Perfluoroalkyl substances and changes in body weight and resting metabolic rate (RMR) in response to weight-loss diets: A prospective study

This is an excellent point.
Obviously the PFASs have a “lipophilic (or “hydrophobic”) end” (at left) where the Fluoride atoms are located, and a “hydrophilic end” (at right):

And come to think it, the C=O (keto group) of chlordecone [below] is hydrophilic, whereas the rest of the box with Cloride atoms is hydrophobic. To those on the GEITP List who have not had chemistry since many years ago, remember the “old partition coefficient,” shaking up any chemical in a mixture of hexane and water and then determining how much of the chemical is in the water phase (on top) or hexane phase (on bottom). PFASs and, to some extent, chlordecone, would be sitting at the interface –– with its hydrophilic end pointed upward and its hydrophobic end pointed downward. 🙂

COMMENT from DWN Therefore, these chemicals would exhibit very complex interactions with specific blood lipids and specific blood proteins. In contrast, dioxins and polychlorinated biphenyls (PCBs) are much more hydrophobic than these organochlorine pesticides.

The Kepone story is even more complicated because –– over and above its lipid affinity –– Kepone specifically binds to some proteins in the blood albumin fraction, further distorting the blood-tissue partition ratio.

I am not sure you need such a complicated explanation to question causality. When dealing with lipophilic substances –– such as PFASs, dioxins, PCBs, organochlorine pesticides (OCPs), etc –– the use of any blood measurement as “an indicator of body content” must be seriously questioned. Metabolic / nutritional manipulations can change the lipid content in blood, thereby increasing or decreasing the distribution of these chemicals from tissue stores into blood.

You will recall that early studies of 2,3,7,8-tetrachloro-p-dioxin in blood, when expressed per wet weight of blood/serum, made no sense until it was realized that the the results had to be expressed per weight of lipids in blood (actually by using a formula for the vatious kinds of lipids in blood). Moreover, weight-loss or weight-regain is known to affect such blood/tissue distribution of some organochlorine pesticides.
COMMENT FROM anonymous

I remain very skeptical. This is not a plausible explanation of causation, and is much more likely to be only an association. Everyone should be aware of Bradford Hill’s “criteria for causation” (list of nine principles).

Any clinician who has watched or experienced the “yo-yo” effect of weight issues in many patients understands that obesity, and weight-loss success, and weight-regain problems –– all represent multifactorial traits –– which as you frequently describe in your GEITP shared-mailing reflects hundreds if not thousands of genes, plus epigenetic factors, plus environmental effects (diet, lifestyle, age, diseases, drug-drug-interactions, etc.). The “environment” in this case might include PFAS levels of exposure as one small component, but obesity represents a complicated response to life stresses, habits, and innumerable extraneous subtle environmental factors (in fact, even being in the company of other overweight people). Association, yes……causation…….nope


This is a “correlation ––> inferred-causation” epidemiological study, and I would appreciate any comments/criticisms about these findings. Perfluoroalkyl substances (PFASs) –– especially perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) –– have been in the news a lot lately, and identified as plausible endocrine disruptors with the potential to perturb weight regulation. Evidence from animal studies has suggested that PFASs may be involved in altering energy metabolism and thyroid hormone homeostasis, likely through activation of various transcriptional factors such as the peroxisome proliferator-activated receptors. However, given species-specific toxicokinetics and tissue distribution of PFASs, extrapolation from animals to humans is always difficult.

Authors [see attached] examined associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting. In the 2-year “POUNDS Lost” randomized clinical trial –– based in Boston, Massachusetts, and Baton Rouge, Louisiana –– which examined effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants (aged 30-70 years). Body weight was measured at baseline and 6, 12, 18, and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6 to 24 months (weight-regain period). [Note that the annoying television ads for “weight-loss programs” describe enthusastically the ‘weight-loss period’, but fail to mention the ‘weight-regain period’.] 🙁

After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight-regain, primarily in women. In women, comparing the highest to the lowest tertiles (statistical divisions of any population into three equal parts, the two extreme groups being divided by the middle group) of PFAS concentrations, the multivariate-adjusted mean weight-regain was: 4.3 vs 2.2 kgfor PFOA; 4.0 vs 2.1 kg for PFOS; 4.7 vs 2.5 kg for perfluorononanoic acid (PFNA); 4.9 vs 2.7 kg for perfluorohexanesulfonic acid; and 4.2 vs 2.5 kg for perfluorodecanoic acid.

Higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight-regain period in both men and women. Caveats (limitations of the study) include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors (i.e. greater obesity among the poor), as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food-packaging and also dense in energy.

Authors conclude that, in this diet-induced weight-loss study, higher baseline plasma PFAS concentrations were associated with a greater weight-regain, especially in women, possibly explained by a slower return to their normal RMR levels. These data convincingly illustrate a potential novel pathway through which PFASs interfere with clinical body weight regulation and metabolism. Possible impact of environmental chemicals on the obesity epidemic thus deserves more attention.

PLoS Med Feb 2o18; 15: e1002502

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