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Environmental Toxins and Damage to the Immune System: Transgenerational Effects

By Roberta Attanasio

The hypothesis of the Developmental Origins of Health and Disease (DOHaD), also called “Barker’s hypothesis”, was formulated a few decades ago and stimulated interest in the fetal origins of adult disorders. Subsequent research by Mohan Manikkam and Michael Skinner helped establish the principle of transgenerational toxicity by showing that the effects of toxic chemicals can extend even to the third generation of offspring.

Photo by Liv Bruce on Unsplash

Indeed, it is now clear that early life development is a critical and unique window of vulnerability during which environmental exposures influence cellular programming in ways that shape health and disease later in life. While most research on the transgenerational effects of environmental chemicals focuses on the reproductive, nervous, or endocrine systems, results from a recently published study show that environmental toxins may also impair the immune system. Paige Lawrence, senior author of the study, said in a press release: “The old adage ‘you are what you eat’ is a touchstone for many aspects of human health. But in terms of the body’s ability to fights off infections, this study suggests that, to a certain extent, you may also be what your great-grandmother ate.”

To carry out the study, researchers exposed pregnant mice to dioxin, a common by-product of industrial production and waste incineration which is also found in some consumer products. Thus, dioxins are environmental pollutants. They belong to the so-called “dirty dozen”—a group of dangerous chemicals known as persistent organic pollutants (POPs). Dioxins are of concern because of their highly toxic potential. In the environment, dioxins tend to accumulate in the food chain. The higher an animal is in the food chain, the higher the concentration of dioxins. Therefore, dioxins are found in greater concentrations in animal-based food products. Once dioxins enter the body, they last a long time because of their chemical stability and their ability to be absorbed by fat tissue, where they are then stored. Their half-life in the body is estimated to be 7 to 11 years. 

After exposing pregnant mothers to dioxin, they assessed the production and function of cytotoxic T cells in the offspring. To do so, they infected the mice with influenza A virus, and found that exposure of the pregnant mothers to dioxin resulted in an impaired cytotoxic T cell response of the offspring against the influenza A virus. The impaired cytotoxic T cell response was observed not only in the offspring of the mice whose mothers where exposed to dioxin, but also in subsequent generations, up to the rodent equivalent of great-grandchildren.  

Lawrence said: “When you are infected or receive a flu vaccine, the immune system ramps up production of specific kinds of white blood cells in response. The larger the response, the larger the army of white blood cells, enhancing the ability of the body to successfully fight off an infection. Having a smaller size army—which we see across multiple generations of mice in this study—means that you’re at risk for not fighting the infection as effectively.”

 

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Author: Roberta Attanasio

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10 Comments

  1. This study is not only interesting but important due to the exposure of dioxins because of factory pollutants in industrialization, processed foods, and pollutants from chemical spills. This toxicity from dioxins can result in weakened immune system of the mother as well as their offspring for generations which could lead to sickly populations. One of the points that interested me the most in the study supported by this article was that dioxins are mainly found in maternal diet with an excessive amount in foods such as dairy, fish, meat, and shellfish and lower levels found in plants, water and air. A study I read titled “A General Model of Dioxin Contamination in Breast Milk: Results from a Study on 94 Women from the Caserta and Naples Areas in Italy” stated that “Toxicological data indicate that about 80%–90% of human exposure is determined by contaminated food”. This means that the population should be mindful in the diet trends that occur since they can have a negative effect on their children as well as their children’s offspring. This data also suggests that veganism and plant-based diets may lead to healthier offspring overall.
    We see even more ways in which environmental pollutants can affect the health of a population and even with the attempt to clean up, these pollutants can cause health issues in the immune system that can be passed down to an offspring and their offspring. The paper that the article was based on says that “For instance, higher levels of dioxins and polychlorinated biphenyls (PCBs) in breast milk, cord, and infant blood correlate with increased respiratory tract infections and reduced responses to vaccination (Hochstenbach et al., 2012; Jusko et al., 2016; Miyashita et al., 2011; Stolevik et al., 2013).” This statement is supported in the article I found which states the amount of dioxins found in breastmilk and its linked to diseases in certain areas of Italy. There is an ongoing debate about whether a mother should breast feed her children but with the above study, it could be argued that mothers exposed to higher levels of TCDD’s should not as it can be more detrimental to the child’s health than good. Another interesting point the article brings up is the mother’s age as a factor when exposing their children to dioxins due to prolonged exposure the older the mother is. This is something that I never thought about and raises the question of whether having children young is the healthier option for the vitality and healthiness of the offspring.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863880/

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  2. The notion that developing fetuses are subject to influence from environmental toxins is not an entirely novel concept. While reading this blog post I thought about the teratogen, thalidomide, which induced several birth defects across the 1950s-1960s. While thalidomide did not induce transgenerational effects it illustrated that embryos in utero are vulnerable to maternal exposure to toxins. Recent work has demonstrated that among environmental factors, parental stress has the potential to influence development. According to a review, epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, such as attention deficit-hyperactivity disorder (ADHD), schizophrenia and autism spectrum disorders. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. For example, one studied employed a chronic variable stress paradigm in which pregnant mice were exposed to various stress conditions (constant light, odor exposure, saturated bedding, etc.) across multiple points in gestation. The results show that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. The researchers posit that their findings are likely due to extended alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity. This stress dysregulation phenotype persisted into the next generation. These findings are significant in that they elucidate the need for further examination into the mechanisms behind transgenerational effects. I think it is fascinating yet troublesome that parental environmental exposure in utero and epigenetic programming have such profound effects on offspring. We must continue to explore this topic so that methods of prevention are developed.

    Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214173/

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  3. Upon reading the above article and the associated hyperlinks, prior to Drs. Manikkam and Skinner (published Jan 2010) establishing concretely that “transgenerational toxicity” exists— evidenced by lingering effects of intrauterine toxicity in non-exposed, third generation offspring—the fetal origins of adult disease (barker hypothesis) was delimited to only being an accepted “perspective” of disease etiology. Or more specifically, suggestive, but not causative. The barker hypothesis in short states, “environmental influences during gestation have an effect on later development” (Skogen & Øverland, 2012). My realization that it was merely considered a “perspective” before as opposed to a stand-alone, accepted hypothesis, led me to inquire just how long the scientific community has reported the transgenerational immunological effects of “persistent organic pollutants,” without these reports gaining traction before the most recent study with dioxin at the epicenter. What I found was an extensive retrospective compiling review of environmental pollutants that are immunotoxicants published September 2010, just eight months are Dr. Manikkam and Skinner. On this list the earliest concrete evidence between pollution and increased immune system susceptibility to infectious disease being what is known and set the stage for regulations Dioxins in the mid-70s. However, I was surprised to find that T-cell immunodeficiency due to intrauterine exposure to BaP (POP found mostly in tobacco smoke and grilled meats) was first evidenced in 1984. Why did it take until 2019 for this to be a “big break” in epidemiology and toxicology to extend studies outward to future generations?

    Should these earlier reports have been substantial in and of themselves, I am wondering what this would have meant for epidemiological surveilling within the last three decades and the preventative measures that could have been invented or extended from their current standards.
    I would be interested to do further review of literature to uncover why there has been extensive focus on the studies that elucidate causation between intrauterine pollutants and increased risk of cardiovascular disease, stroke, obesity, and cancer later in life; but not the development and programming of the immune system (Winans, Humble, & Lawrence, 2011). I draw this comparison with immense interest specifically because the aforementioned disease states are slow building, whereas, an infectious disease in the presence of compromised innate and adaptive immunity could be fatal within a short period of time.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033466/

    Skinner, M. K., Manikkam, M., & Guerrero-Bosagna, C. (2010). Epigenetic transgenerational actions of environmental factors in disease etiology. Trends in Endocrinology & Metabolism, 21(4), 214-222. doi:10.1016/j.tem.2009.12.007
    Skogen, J. C., & Øverland, S. (2012). The fetal origins of adult disease: a narrative review of the epidemiological literature. JRSM Short Reports, 3(8), 1-7. doi:10.1258/shorts.2012.012048
    Winans, B., Humble, M. C., & Lawrence, B. P. (2011). Environmental toxicants and the developing immune system: A missing link in the global battle against infectious disease? Reproductive Toxicology, 31(3), 327-336. doi:10.1016/j.reprotox.2010.09.004
    Urso, P., & Gengozian, N. (1984). Subnormal expression of cell‐mediated and humoral immune responses in progeny disposed toward a high incidence of tumors afterin uteroexposure to benzo[a]pyrene. Journal of Toxicology and Environmental Health, 14(4), 569-584. doi:10.1080/15287398409530606

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  4. The fetal origins hypothesis by Barker which formed the basis for the Developmental Origins of Health and Disease (DOHaD) has lacked concrete scientific proof until recent studies such as described above. The evidence for the phenomenon was generally observational and gained more ground in fields like economics where observational studies linked fetal shocks and circumstances to later life test scores, educational attainment and wealth status.

    It is daunting enough that a mother’s diet, exercise or lack thereof, and intake of alcohol or drugs can affect her baby. Those can be controlled to an extent. The growing evidence that the effect of environmental pollutants and toxins which she mostly has no control over, can determine health outcomes for her baby, as well generations thereafter, imposes a big responsibility.

    This evidence validates the worldwide effort that is being invested in going green in the effort to limit pollution and protect the environment. The rational for going green has been that it will result in better living conditions for later generations. It is interesting to know that the environment needs to be saved now so that its effects on us now will not be passed on to the next generation as well. Though it sounds like the same goal, the latter imposes a greater urgency to mitigate environmental pollution.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140221/#R100

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  5. Based on the information from this article, research done by Mohan Manikkam and Michael Skinner helped establish the principle of transgenerational toxicity by showing that the effects of toxic chemicals can extend even to the third generation of offspring. This is kinda shocking to me that this could affect 3 generations of offspring.
    The first question I have is “Why is this so powerful? What is the cause? Is this toxicity strong enough to cause gene mutation or chromosome crossover or it alters gene expression? Is this genetic inheritance or non-genetic inheritance”?
    I did some researches and found an article provide very helpful information based on my questions.
    Researchers did experiment and found that parental environmental conditions were found to have a transgenerational effect on offspring life-history traits is through non-genetic inheritance. epigenetic factors such as DNA methylation, histone modifications, chromatin structure and noncoding RNA, they can alter the expression of immune functions through non-heritable effects that regulate the genome activity. The changes in immunity will remain in the next generation even if exposure to an environmental pollutant is no longer apparent.
    For more information, please refer to the article below.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373569/

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    • I actually had the same questions running through my mind as I was reading the article! I kept wondering how these transgenerational effects on the immune system fit within the model of Mendelian genetics. I was previously aware of the precautions pregnant women needed to take to avoid environmental toxins since of course the fetus was sharing the same blood and oxygen supplies. I never considered the transgenerational effects of those toxins, and the scariest part is that most of the time we cannot control the air we breathe or the way our food is processed. I was very interested in the article you shared that illustrates the negative transgenerational effects of parental exposure to heavy metals such as copper on immunity. I began to question if the timing of toxic exposure during fetal development had more of an impact than the composition of the toxin. For example, does parental exposure to the same toxin before conception have similar inherited effects as exposure during early or late fetal development? However, a comparative study of successive generations of humans is difficult to carry out. The epigenetic factors you mentioned including DNA methylation, histone modifications, etc. are an interesting point of research to delve further into the mechanisms of actions of environmental toxins on immunity. I conducted further research on transgenerational inheritance and found an article showing the effects of parental postnatal trauma in a mouse model up to the 4th generation of offspring. The article reported epigenetic changes in the male germline and offspring tissues that resulted in behavioral and metabolic symptoms. I think this would be a solid model to continue the study of transgenerational epigenetic inheritance on the immune system.

      Please refer to the article’s link below for more information.
      https://www.ncbi.nlm.nih.gov/pubmed/30349741

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    • The hypothesis that xenobiotic exposure during fetal development may alter gene expression patterns in a heritable manner through modifying the epigenome is the most common and currently data supported as seen in the study above. However, it is speculated that apart from transgenerational transmission directly through the gametes, somatic epigenetic modifications could also contribute to changes in the gamete. Somatic to germline transmission is attributed to the role of regulatory RNAs. If this is the case, the total sum of environmental toxins that a person exposed to, whether male or female may be transmitted through generations as well. This is sobering!!

      https://www.ncbi.nlm.nih.gov/pubmed/23257323/

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  6. Reading this blog post, I thought it was a bit alarming that dioxin-mediated toxicity can be passed down onto three more generations, considering that dioxin is toxic even in minute quantities and can substantially alter how a host organism mounts an immune response.

    I wanted to learn more about how dioxin interacts with the cytotoxic T-cells and uncover why dioxin is so toxic to our immune system. Specifically, I wanted to find out more about the location of the cytotoxic T-cell suppression (whether it occurred in the primary or secondary lymphoid organs) and whether the toxicity of dioxin was mediated by some sort of surface molecule or protein on the cytotoxic T-cells that facilitated this interaction.

    Through my research, I learned that mice subjected to dioxin treatment had substantial impairments occurring in the primary lymphoid organs including the bone marrow and the thymus, which affected their ability to mount an effective immune response to ward off infection. This toxicity was observed even when the mice were subjected to trace amounts of dioxin.

    Dioxin specifically interacts with the Aryl Hydrocarbon Receptor (AhR) which is expressed on the cell membranes of both CD8+ cytotoxic T-cells and the CD4+ helper T-cells. The AhR has another protein that it interacts with called the AhR nuclear translocator (ARNT) which is a transcription factor. By going inside the nucleus, ARNT modulates the transcription of genes in the dioxin response elements region which play critical roles in the activation, proliferation, and differentiation of T-cells, paramount for generating an effective immune response, notably the cytotoxic T lymphocyte (CTL) response. In this manner, dioxin is able to disable the body’s immune response, making the host more susceptible to infections.

    For more information, please see the research study referenced below.

    Reference:
    Kerkvliet, N. I., Shepherd, D. M., & Baecher-Steppan, L. (2002). T Lymphocytes Are Direct, Aryl Hydrocarbon Receptor (AhR)-Dependent Targets of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD): AhR Expression in Both CD4+ and CD8+ T Cells Is Necessary for Full Suppression of a Cytotoxic T Lymphocyte Response by TCDD. Toxicology & Applied Pharmacology, 185(2), 146.

    https://www.ncbi.nlm.nih.gov/pubmed/12490139

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    • When I finished reading your comment, I wanted to know more about this “AhR” receptor and I found that scientists are still trying to isolate its endogenous ligand! The receptor is studied heavily in toxin metabolism because it is considered an environment sensor. Upon its activation by TCDD (dioxin), PCBs, and PAHs that bind to AhR, as you stated T lymphocytes are suppressed at the level of primary lymphoid tissues. Crazily, agonists for this receptor also diminish memory T cell response/pool to the same type of infections over time BUT paradoxically the AhR is necessary to mediate T helper 2 cells via dendritic-dependent interactions in the lungs because the loss of this receptor leads to heightened inflammatory response to allergic reactions. “You’re damned if you do, damned if you don’t.”

      Lawrence, B. P. (2004). Activation of the Aryl Hydrocarbon Receptor Diminishes the Memory Response to Homotypic Influenza Virus Infection but Does Not Impair Host Resistance. Toxicological Sciences, 79(2), 304-314. doi:10.1093/toxsci/kfh094

      References:
      Thatcher, T. H., Williams, M. A., Pollock, S. J., McCarthy, C. E., Lacy, S. H., Phipps, R. P., & Sime, P. J. (2015). Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function. Immunology, 147(1), 41-54. doi:10.1111/imm.12540

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  7. Reading this blog post, I thought it was a bit alarming that dioxin-mediated toxicity can be passed down onto three more generations, considering that dioxin is toxic even in minute quantities and can substantially alter how a host organism mounts an immune response.

    I wanted to learn more about how dioxin interacts with the cytotoxic T-cells and uncover why dioxin is so toxic to our immune system. Specifically, I wanted to find out more about the location of the cytotoxic T-cell suppression (whether it occurred in the primary or secondary lymphoid organs) and whether the toxicity of dioxin was mediated by some sort of surface molecule or protein on the cytotoxic T-cells that facilitated this interaction.

    Through my research, I learned that mice subjected to dioxin treatment had substantial impairments occurring in the primary lymphoid organs including the bone marrow and the thymus, which affected their ability to mount an effective immune response to ward off infection. This toxicity was observed even when the mice were subjected to trace amounts of dioxin.

    Dioxin specifically interacts with the Aryl Hydrocarbon Receptor (AhR) that is expressed on the cell membranes of both CD8+ cytotoxic T-cells and the CD4+ helper T-cells. The AhR has another protein that it interacts with called the AhR nuclear translocator (ARNT) which is a transcription factor. By going inside the nucleus, ARNT modulates the transcription of genes in the dioxin response elements region which play critical roles in the activation, proliferation, and differentiation of T-cells, paramount for generating an effective immune response, notably the cytotoxic T-lymphocyte (CTL) response. In this manner, dioxin is able to disable the body’s immune response, making the host more susceptible to infections.

    For more information, please see the research study referenced below.

    Reference:
    Kerkvliet, N. I., Shepherd, D. M., & Baecher-Steppan, L. (2002). T Lymphocytes Are Direct, Aryl Hydrocarbon Receptor (AhR)-Dependent Targets of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD): AhR Expression in Both CD4+ and CD8+ T Cells Is Necessary for Full Suppression of a Cytotoxic T Lymphocyte Response by TCDD. Toxicology & Applied Pharmacology, 185(2), 146.

    https://www.ncbi.nlm.nih.gov/pubmed/12490139

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