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

The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. In an effort to gain in- sight into the physiological role of the AHR and to develop models useful in risk assessment, gene targeting was used to inactivate the murine Ahr gene by homologous recombination. Ahr 2/2 mice are viable and fertile but show a spectrum of hepatic defects that indicate a role for the AHR in normal liver growth and development. The Ahr 2/2 phenotype is most severe between 0-3 weeks of age and involves slowed early growth and hepatic defects, including reduced liver weight, transient microvesicular fatty metamorphosis, prolonged extramedul- lary hematopoiesis, and portal hypercellularity with thicken- ing and fibrosis.

Characterization of a murine Ahr null allele: Involvement of the Ah receptor in hepatic growth and development (dioxiny2,3,7,8-tetrachlorodibenzo-p-dioxinygene targetingyliver)

Bisphenol A--sources, toxicity and biotransformation.

Drug metabolism and disposition : the biological fate of chemicals.

Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on r...

/pdf/bisphenol-a-and-reproductive-health-update-of-experimental-1cnofc6fnh.pdf

Bisphenol A and reproductive health: Update of experimental and human evidence, 2007-2013

Evidence for bisphenol A-induced female infertility: a review (2007–2016)

The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice.

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.

Di-n-butyl phthalate (DBP) is present in many consumer products, such as infant, beauty, and medical products. Several studies have shown that DBP causes reproductive toxicity in rodents, but no studies have evaluated its effects on ovarian follicles. Therefore, we used a follicle culture system to evaluate the effects of DBP on antral follicle growth, cell cycle and apoptosis gene expression, cell cycle staging, atresia, and 17bestradiol (E 2 ) production. Antral follicles were isolated from adult CD-1 mice and exposed to DBP at 1, 10, 100, and 1000 lg/ ml for 24 or 168 h. Follicles treated with vehicle or DBP at 1– 100 lg/ml grew over time, but DBP at 1000 lg/ml significantly suppressed follicle growth. Regardless of effect on follicle growth, DBP-treated follicles had decreased mRNA for cyclins D2, E1, A2, and B1 and increased p21. Levels of the proapoptotic genes Bax, Bad, and Bok were not altered by DBP treatment, but DBP 1000 lg/ml increased levels of Bid and decreased levels of the antiapoptotic gene Bcl2. DBP-treated follicles contained significantly more cells in G 1 phase, significantly less cells in S, and exhibited a trend for fewer cells in G 2 . Although DBP did not affect E 2 production and atresia at 24 h, follicles treated with DBP had reduced levels of E 2 at 96 h and underwent atresia at 168 h. These data suggest that DBP targets antral follicles and alters the expression of cell cycle and apoptosis factors, causes cell cycle arrest, decreases E 2 , and triggers atresia, depending on dose. 17b-estradiol, antral follicle, apoptosis, atresia, cell cycle, ovary, phthalate, toxicology

Ayelet Ziv-Gal

Papers

Evidence for bisphenol A-induced female infertility: a review (2007–2016)

The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice.

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice.

Di-n-Butyl Phthalate Disrupts the Expression of Genes Involved in Cell Cycle and Apoptotic Pathways in Mouse Ovarian Antral Follicles

Bisphenol A inhibits cultured mouse ovarian follicle growth partially via the aryl hydrocarbon receptor signaling pathway