Correlation and Causality: Alcohol and Diabetes to BPA and Estrogen Disruption

Alcohol and Diabetes:

From a purely health-oriented perspective, alcohol is one of those things where a little seems to be good and more than a little puts you at risk for a bad health outcome. One of the positive things small regular intake can do for you is protect you from diabetes. There is good epidemiological evidence that this is the case. Light drinkers are less likely to develop diabetes than those who abstain.

Samples prepared for analysis. 

As most people know, just because two things occur together does not mean that one caused the other. Correlation and causality are two different things. It is important to keep this in mind when reading about human health studies in the news. Epidemiology is a wonderful tool however, and provides clues to problems that might have gone unnoticed. In addition to identifying potential problems correlational (and epidemiological) studies are important in evaluating how a problem identified in the lab may be harming people in the real world. Are light drinkers more likely to eat better, exercise better, be healthier than those who drink more alcohol or even none at all?

An important next step is figuring out why the correlation exists.  Here is a case where epidemiology observed something (low alcohol = less diabetes, high alcohol = more diabetes) and experimental study identified a physiological reason that explains those observations.    He et al. (2007) discovered that light alcohol intake activates a biochemical pathway that has a positive influence on removal of blood sugar from the blood stream. Higher alcohol intake disrupts glucose management by activating an additional protein that blocks the positive effects seen with light alcohol intake.  This discovery helps explain why you can see two different outcomes with alcohol.  At first light it may have seemed that scientific studies conflicted each other.  The appearance of contradiction may lead some people to throw up their hands and decide to disregard health news or science in general.

Sometimes we need to keep working at the puzzle.

There may be a similar issue with environmental contaminants.  Sometimes a relationship is observed and someone publishes on it, and there there are a flurry of other studies that confirm or don't confirm the relationship, expand it or limit it.  Identifying the mechanism and understanding how it works under varied circumstances becomes essential.  There are now many correlational studies that show that Bisphenol A (BPA) intake is associated with health problems.  There are also mechanistic studies that show how BPA interacts with estrogen receptors and causes things to go arwy.  One could stop here and take steps to remove BPA from use.  Environmentalists and children's health advocates could claim victory.  This might result in fewer birth defects, less obesity, less diabetes, fewer behavioral problems in children etc.  But it might not.

Plastics are more complex than they seem.  Even without BPA many of the chemicals that go into or are released from different plastics may be may activate estrogen receptors.  Would people be exposed to less estrogenic chemicals if BPA is banned?  We still don't know.  While many studies have used data on concentrations of BPA or BPA-metabolites, to the best of my knowledge no one has looked at total exposures to estrogenic chemicals originating from plastics.  (There are also estrogenic chemicals from sources other than plastics too).   Does removing BPA from a plastic actually make it less estrogenic?  Is BPA, rather than other chemicals coming off of plastics, the main source of dietary exposures to estrogenic compounds?

Plastics are amazing, really, and have made many positive and important contributions to our economy and quality of life.  For information on how plastics benefit the environment and contribute to quality of life take a look at this pdf from the British Plastics Federation.  Its taken tremendous effort and ingenuity to develop polymers.  We can figure out where they might cause problems in the environment or in human health by continuing polymer research and including within, cell and molecular studies.  We should not have to leave epidemiology to discover problems that could have been avoided after the fact. 

He L, Marecki JC, Serrero G, Simmen FA, Ronis MJ, & Badger TM (2007). Dose-dependent effects of alcohol on insulin signaling: partial explanation for biphasic alcohol impact on human health. Molecular endocrinology (Baltimore, Md.), 21 (10), 2541-50 PMID: 17622585

Nguyen KH, Lee JH, & Nyomba BL (2012). Ethanol causes endoplasmic reticulum stress and impairment of insulin secretion in pancreatic β-cells. Alcohol (Fayetteville, N.Y.), 46 (1), 89-99 PMID: 21840159

What are obesogens?

Living things are delicate, resilient and tenacious.  Their chemistry is fascinating.  We are molecular machines, in a sense, and fine tuned to interact with the external world.  The chemical systems that make us who and what we are took many millions of years to develop.  It is incredible that we are now able to synthesize molecules by ingenuity.  Chemical engineering, pharmaceutical companies and even the much maligned agrochemical industry have, and are, incredibly important to where we stand now.  The drugs, and even pesticides, that have been produced have saved countless lives. It is just now that we have calmed down a little from the excitement of synthesizing new molecules, and started looking at the unintended effects these new molecules have on biochemistry.  Things that alter our biochemistry can alter our health.   Sometimes they can alter the developmental paths we follow in utero. It would be wonderful if inadvertent exposures to new molecules had beneficial effects.  Its possible.  As with most things, the good things that happen by accident usually go unnoticed. However, as in most situations, it is far easier to be destructive than constructive. 

So, back to the post title: what are obesogens?

Obesity can make your life harder than it needs to be

Obesogens are chemicals that change the way fats (lipids) are handled.  Exposure, especially early in life, may influence patterns of fat distribution, the way the body uses fat, and/or the way fat is synthesized.  It is possible that some chemicals might make us develop as lean, fat burning machines.  This would be a huge problem if we ever have a famine, but that is not our current issue.  Obesity, and its associated health problems, is on the rise.  Some of the chemicals that may be acting as obesogens in people are:

Organotins (used in marine paints, production of plastics, pesticides. Exposure may come through seafood, produce, drinking water and plastics.

Bisphenol A (BPA): from plastics.

Phthalates: from plastics

 Perfluoroalkyll compounds (PFCs): water repellant fabrics, stain preventing treatments.

How to avoid obesogens.

Avoid plastics when possible.  Avoid fabrics treated with water repellants or stain blockers.  Avoid carpet treatments.  

Grün F, & Blumberg B (2006). Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology, 147 (6 Suppl) PMID: 16690801
 

Thayer KA, Heindel JJ, Bucher JR, & Gallo MA (2012). Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environmental health perspectives, 120 (6), 779-89 PMID: 22296744

Plastics, Diabetes and Obesity

Things start to get interesting when the results human epidemiology and animal exposure studies meet.  Epidemiology studies of human exposures to a xenoestrogen like BPA show relationships between exposure and diabetes, or exposure and obesity.  But it is very difficult to say that exposure to a plastics component causes obesity, diabetes or heart disease.  People who are exposed to a lot of xenoestrogens may eat more canned food and have more BPA (or similar) circulating in their systems, but people who eat a lot of canned and packaged food may also eat poorly, exercise less, and/or be less educated compared to someone who has very little plastics exposure.  

This is why animal studies are so important.  When the results of controlled animal studies are similar to trends we are observing in people the case for concern about a particular chemical jumps.  Many people oppose animal studies for ethical reasons, but sometimes leaving questions unanswered is unethical as well.  

There is increasing evidence that chemicals in the environment may be contributing to diabetes and obesity. This is not to say that there is no such thing as good habits, but biochemical variables, set during early life, may make it harder to regulate things like blood sugar and weight.  For current reviews and discussion take a look at:

• Toxic environment and obesity pandemia: Is there a relationship?
• Impact of environmental endocrine disrupting chemicals on the development of obesity.

Here is animal evidence for a relationship between exposure to bisphenol A, (and possibly other chemicals that are structurally similar)  and diabetes: Bisphenol A Exposure during Pregnancy Disrupts Glucose Homeostasis 
in Mothers and Adult Male Offspring. As discussed in previous posts, nearly everyone is exposed to Bisphenol A (BPA) and probably to other xenoestrogens through consumption of food and beverages packaged in plastic.  It is an interesting study.  It shows that exposures during pregnancy will affect offspring into adulthood.  Whether or not this is happening in people is unknown, and not testable. 

Katzenellenbogen JA (1995). The structural pervasiveness of estrogenic activity. Environmental health perspectives, 103 Suppl 7, 99-101 PMID: 8593885
 

Newbold RR (2010). Impact of environmental endocrine disrupting chemicals on the development of obesity. Hormones (Athens, Greece), 9 (3), 206-17 PMID: 20688618
 

Alonso-Magdalena P, Vieira E, Soriano S, Menes L, Burks D, Quesada I, & Nadal A (2010). Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environmental health perspectives, 118 (9), 1243-50 PMID: 20488778

Xenoestrogens and Plastics

This post covers one of the problems posed by endocrine disruptors (ECDs) that I don't think has gotten a lot attention, or at least broad enough attention. This is the issue of estrogen-mimics.  These are also known as Xenoestrogens.    A lot of people seem to be aware of BPA and take steps to avoid it. However, BPA is a relatively small part of the story. Plastics labeled BPA-free may not be Estrogen Activity-Free at all (Yang et al. 2011). Normal estrogen acts by docking at an estrogen-receptor, like a lock fitting into a key, and turns on various biochemical pathways.  These pathways play important roles in maintaining normal function in various tissue, allow girls to develop normally through puberty, make reproduction possible, organize behavioral responses and neurological function among other things. 

The problem with xenoestrogens is that the body can't tell the difference between these molecules and natural estrogen.  Its an issue of molecular structure or shape (Katzenellenboggen 1995).  That means biochemical pathways can be turned on at inappropriate times, upsetting the normal course of development, including brain development.  It may also mean that more estrogen activity is happening because estrogen-regulated cell activity is ramped up.  This might mean more cell division and change in estrogen-sensitive tissue, which can increase risk of breast cancer. There is also evidence that xenoestrogens can harm male development as well (Ogura et al. 2007).  

A normal three-year old performs with her toy cat

Many chemicals have estrogen-activity.  Some chemicals are more estrogenic than others.  Household products, dusts, plastics, cosmetics, personal care products may all contain estrogenic chemicals.  Note that, dust aside, there are products that don't contain estrogenic chemicals.  For example, plastics can be produced that do not have estrogenic activity. 

It may just be hard to find them.  For example, the only company I know of that produces a plastic water bottle that is independently certified as Estrogen Activity Free is a small company called The Water Geeks.  The Headline on the Link says BPA-Free, but these are Estrogen-Activity Free as well.  A small company, Certichem, run by a bunch of University of Texas professors, certifies chemicals as Estrogen-Actity Free.  They also test things for androgen and anti-androgen activity as well.  

BPA-Free is great, but BPA bottles and cans are not necessarily Estrogen-Activity Free.  I try to use glass, which is not always practical or even permitted in some situations.  We probably don't want to see fields of pee-wee soccer players running around with glass bottles, and a lot of boxes probably don't want to see exhausted athletes staggering around with glass either. 

The Environmental Working Group provides a website that will help you identify products that contain fewer ECDs.  They also have a lot of other well-written and informative material on the topic of chemicals in the environment.  You can read more about Endocrine Disruption and the concerns of the scientific and medical communities in this pdf published by The Endocrine Society.

Katzenellenbogen JA (1995). The structural pervasiveness of estrogenic activity. Environmental health perspectives, 103 Suppl 7, 99-101 PMID: 8593885  

Yang CZ, Yaniger SI, Jordan VC, Klein DJ, & Bittner GD (2011). Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environmental health perspectives, 119 (7), 989-96 PMID: 21367689  

Ogura Y, Ishii K, Kanda H, Kanai M, Arima K, Wang Y, & Sugimura Y (2007). Bisphenol A induces permanent squamous change in mouse prostatic epithelium. Differentiation; research in biological diversity, 75 (8), 745-56 PMID: 17459086

Ogura Y, Ishii K, Kanda H, Kanai M, Arima K, Wang Y, & Sugimura Y (2007). Bisphenol A induces permanent squamous change in mouse prostatic epithelium. Differentiation; research in biological diversity, 75 (8), 745-56 PMID: 17459086

What are endocrine disruptors?

The next several posts will be devoted to the subject of endocrine disruption with a focus on environmental chemicals that interfere with sex steroids, chiefly estrogens and androgens. Most people are probably familiar with estrogen and testosterone. These are steroids produced by the human body (and the bodies of other species) that play important roles in sexual development and reproduction. They also play many other related roles, influence growth and tissue maintenance, neurological function and behavior.

 An endocrine disruptor is a chemical agent that interferes with very complex, inter-regulating and intertwined endocrine systems. Interference with one steroid hormone can produce chain reactions that impact other hormones that, in turn, influence other systems and other hormones. For example, Bisphenol A, an estrogen mimic will change production of Prolactin (Steinmetz et al. 1997).

A young boy ponders something.

The effects of endocrine disruptors can be strongest during critical periods such as fetal development, infancy, adolescence, conception and pregnancy. These are times of important changes that will have long-term consequences for a child (fry, larvae, pup, chick etc.) and its future children. Thousands of chemicals have been found to be endocrine disruptors. Some of them are very resistant to degradation and remain in the environment and in people's bodies for decades or longer. Many of these are no longer in use even though with can still easily detect them. They were found to be a threat to health and were banned and/or replaced with something less dangerous. There are many other chemicals in use that have not been tested. There are others that are current foci of research and debate. These chemicals were not developed to cause harm to humans (at least not most of them), rather they were found to be harmful after they were already in use. An example that you may be aware of is the plastics additive Bisphenol A.

Bisphenol A is commonly called BPA. After years of debate and conflict among interested parties BPA has been banned from baby bottles in the US. Manufacturers are adapting and produced new products. Consumers can easily find BPA-Free materials and it seems likely that BPA will leave many markets.  While BPA may be in decline the issue of endocrine disruptors is far from resolved. The plastic products used to make some BPA-Free plastics also appear to be endocrine disruptors (Yang et al. 2011.) Some of them appear to be more disruptive than the BPA-laced plastics they are meant to replace.  It would be better to produce Endocrine-Disruptor-free products Instead of  BPA-Free products

It is very difficult to pull something out of the market once it is already there. People's livelihoods have become dependent on continuing use, reputations are at stake, there may be millions of dollars spent on legal fees,  on efforts to fund studies that would show that the product in question was harmless after all, and then more time and more money spent arguing why banning a product would be unfeasible and not worth the cost of replacing it, developing alternative technology, or cleaning up environmental messes. Banning chemicals after they become part of the economy is hugely wasteful, makes people on both sides of the playing field upset and erodes public confidence. We may discuss this in greater detail later, but for now, just be aware that the chemical problem of endocrine disruptors is also an economic and then a political problem as well. This should be resolved eventually, but until then, we may have a very interesting, and for some a painful, ride. Steinmetz R, Brown NG, Allen DL, Bigsby RM, & Ben-Jonathan N (1997). The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology, 138 (5), 1780-6 PMID: 9112368 Yang CZ, Yaniger SI, Jordan VC, Klein DJ, & Bittner GD (2011). Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environmental health perspectives, 119 (7), 989-96 PMID: 21367689

Steinmetz R, Brown NG, Allen DL, Bigsby RM, & Ben-Jonathan N (1997). The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology, 138 (5), 1780-6 PMID: 9112368  

Yang CZ, Yaniger SI, Jordan VC, Klein DJ, & Bittner GD (2011). Most plastic products release estrogenic chemicals: a potential health problem that can be solved. Environmental Health Perspectives, 119 (7), 989-96 PMID: 21367689