Intergenerational effects of endocrine-disrupting compounds: a review of the Michigan polybrominated biphenyl registry.
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ABSTRACT:
SUBMITTER: Curtis SW
PROVIDER: S-EPMC6275560 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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Intergenerational effects of endocrine-disrupting compounds: a review of the Michigan polybrominated biphenyl registry.
Curtis Sarah W SW Conneely Karen N KN Marder Mary E ME Terrell Metrecia L ML Marcus Michele M Smith Alicia K AK
Epigenomics 20180611 6
Endocrine-disrupting compounds (EDCs) are a broad class of chemicals present in many residential products that can disrupt hormone signaling and cause health problems in humans. Multigenerational cohorts, like the Michigan polybrominated biphenyl registry, are ideal for studying the effects of intergenerational exposure. Registry participants report hormone-related health problems, particularly in those exposed before puberty or those in the second generation exposed through placental transfer o ...[more]
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Project description:Endocrine-disrupting compounds are associated with altered epigenetic regulation and adverse health outcomes, although inconsistent results suggest that people have varied responses to the same exposure. Interpersonal variation in response to environmental exposures is not identified using standard, population-based methods. However, methods that capture an individual's response, such as analyzing stochastic epigenetic mutations (SEMs), may capture currently missed effects of environmental exposure. To test whether polybrominated biphenyl (PBB) was associated with SEMs, DNA methylation was measured using Illumina's MethylationEPIC array in PBB-exposed individuals, and SEMs were identified. Association was tested using a linear regression with robust sandwich variance estimators, controlling for age, sex, lipids, and cell types. The number of SEMs was variable (range: 119-18,309), and positively associated with age (p = 1.23e-17), but not with sex (p = 0.97). PBBs and SEMs were only positively associated in people who were older when they were exposed (p = 0.02 vs. p = 0.91). Many subjects had SEMs enriched in biological pathways, particularly in pathways involved with xenobiotic metabolism and endocrine function. Higher number of SEMs was also associated with higher age acceleration (intrinsic: p = 1.70e-3; extrinsic: p = 3.59e-11), indicating that SEMs may be associated with age-related health problems. Finding an association between environmental contaminants and higher SEMs may provide insight into individual differences in response to environmental contaminants, as well as into the biological mechanism behind SEM formation. Furthermore, these results suggest that people may be particularly vulnerable to epigenetic dysregulation from environmental exposures as they age.
| S-EPMC6691996 | biostudies-literature
Project description:BackgroundPolybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes.ObjectivesIn this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry.MethodsHRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB in utero or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB-153 separately for each generation and ΣPCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow.ResultsMean levels were 1.75 ng/mL [standard deviation (SD): 13.9] for PBB-153 and 1.04 ng/mL (SD: 0.788) for ΣPCB. Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) p<0.2], respectively. There were 2,861 features associated with ΣPCB (FDR p<0.2). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with ΣPCB in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with ΣPCB levels (level 1 evidence).ConclusionsOur results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that ΣPCB was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health. https://doi.org/10.1289/EHP12657.
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Project description:Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our environment. Individuals may or may not experience clinical health issues from being exposed to the increasing environmental pollution in daily life, but an issue of high concern is that also the non-exposed progeny may encounter consequences of these ancestral exposures. Progress in understanding epigenetic mechanisms opens new perspectives to estimate the risk of man-made EDCs. However, the field of epigenetic toxicology is new and its application in public health or in the understanding of disease etiology is almost non-existent, especially if it concerns future generations. In this review, we investigate the literature on transgenerational inheritance of diseases, published in the past 10 years. We question whether persistent epigenetic changes occur in the male germ line after exposure to synthesized EDCs. Our systematic search led to an inclusion of 43 articles, exploring the effects of commonly used synthetic EDCs, such as plasticizers (phthalates and bisphenol A), pesticides (dichlorodiphenyltrichloroethane, atrazine, vinclozin, methoxychlor), dioxins, and polycyclic aromatic hydrocarbons (PAHs, such as benzo(a)pyrene). Most studies found transgenerational epigenetic effects, often linked to puberty- or adult-onset diseases, such as testicular or prostate abnormalities, metabolic disorders, behavioral anomalies, and tumor development. The affected epigenetic mechanisms included changes in DNA methylation patterns, transcriptome, and expression of DNA methyltransferases. Studies involved experiments in animal models and none were based on human data. In the future, human studies are needed to confirm animal findings. If not transgenerational, at least intergenerational human studies and studies on EDC-induced epigenetic effects on germ cells could help to understand early processes of inheritance. Next, toxicity tests of new chemicals need a more comprehensive approach before they are introduced on the market. We further point to the relevance of epigenetic toxicity tests in regard to public health of the current population but also of future generations. Finally, this review sheds a light on how the interplay of genetics and epigenetics may explain the current knowledge gap on transgenerational inheritance.
| S-EPMC7218615 | biostudies-literature
Project description:Against the backdrop of towering ecological health implications of estrogen pollution and the inefficacies associated with cost-intensive treatment techniques, this study recorded the earliest attempt of developing an inexpensive bacterial laccase-based biocatalysts for biodegradation of EDCs (Endocrine disrupting compounds), particularly estrogens. First, a central composite design was used to investigate the interactive effects of pH (6.0-8.0), inoculum size (100-500 U/mL), and copper (Cu) (25-75 mg/L) on laccase activity and estrogen degradation respectively. Thereafter, biocatalysts was synthesized comprising laccase and glass beads or silver impregnated clay granules (SICG), which was further used to treat estrogen infused aquatic matrices under different reaction conditions. Maximum laccase activities and estrogen removal for the two tested laccases were 620 U/mL (85.8-92.9%) and 689.8 U/mL (86.8-94.6%) for Lysinibacillus sp. BP1 and Lysinibacillus sp. BP2, respectively, within 72 h, under conditions of optimal inoculum size and/or Cu concentration. Apart from a higher estrogen removal rate compared to free laccased, the biocatalysts were more resistant to temperature, pH and other environmental perturbations, and had enhanced storage ability and reusability. In comparison to clay, beads had a higher potential for recyclability and were more stable under certain experimental factors such as pH, reuse, and temperature, as well as storage conditions. Immobilized enzymes were able to remove 100% of E2, as well as over 90% of E1 and EE2, in 24 h, indicating that they could be scaled up to benchtop bioreactor levels.
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| S-EPMC9215202 | biostudies-literature
Project description:BackgroundBrominated flame retardants, including polybrominated biphenyls (PBB), are persistent compounds reported to affect sex hormones in animals; less is known about potential effects in humans. An industrial accident in 1973-1974 exposed Michigan residents to PBB through contaminated food. We examined whether this exposure to PBB had long-term effects on menstrual cycle function.MethodsIn 2004-2006, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications. Participants kept daily diaries and provided daily urine samples for up to 6 months. We assayed the urine samples for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). We fit linear mixed models among women aged 35-42 years to describe the relation between serum PBB levels and log-transformed, creatinine-adjusted daily endocrine levels among women who were premenarchal during the exposure incident in 1973-1974 (n = 70).ResultsWe observed that high (>3.0 parts per billion [ppb]) and medium (>1.0-3.0 ppb) PBB exposure were associated with lower E13G levels across the menstrual cycle and lower FSH levels during the follicular phase, compared with low PBB exposure (≤1.0 ppb). High PBB exposure was also associated with lower Pd3G levels across the cycle compared with low PBB exposure, whereas Pd3G levels were similar in women with medium and low PBB exposure.ConclusionOur results are consistent with a hypothesized effect of exposure to an exogenous estrogen agonist but the modest sample size of the study requires cautious interpretation.
| S-EPMC6679744 | biostudies-literature
Project description:PurposeEndocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB).MethodsCross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the β value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings.ResultsIn total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort.ConclusionWe found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).
| S-EPMC7056781 | biostudies-literature
Project description:Widespread polybrominated biphenyls (PBBs) contamination occurred in Michigan from 1973 to 1974, when PBBs were accidentally substituted for a nutritional supplement in livestock feed. People who lived in the state were exposed to PBBs via several routes including ingestion, inhalation and skin absorption. PBBs sequestered in lipid-rich matrices such as adipose tissue, are slowly eliminated after entering the human body, and can also be transferred from a mother to her offspring through the placenta and breastfeeding. Due to the long biological half-lives of PBBs, as well as concerns from the exposed community, biomonitoring measurements were conducted from 2012 to 2015. Because of their similar structures, serum PBBs, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) were all measured 40 years after the PBB contamination incident (N = 862). The serum PBB-153 levels among the original highly-exposed groups (i.e., chemical workers, the family of chemical workers, and individuals who lived on or received food from the contaminated farms) remains significantly higher than other Michigan residents. Several predictors such as sampling age, sex, and smoking status were significantly associated with the serum levels of some persistent organic pollutants (POPs). Higher average values and also wider ranges of serum POP levels were found in this study compared to the National Health and Nutrition Examination Survey (NHANES), with the most substantial difference in serum PBB-153. This was true for all groups of Michigan residents including those who were not part of the above-described highly-exposed groups. Moreover, the people born after the contamination incident began also have higher serum PBB-153 levels when compared with more recent NHANES data (2010-2014), which suggests potential intergenerational exposure and/or continued environmental exposure following the contamination period.
| S-EPMC7201813 | biostudies-literature