., Polizzi, A., Paris, A., Priymenko, N., Bertrand-Michel, J., Pineau, T., Guillou, H., Martin, P.G., and Mselli-Lakhal, L. 2012. Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver. Hepatology 55(2): 395-407.

65. Hugo, E.R., Brandebourg, T.D., Woo, J.G., Loftus, J., Alexander, J.W., Ben- Jonathan, N. 2008. Bisphenol A at environmentally relevant doses inhibits adi- ponectin release from human adipose tissue explants and adipocytes. Environmental Health Perspectives 116(12): 1642-1647.

66. Menale, C., Piccolo, M.T., Cirillo, G., Calogero, R.A., Papparella, A., Mita, L., Del Giuduce, E.M., Diano, N., Crispi, S., and Mita, D.G. 2015. Bisphenol A effects on gene expression in children adipocytes: association to metabolic disorders. Journal of Molecular Endocrinology 54(3): 289-303.

67. Savastano, S., Tarantino, G., D’Esposito, V., Passaretti, F., Cabaro, S., Liotti, A., Liguoro, D., Perruolo, G., Ariemma, F., Finelli, C., Bequinot, F., Formisano, P., and Valentino, R. 2015. Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. Journal of Translational Medicine 13(1): 1-7.

68. Seidlová-Wuttke, D., Jarry, H., Christoffel, J., Rimoldi, G., and Wuttke, W. 2005. Effect of bisphenol-A (BPA), dibutylphtalate (DBP), benzophenone-2 (BP2), procymidone (Proc), and linurone (Lin) on fat tissue, a variety of hormones and metabolic parameters: A 3 month comparison with effects of estradiol (E2) in ovariectomized (ovx) rats. Toxicology 213: 13-24.

DIABETES

69. Alonso-Magdalena, P., Morimoto, S., Ripoll, C., Fuentes, E., and Nadal, A. 2006. The estrogenic effect of bisphenol A disrupts pancreatic β-cell function in vivo and induces insulin resistance. Environmental Health Perspectives 114(1): 106-112.

70. Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., and Ropero, A.B. 2009. The pancreatic beta-cell as a target of estrogens and xenoestrogens: implica- tions for blood glucose homeostasis and diabetes. Molecular and Cellular Endocrinology 304:63-68.

71. Bouchard, L., Thibault, S., Guay, S.P., Santure, M., Monpetit, A., St. Pierre, J., Perron, P., and Brisson, D. 2010. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care 33(11): 2436 – 2441.

72. Savastano, S., Tarantino, G., D’Esposito, V., Passaretti, F., Cabaro, S., Liotti, A., Liguoro, D., Perruolo, G., Ariemma, F., Finelli, C., Bequinot, F., Formisano, P., and Valentino, R. 2015. Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. Journal of Translational Medicine 13(1): 1-7.

METABOLIC

73. Ellero-Simatos, S., Claus, S.P., Benelli, C., Forest, C., Letourneur, F., Cagnard, N., Beaune, P.H., and de Waziers, I. 2011. Combined Transcriptomic–1H NMR Metabonomic Study Reveals That Monoethylhexyl Phthalate Stimulates Adipogenesis and Glyceroneogenesis in Human Adipocytes. Journal of Proteome Research 10(12): 5493-5502.

74. Hofmann, P.J., Schomburg, L., and Köhrle, J. 2009. Interference of endocrine disrupters with thyroid hormone receptor-dependent transactivation. Toxicological Sciences 110(1): 125-137.

75. Marmugi, A., Ducheix, S., Lasserre, F., Polizzi, A., Paris, A., Priymenko, N., Bertrand-Michel, J., Pineau, T., Guillou, H., Martin, P.G., and Mselli-Lakhal, L. 2012. Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver. Hepatology 55(2): 395-407.

76. Schmutzler, C., Bacinski, A., Gotthardt, I., Huhne, K., Ambrugger, P., Klammer, H., Schlecht, C., Hoang-Vu, C., Gruters, A., Wuttke, W., Jarry, H., and Köhrle, J. 2007. The UV filter benzophenone 2 interferes with the thyroid hormone axis in rats and is a potent in vitro inhibitor of human recombinant thyroid peroxidase. Endocrinology 115(Suppl. 1): 77–83.

77. Hugo, E.R., Brandebourg, T.D., Woo, J.G., Loftus, J., Alexander, J.W., and Ben-Jonathan, N. 2008. Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environmental Health Perspectives 116: 1642-1647.

NEUROLOGICAL

78. Fang, F., Chen, D., Yu, P., Qian, W., Zhou, J., Liu, J., Gao, R., Wang, J., and Xiao, H. 2015. Effects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice. General and Comparative Endocrinology 212: 44-50.

79. El-Missiry, M.A., Othman, A.I., Al-Abdan, M.A., and El-Sayed, A.A. 2014. Melatonin ameliorates oxidative stress, modulates death receptor pathway proteins, and protects the rat cerebrum against bisphenol-A-induced apoptosis. Journal of the Neurological Sciences 347(1): 251-256.

80. Kundakovic, M., and Champagne, F.A. 2011. Epigenetic perspective on the developmental effects of bisphenol A. Brain, Behavior, and Immunity 25(6): 1084-1093.

81. Hofmann, P.J., Schomburg, L., and Köhrle, J. 2009. Interference of endocrine disrupters with thyroid hormone receptor-dependent transactivation. Toxicological Sciences 110(1): 125-137.

82. Testa, C., Nuti, F., Hayek, J., De Felice, C., Chelli, M., Rovero, P., Latini, G., and Papini, A.M. 2012. Di-(2-ethylhexyl) phthalate and autism spectrum disorders. ASN Neuro 4(4): 223-229.

83. Clark-Taylor, T., and Clark-Taylor, B.E. 2004. Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial β-oxidation by long chain acyl-CoA dehydrogenase. Medical Hypotheses 62(6): 970-975.

84. Fang, L., Wuptra, K., Chen, D., Li, H., Huang, S.-K., Jin, C., and Yokoyama, K. K. 2014. Environmental-stress-induced Chromatin Regulation and its Heritability. Journal of Carcinogenesis & Mutagenesis, 5(1), 22058.

REPRODUCTIVE

85. Hannon, P.R., Peretz, J., and Flaws, J. 2014. Daily exposure to Di (2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biology of Reproduction 90(6): 136.

86. Hannon, P.R., and Flaws, J.A. 2015. The effects of phthalates on the ovary. Frontiers in Endocrinology 6:8.

87. León-Olea, M., Martyniuk, C.J., Orlando, E.F., Ottinger, M.A., Rosenfeld, C.S., Wolstenholme, J.T., and Trudeau, V.L. 2014. Current concepts in neuroendocrine disruption. General and Comparative Endocrinology 203: 158-173.

88. Meeker, J.D., and Ferguson K.K. 2014. Urinary phthalate metabolites are associated with decreased serum testosterone in men, women, and children from NHANES 2011–2012. The Journal of Clinical Endocrinology & Metabolism 99(11): 4346-4352

89. Hannon, P. R., Peretz, J., and Flaws, J. A. 2014. Daily Exposure to Di(2-ethylhexyl) Phthalate Alters Estrous Cyclicity and Accelerates Primordial Follicle Recruitment Potentially Via Dysregulation of the Phosphatidylinositol 3-Kinase Signaling Pathway in Adult Mice. Biology of Reproduction 90(6), 136.

90. Braun, J.M., Just, A.C., Williams, P.L., Smith, K.W., Calafat, A.M., and Hauser, R. 2014. Personal care product use and urinary phthalate metabolite and paraben concentrations during pregnancy among women from a fertility clinic. Journal of Exposure Science and Environmental Epidemiology 24(5): 459-466.

91. Soares, A., Guieysse, B., Jefferson, B., Cartmell, E., and Lester, J.N. 2008. Nonylphenol in the environment: a critical review on occurrence, fate, toxicity and treatment in wastewaters. Environment International 34(7): 1033-1049.

92. Lyche, J.L., Gutleb, A.C., Bergman, Å., Eriksen, G.S., Murk, A.J., Ropstad,Lyche, J.L., Gutleb, A.C., Bergman, Å., Eriksen, G.S., Murk, A.J., Ropstad, E., Saunders, M., and Skaare, J.U. 2009. Reproductive and developmental toxicity of phthalates – a review. Journal of Toxicololgy and Environmental Health B Critical Reviews 12(4): 225-249.

93. Wetherill, Y.B., Akingbemi, B.T., Kanno, J., McLachlan, J.A., Nadal, A., Sonnenschein, C., Watson, C.S., Zoeller, R.T., and Belcher, S.M. 2007. In vitro molecular mechanisms of bisphenol A action. Reproductive Toxicology 24(2): 178-198.

94. Vega, A., Baptissart, M., Caira, F., Brugnon, F., Lobaccaro, J.-M. A., and Volle, D. H. 2012. Epigenetic: a molecular link between testicular cancer and environmental exposures. Frontiers in Endocrinology 3: 150.

DEVELOPMENTAL

95. Resendiz, M., Mason, S., Lo, C.-L., and Zhou, F. C. 2014. Epigenetic regulation of the neural transcriptome and alcohol interference during development. Frontiers in Genetics 5: 285.

96. Mason, S., and Zhou, F. C. 2015. Editorial: Genetics and epigenetics of fetal alcohol spectrum disorders. Frontiers in Genetics 6: 146.

97. Kim, J.H., Sartor, M. A., Rozek, L.S., Faulk, C., Anderson, O.S., Jones, T.R., Nahar, M.S., and Dolinoy, D.C. 2014. Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome. BMC Genomics 15:30.

98. Walker, C. L. 2011. Epigenomic Reprogramming of the Developing Reproductive Tract and Disease Susceptibility in Adulthood. Birth Defects Research. Part A, Clinical and Molecular Teratology 91(8), 666–671.

99. Vega, A., Baptissart, M., Caira, F., Brugnon, F., Lobaccaro, J.-M. A., and Volle, D. H. 2012. Epigenetic: a molecular link between testicular cancer and environmental exposures. Frontiers in Endocrinology 3: 150.

100. Zhang, Z., Chen, S., Feng, Z., and Su, L.J. 2015. Pregnancy Exposures Determine Risk of Breast Cancer in Multiple Generations of Offspring. In: Environmental Epigenetics. Springer London. pp. 75-103.

101. Cao, J., Rebuli, M.E., Rogers, J., Todd, K.L., Leyrer, S.M., Ferguson, S.A., and Patisaul, H.B. 2013. Prenatal Bisphenol A Exposure Alters Sex-Specific Estrogen Receptor Expression in the Neonatal Rat Hypothalamus and Amygdala. Toxicological Sciences 133(1), 157–173.

102. Crinnion, W.J. 2010. Toxic effects of the easily avoidable phthalates and parabens. Alternative Medicine Review 15(3): 190-196.

ALLERGIES

103. Wang, I.-J., Karmaus, W. J., Chen, S.-L., Holloway, J. W., and Ewart, S. 2015. Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation. Clinical Epigenetics 7(1): 27.

104. Dodson, R.E., Nishioka, M., Standley, L.J., Perovich, L.J., Brody, J.G., and Rudel, R.A. 2012. Endocrine disruptors and asthma-associated chemicals in consumer products. Environmental Health Perspectives 120(7): 935.

105. Hoppin, J.A., Jaramillo, R., London, S.J., Bertelsen, R.J., Salo, P.M., Sandler, D.P., Zeldin, D.C. 2013. Phthalate exposure and allergy in the U.S. population: results from NHANES 2005–2006. Environmental Health Perspectives 121: 1129–1134.

106. Markey, C.M., Wadia, P.R., Rubin, B.S., Sonnenschein, C., and Soto, A.M. 2005. Long-term effects of fetal exposure to low doses of the xenoestrogen Bisphenol-A in the female mouse genital tract. Biology of Reproduction 72: 1344-1351.

107. Benachour, N., and Aris, A. 2009. Toxic effects of low doses of Bisphenol-A on human placental cells. Toxicology and Applied Pharmacology 241: 322-328.

108. LaPensee, E.W., Tuttle, T.R., Fox, S.R., and Ben-Jonathan, N. 2009. Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-α-positive and –negative breast cancer cells. Environmental Health Perspectives 117(2): 175-180.

109. vom Saal, F.S., and Welshons, W.V. 2006. Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A. Environmental Research 100: 50-76.

110. Baldi, E., and Muratori, M. 2013. Genetic damage in human spermatozoa. Advances in Experimental Medicine and Biology 791. New York. Springer-Verlag. 195p.

======== additional citations to be integrated consistent with the previous ============

obesity

UPF1-Consumption of ultra-processed foods and the risk of overweight and obesity, and weight trajectories in the French cohort NutriNet-Santé — https://cel.archives-ouvertes.fr/AGROPOLIS/hal-02377022v1

UPF2-Costa, C., Del-Ponte, B., Assunção, M., & Santos, I. (2018). Consumption of ultra-processed foods and body fat during childhood and adolescence: A systematic review. Public Health Nutrition, 21(1), 148-159. doi:10.1017/S1368980017001331

UPF3-Nardocci, M., Leclerc, B., Louzada, M. et al. Consumption of ultra-processed foods and obesity in Canada. Can J Public Health 110, 4–14 (2019). https://doi.org/10.17269/s41997-018-0130-x

UPF4-Consumption of ultra – processed foods and body fat during childhood and adolescence: a systematic review — https://www.cambridge.org/core/journals/public-health-nutrition/article/consumption-of-ultraprocessed-foods-and-body-fat-during-childhood-and-adolescence-a-systematic-review/49F56538F32B05C3526E1C5523910A9A

UPF5-Ultra-processed food consumption and excess weight among US adults — https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/ultraprocessed-food-consumption-and-excess-weight-among-us-adults/5D2D713B3A85F5C94B0C98A1F224D04A

UPF6-Ultraprocessed food consumption and risk of overweight and obesity: the University of Navarra Follow-Up (SUN) cohort study — https://academic.oup.com/ajcn/article/104/5/1433/4564389

UPF7-Clinical and Translational Report| Volume 30, ISSUE 1, P67-77.e3, July 02, 2019, Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake,Kevin D. Hall et. al Published:May 16, 2019DOI:https://doi.org/10.1016/j.cmet.2019.05.008

UPF8-Laster, J., Frame, L.A. Beyond the Calories—Is the Problem in the Processing?. Curr Treat Options Gastro 17, 577–586 (2019). https://doi.org/10.1007/s11938-019-00246-1

UPF9-Schulze, Kai and Adams, Jean and White, Martin, Associations Between Sales of Ultra-Processed Food Products and Prevalence of Adiposity and Diabetes Mellitus: A Panel Analysis of 76 Countries Between 2001-2016 (05/29/2019 09:47:18).

Diabetes

UPF10-B Srour, L K Fezeu, E Kesse-Guyot, B Allès, E Chazelas, M Deschasaux, S Hercberg, C A Monteiro, C Julia, M Touvier, Ultra-processed food intake and risk of type 2 diabetes in a French cohort of middle-aged adults, European Journal of Public Health, Volume 29, Issue Supplement_4, November 2019, ckz185.388, https://doi.org/10.1093/eurpub/ckz185.388

UPF11-Role of diet in type 2 diabetes incidence: umbrella review of meta-analyses of prospective observational studies Manuela Neuenschwander, Aurélie Ballon, Katharina S Weber, Teresa Norat, Dagfinn Aune, Lukas Schwingshackl, Sabrina Schlesinger BMJ. 2019; 366: l2368. Published online 2019 Jul 3. doi: 10.1136/bmj.l2368

UPF12-Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies Lukas Schwingshackl, Georg Hoffmann, Anna-Maria Lampousi, Sven Knüppel, Khalid Iqbal, Carolina Schwedhelm, Angela Bechthold, Sabrina Schlesinger, Heiner Boeing Eur J Epidemiol. 2017; 32(5): 363–375. Published online 2017 Apr 10. doi: 10.1007/s10654-017-0246-y

 

Cardiovascular disease

UPF13-B Srour, L K Fezeu, E Kesse-Guyot, B Allès, E Chazelas, M Deschasaux, S Hercberg, C A Monteiro, C Julia, M Touvier, Ultra-processed food intake and cardiovascular disease risk in the NutriNet-Santé prospective cohort, European Journal of Public Health, Volume 29, Issue Supplement_4, November 2019, ckz185.059, https://doi.org/10.1093/eurpub/ckz185.059
Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé)BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1451 (Published 29 May 2019) BMJ 2019;365:l1451

UPF14-Smiljanec, K. (2020), Ultra‐processed Food Consumption and Vascular Health. The FASEB Journal, 34: 1-1. doi:10.1096/fasebj.2020.34.s1.05472

UPF15-Moreira PV, Baraldi LG, Moubarac JC, et al. Comparing different policy scenarios to reduce the consumption of ultra-processed foods in UK: impact on cardiovascular disease mortality using a modelling approach. PLoS One. 2015;10(2):e0118353. Published 2015 Feb 13. doi:10.1371/journal.pone.0118353

 

Cancer

UPF16-Bishop KS, Ferguson LR. The interaction between epigenetics, nutrition and the development of cancer. Nutrients. 2015;7(2):922‐947. Published 2015 Jan 30. doi:10.3390/nu7020922

UPF17-Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort – BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k322 (Published 14 February 2018) Cite this as: BMJ 2018;360:k322

UPF18-Association between consumption of ultra – processed foods and all cause mortality: SUN prospective cohort study — https://www.bmj.com/content/365/bmj.l1949.full

UPF19-Ferguson, L.R., Chen, H., Collins, A.R., Connell, M., Damia, G., Dasgupta, S., Malhotra, M., Meeker, A.K., Amedei, A., Amin, A. et al. 2015. Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Seminars in Cancer Biology 35: S5-24.

 

Partial list of relevant links