A small but growing body of scientific research is exploring the link between common pollutants and the dysregulation of the endocannabinoid system (ECS). This link may prove to be a significant factor in why exposure to endocrine-disrupting chemicals, even in tiny amounts, is harmful to human health.
Endocrine disruptors are a large and diverse class of chemicals defined not by how they’re used in products, but by how they act in the human body. Like the more recently discovered ECS, the endocrine system directs a range of biological processes including energy metabolism and reproductive function. Common endocrine-disrupting chemicals include Bisphenol A (BPA) and its substitutes BPS and BPF; per- and polyfluouralkyl substances (PFASs), of which there are nearly 5,000; phthalates; parabens; and organophosphate pesticides like malathion and chlorpyrifos.
By mimicking, blocking, or otherwise interfering with naturally occurring hormones, including estrogens and androgens, endocrine disruptors can throw the body off balance and trigger a cascade of adverse health effects, even decades down the line. They may also weaken our ability to ward off diseases like COVID-19, according to a recent article in Environmental Health News.
Highly Sensitive Systems
Researchers around the world are working to understand these ubiquitous chemicals and their health effects. For instance, how does exposure to endocrine-disrupting chemicals affect cancer or diabetes risk? How large or small of a dose should we be concerned about? And how does sensitivity to these chemicals vary across life stages, from the womb to adulthood?
By interfering with naturally occurring hormones, endocrine disruptors can throw the body off balance and trigger a cascade of adverse health effects.
A small team of scientists based in Italy has been investigating a decidedly niche corner of the field: the link between endocrine disruptors and the ECS.
At a glance, it makes sense to connect the two. Both regulate the internal balance, or homeostasis, of body systems. Both incorporate parts of the brain and various other organs. Within the context of traditional toxicology, both appear to be highly sensitive systems that exhibit nonlinear dose-response curves, meaning high doses don’t necessarily have a greater effect than low doses. And evidence to date suggests that both can easily be influenced or perturbed by exogenous compounds – endocrine-disrupting chemicals in one case and synthetic or plant-based cannabinoids in the other.
Over the past five years, a research team lead by Oliana Carnevali, a professor of developmental biology at Italy’s Polytechnic University of Marche and an expert in endocrinology, has published five papers investigating the role of the ECS – including receptors, metabolic enzymes, and endogenous cannabinoids – in mediating some of the observed effects of endocrine disruptors.
“Considering the well-documented negative effects of endocrine-disrupting chemicals on the reproductive system and on lipid metabolism, we hypothesized that all this had to do with the ECS, which operates on many physiological aspects including reproduction and the energy homeostasis,” Carnevali and coauthor Isabel Forner-Piquer, a postdoctoral researcher, wrote in an email to Project CBD.
These studies were performed in two species of fish common in toxicological research – the freshwater zebrafish and the marine gilthead seabream – and are therefore not directly transferable to human experience. The researchers exposed adult fish to two known endocrine disruptors, the plastic additives BPA and Di-isononyl phthalate (DiNP). True to their hypothesis, their findings suggest a role for the ECS in regulating endocrine disruption.
The researchers found that chronic exposure to both chemicals for 21 days, at levels considered environmentally relevant, were enough to alter the ECS in both animal models. These contaminants altered the system in three susceptible tissues – the brain, the liver, and the gonads – and at three different levels: gene expression, enzymatic activity, and endocannabinoid levels.
“Over the last three decades, the ECS has emerged as a new cell-signaling system, like another kind of ‘hormone,’ with an important role to maintain human and non-human health,” the two authors wrote in an email. “Indeed, we know that when the ECS is deregulated, it is the starting point for several health disorders. Consequently, nowadays, the ECS is approached as a therapeutic target for several pathologies. Its alteration by endocrine-disrupting chemicals makes us hypothesize a negative effect on general animal welfare with a strong impact on wild animals as well as human.”
To test this hypothesis, Carnevali’s team is moving forward with human studies. Research is in progress to investigate relationships between levels of endocrine-disrupting chemicals in blood and urine and the expression of genes in sperm coding for enzymes involved in the synthesis and degradation of the major endocannabinoids.
BPA and other endocrine disrupters may induce adverse pregnancy outcomes by acting on the endocannabinoid system.
Outside of this group, however, the role of the endocannabinoid system in mediating the health impacts of endocrine disruptors has received only sporadic attention in the scientific literature during the past two decades. These studies provide examples of perturbation of the ECS by parabens, BPA, chlorpyrifos, and 4-NP, a compound in laundry detergents known to contaminate food and drinking water.
In 2002, a study by researchers from the University of California at Berkeley found that the CB1 receptor – which mediates the effects of THC and endogenous cannabinoids through the central nervous system – was inhibited by chlorpyrifos and other organophosphate pesticides.
A 2008 study by UC Berkeley researchers demonstrated that organophosphorous chemicals block the endocannabinoid-degrading enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), leading to elevated levels of endocannabinoids in the brain and to dysregulated cannabinoid receptor signaling.
In 2011, Italian scientists reported in General and Comparative Endocrinology that constant stress from exposure to estrogen-mimicking chemicals induced changes in FAAH and cannabinoid receptor functioning in goldfish.
Also in 2011, a paper by researchers at Simon Fraser University in British Columbia demonstrated that various common phthalates can inhibit binding to CB1 receptors.
In 2016, a study by a third group of Italian scientists in Pharmacological Research showed that Bisphenol A exposure changes gene expression and downregulates the CBI receptor, resulting in weight loss and “anorexigenic effects” in male mice.
A 2017 report in the International Journal of Toxicology by researchers at Mississippi State University found that exposure to chlorpyrifos inhibited endocannabinoid metabolizing enzymes (FAAH and MAGL) in rats.
And in 2018, Polish investigators, writing in Chemosphere, concluded that BPA and other endocrine disrupters may induce adverse pregnancy outcomes by acting on the ECS.
Parabens in Personal Care Products
Scientists in Tennessee and California collaborated on a 2016 study which demonstrated that some biological effects associated with exposure to parabens, chemicals used widely as preservatives in personal care products, could be due to direct interference with the ECS through FAAH.
Senior author Bruce Hammock, a professor at the University of California at Davis whose lab specializes in pesticide biotechnology, said that while this in vitro laboratory research isn’t necessarily applicable to human experience, it provides further evidence that endocrine disruptors may interact with the ECS as well as the endocrine system.
Some biological effects associated with exposure to parabens, widely used as preservatives in personal care products, could be due to direct interference with the endocannabinoid system.
“In general it is very hard to relate quantitatively endocrine disruptors in the lab to actual effect in the field, with parabens a case in point, but it is an interesting topic,” he said. “All these systems are talking to each other.”
Endocrine-disruption expert and former National Institute of Environmental Health Sciences administrator Jerry Heindel agrees. Evidence to date shows that at least some endocrine-disrupting chemicals act on the ECS. It makes sense more broadly that the ECS may well be mediating different health outcomes known to be associated with exposure to endocrine disruptors, Heindel said.
Angel Nadal of Spain’s Miguel Hernández University of Elche, also an expert in endocrine disruptors, said the idea of chemical pollutants acting directly on the ECS was new to him, but plausible. “This is an area that needs further research,” he said.
Nate Seltenrich is an independent science journalist based in the San Francisco Bay Area. He covers a wide range of subjects including environmental health, pharmacology, and neuroscience.
Copyright, Project CBD. May not be reprinted without permission.
Bisset KM, Dhopeshwarkar AS, Liao C, Nicholson RA. The G protein-coupled cannabinoid-1 (CB1) receptor of mammalian brain: inhibition by phthalate esters in vitro. Neurochem Int.2011 Oct;59(5):706-13. doi: 10.1016/j.neuint.2011.06.019. Epub 2011 Jul 7. PubMed PMID: 21763743.
Buntyn RW, Alugubelly N, Hybart RL, Mohammed AN, Nail CA, Parker GC, Ross MK, Carr RL.Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Sep/Oct;36(5):395-402. doi: 10.1177/1091581817725272. Epub 2017 Aug 18. PubMed PMID: 28820005; PubMed Central PMCID: PMC5585048.
Carr RL, Borazjani A, Ross MK. Effect of developmental chlorpyrifos exposure, on endocannabinoid metabolizing enzymes, in the brain of juvenile rats. Toxicol Sci. 2011 Jul;122(1):112-20. doi: 10.1093/toxsci/kfr081. Epub 2011 Apr 20. PubMed PMID: 21507991; PubMed Central PMCID: PMC3143466.
Forner-Piquer I, Mylonas CC, Fakriadis I, Papadaki M, Piscitelli F, Di Marzo V, Calduch-Giner J, Pérez-Sánchez J, Carnevali O. Effects of diisononyl phthalate (DiNP) on the endocannabinoid and reproductive systems of male gilthead sea bream (Sparus aurata) during the spawning season. Arch Toxicol. 2019 Mar;93(3):727-741. doi: 10.1007/s00204-018-2378-6. Epub 2019 Jan 2. PubMed PMID: 30600365.
Forner-Piquer I, Mylonas CC, Calduch-Giner J, Maradonna F, Gioacchini G, Allarà M, Piscitelli F, Di Marzo V, Pérez-Sánchez J, Carnevali O. Endocrine disruptors in the diet of male Sparus aurata: Modulation of the endocannabinoid system at the hepatic and central level by Di-isononyl phthalate and Bisphenol A. Environ Int. 2018 Oct;119:54-65. doi: 10.1016/j.envint.2018.06.011. Epub 2018 Jun 19. PubMed PMID: 29933238.
Forner-Piquer I, Santangeli S, Maradonna F, Rabbito A, Piscitelli F, Habibi HR, Di Marzo V, Carnevali O. Disruption of the gonadal endocannabinoid system in zebrafish exposed to diisononyl phthalate. Environ Pollut. 2018 Oct;241:1-8. doi: 10.1016/j.envpol.2018.05.007. Epub 2018 May 21. PubMed PMID: 29793103.
Forner-Piquer I, Maradonna F, Gioacchini G, Santangeli S, Allarà M, Piscitelli F, Habibi HR, Di Marzo V, Carnevali O. Dose-Specific Effects of Di-Isononyl Phthalate on the Endocannabinoid System and on Liver of Female Zebrafish. Endocrinology. 2017 Oct 1;158(10):3462-3476. doi: 10.1210/en.2017-00458. PubMed PMID: 28938452.
Kodani SD, Overby HB, Morisseau C, Chen J, Zhao L, Hammock BD. Parabens inhibit fatty acid amide hydrolase: A potential role in paraben-enhanced 3T3–L1 adipocyte differentiation. Toxicol Lett. 2016 Nov 16;262:92-99. doi: 10.1016/j.toxlet.2016.09.011. Epub 2016 Sep 19. PubMed PMID: 27659731; PubMed Central PMCID: PMC5096949.
Martella A, Silvestri C, Maradonna F, Gioacchini G, Allarà M, Radaelli G, Overby DR, Di Marzo V, Carnevali O. Bisphenol A Induces Fatty Liver by an Endocannabinoid-Mediated Positive Feedback Loop. Endocrinology. 2016 May;157(5):1751-63. doi: 10.1210/en.2015-1384. Epub 2016 Mar 25. PubMed PMID: 27014939; PubMed Central PMCID: PMC6285285.
Nomura DK, Blankman JL, Simon GM, Fujioka K, Issa RS, Ward AM, Cravatt BF, Casida JE.Activation of the endocannabinoid system by organophosphorus nerve agents. Nat Chem Biol. 2008 Jun;4(6):373-8. doi: 10.1038/nchembio.86. Epub 2008 Apr 27. PubMed PMID: 18438404; PubMed Central PMCID: PMC2597283.
Pomatto V, Palermo F, Mosconi G, Cottone E, Cocci P, Nabissi M, Borgio L, Polzonetti-Magni AM, Franzoni MF. Xenoestrogens elicit a modulation of endocannabinoid system and estrogen receptors in 4NP treated goldfish, Carassius auratus. Gen Comp Endocrinol. 2011 Oct 1;174(1):30-5. doi: 10.1016/j.ygcen.2011.08.001. Epub 2011 Aug 10. PubMed PMID: 21855545.
Suglia A, Chianese R, Migliaccio M, Ambrosino C, Fasano S, Pierantoni R, Cobellis G, pChioccarelli T. Bisphenol A induces hypothalamic down-regulation of the the cannabinoid receptor 1 and anorexigenic effects in male mice. Pharmacol Res. 2016 Nov;113(Pt A):376-383. doi: 10.1016/j.phrs.2016.09.005. Epub 2016 Sep 15. PubMed PMID: 27641926.
Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee DH, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012 Jun;33(3):378-455. doi: 10.1210/er.2011-1050. Epub 2012 Mar 14.
Zbucka-Kretowska M, Zbucki R, Parfieniuk E, Maslyk M, Lazarek U, Miltyk W, Czerniecki J, Wolczynski S, Kretowski A, Ciborowski M. Evaluation of Bisphenol A influence on endocannabinoid system in pregnant women. Chemosphere. 2018 Jul;203:387-392. doi: 10.1016/j.chemosphere.2018.03.195. Epub 2018 Mar 30. PubMed PMID: 29627605.