The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

https://apps.who.int/iris/bitstream/10665/78102/1/WHO_HSE_PHE_IHE_2013.1_eng.pdf

State of the Science of Endocrine Disrupting Chemicals - 2012

Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

/pdf/endocrine-disruptors-from-endocrine-to-metabolic-disruption-212fm2fkju.pdf

Endocrine Disruptors: From Endocrine to Metabolic Disruption

It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child ...

https://www.physiology.org/doi/pdf/10.1152/physrev.00017.2015

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility

Restrictions on the use of polybrominated diphenyl ethers (PBDEs) have resulted in the increased use of alternate flame retardant chemicals to meet flammability standards. However, it has been difficult to determine which chemical formulations are currently being used in high volumes to meet flammability standards since the use of flame retardant formulations in consumer products is not transparent (i.e., not provided to customers). To investigate chemicals being used as replacements for PentaBDE in polyurethane foam, we analyzed foam samples from 26 different pieces of furniture purchased in the United States primarily between 2003 and 2009. Samples included foam from couches, chairs, mattress pads, pillows, and, in one case, foam from a sound-proofing system of a laboratory-grade dust sieve, and were analyzed using gas chromatography mass spectrometry. Fifteen of the foam samples contained the flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCPP; 1−5% by weight), four samples contained tris(1-ch...

Detection of organophosphate flame retardants in furniture foam and U.S. house dust.

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants, and the general population is exposed through products such as upholstery, building materials, insulation, electronic equipment, and contaminated food. PBDEs are added to polymers without being chemically bound and can leach into the environment, where they settle with air particles and sludge. They are persistent, and some—BDE-47, BDE-99, and BDE-153—can accumulate in lipid-rich tissues (Agency for Toxic Substances and Disease Registry 2004; Sjodin et al. 2003).

Concentrations of PBDE in human European breast milk samples are generally low compared with those in the United States, and considered to be well below the estimated lowest observed adverse effect level (LOAEL) of 1 mg/kg/day (Darnerud et al. 2001). Two technical mixtures, penta- and octa-mixtures of PBDEs, have been banned from use in Europe since 2003 (Darnerud et al. 2001), and Swedish studies indicated a decrease in breast milk levels since the middle of the 1990s (Meironyte et al.1999; Sjodin et al. 2003). However, annual production rates of some PBDEs are still considerable in some areas (Alaee et al. 2006; Betts 2002; Law et al. 2006). Animal studies show that some PBDEs exhibit endocrine-disrupting activity, which has been studied predominantly for thyroid hormone transport and metabolism (Legler and Brouwer 2003), but data on adverse effects on reproductive outcome after gestational exposure are also emerging (Lilienthal et al. 2006).

The prevalence of cryptorchidism in newborn boys appears to have increased in some areas, such as Great Britain and Denmark, over the past decades, and its current prevalence is considerably higher in Denmark than in Finland (Anonymous 1986; Boisen et al. 2004). Although the reason for this is as yet unknown, the rapid increase in prevalence suggests that environmental factors are involved (Sharpe 2006; Skakkebaek et al. 2001). Adverse effects of fetal exposure to environmental chemicals on testicular descent and hormonal function may be detectable during the short physiologic activation of the pituitary–gonadal axis at approximately 3 months of age (Andersson et al. 1998; Main et al. 2000, 2006b; Suomi et al. 2006).

In this study we aimed to evaluate the association between exposure to 14 PBDEs (BDEs 28, 47, 66, 71, 75, 77, 85, 99, 100,119, 138, 153, 154, 183) in newborn boys and the position and function of the testes.

Flame retardants in placenta and breast milk and cryptorchidism in newborn boys.

In animal studies, exposure to dioxins has been associated with disrupted development of the male reproductive system, including testicular maldescent. Some polychlorinated biphenyls (PCBs) have also dioxin-like effects. In addition, one previous case-control study has reported an association between congenital cryptorchidism and colostrum PCB levels. We performed a case-control study to evaluate whether congenital cryptorchidism in boys was associated with increased levels of dioxins or PCBs in placenta reflecting foetal exposure. In addition, associations between placenta levels of these chemicals and reproductive hormone levels in boys at 3 months were studied. Placentas were collected in a Danish-Finnish joint prospective cohort study on cryptorchidism (1997-2001). The boys were examined for cryptorchidism at birth and at 3 months. Altogether, 280 placentas [112 Finnish (56 cases, 56 controls) and 168 Danish (39 cases, 129 controls)] were analysed for 17 toxic polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and 37 PCBs (including 12 dioxin-like PCBs). Infant serum samples taken at 3 months were analysed for reproductive hormones. No significant differences between cases and controls were observed in either country in dioxin WHO-TEq levels (median 9.78 vs. 8.47 pg/g fat, respectively, in Finland, and 11.75 vs. 10.88 pg/g fat in Denmark) or PCB WHO-TEq levels (median 2.12 vs. 2.15 pg/g fat in Finland, 2.34 vs. 2.10 pg/g fat in Denmark) or total-TEq levels (median 11.66 vs. 10.58 pg/g fat in Finland, 13.94 vs. 13.00 pg/g fat in Denmark). Placenta WHO-TEq levels of dioxins were not associated with infant reproductive hormone levels at 3 months. In Finland, PCB WHO-TEq levels in placenta associated positively with infant LH levels. WHO-TEq levels of dioxins and PCBs and total-TEq levels were higher in Danish than Finnish samples. In conclusion, no association between placenta levels of dioxins or PCBs and congenital cryptorchidism was found. Significant country differences in chemical levels were observed.

Erno Sundqvist

Papers

Flame retardants in placenta and breast milk and cryptorchidism in newborn boys.

Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta.