Editorial: Frontiers in Endocrinology Endocrine Disruptors in Molecular and Structural Endocrinology

Julianne M. Hall ^*

• Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, United States

cellular, and tissue structure and composition, and induce genomic modifications. This topic conveys new insights into the role of EDCs in altering endocrine function at the molecular and structural levels and informs about new methods of screening for toxicological effects.EDCs have a pivotal role in altering metabolism, energy balance, appetite, and adiposity.Numerous epidemiological studies highlight a causal relationship between EDC exposure and obesity, and appropriately these agents are now referred to as 'environmental obesogens.' Bisphenol A (BPA), a persistent chemical in household, industrial, and medical products is an established obesogen, as levels detected in humans are associated with increased adiposity.While the manufacturing of BPA-free products has become more prevalent, the compounds that replace it, Bisphenol S (BPS) and Bisphenol F (BPF), and Bisphenol AF (BPAF), have endocrine disrupting activities. In this issue, Varghese and Hall highlight the current mechanistic and epidemiological data on BPA substitutes and their potential obesogenic properties. BPA substitutes have been detected in the majority of human urine samples worldwide, and elevated levels are significantly associated with obesity and other indices of metabolic disease.Using established cellular and animal models of adipogenesis, pro-obesogenic effects of BPS and BPF were identified, and these actions involved activation of the nuclear receptor peroxisome proliferator-activated receptor g (PPARg) and upregulation of PPARg-regulated adipogenic gene expression. It was also revealed that obesogenic effects of BPS are more pronounced than those observed for BPA during both prenatal and postnatal exposures. These observations raise the question whether public health measures should be invoked to regulate exposure to BPA substitutes as has been done for BPA.In addition to PPARg, several other nuclear receptors, including the structurally related PPARα, are involved in regulation of energy utilization. Whereas PPARg activation is associated with insulin sensitization and adipocyte differentiation, PPARα reduces triglyceride levels by enhancing fatty acid oxidation and is involved in regulation of energy homeostasis. Numerous EDCs are known to alter the activities of PPARa and PPARg. However, current international Organization for Economic Co-operation and Development (OECD) chemical regulatory testing methods lack screening protocols to detect agents with obesogenic activities. The development of such procedures would require identification of reference chemicals for validation and test controls. Ozcagli et al. compiled an expansive review and evaluation of chemicals that may be suitable for the development of PPARa and PPARg activation assays and white adipose tissue adipogenic assessments. The criteria of chemical selection for evaluation was based on possession of the necessary structural and physico-chemical properties that enable interaction with PPARs and ability to alter their transcriptional activities and subsequent metabolic actions.The authors identify 41 chemicals as a source list, including numerous EDCs such as BPA, phthalates, pesticides (DDT), as well as known PPARa and g agonists and antagonists. The work provides a significant contribution to the OECD guidelines, allowing for enhanced screening and detection of potential obesogenic activities of chemicals to inform regulatory measures.Another aspect of EDC action is the 'window of exposure,' referring to how the timing of EDC exposure during development may impact health outcomes. Traditionally, many of the riskassessment studies of EDCs on female reproductive toxicity have been conducted in rodent models using a 28-day exposure model. However, in order to optimize toxicological test methods, it is important to determine which developmental periods are most vulnerable to EDC exposure in order to design studies using animals at an age that optimizes sensitivity. In this topic, Boberg et al. compare the effects of EDCs on female endocrine-dependent reproductive hallmarks in rodents during pre-pubertal exposure compared to that of adults. The authors hypothesize that early exposure may allow for more sensitive assessment of reproductive toxicity due to the ability to include pubertal onset as an additional endpoint. In analysis of 2 established EDCs, the estrogen diethylstilbestrol and the steroid synthesis inhibitor ketoconazole, reproductive-related outcomes such as estrous cyclicity, and ovarian follicular histology are comparable regardless of life-stage. The pre-pubertal cohort was sensitive to acceleration in female pubertal reproductive hallmarks and the adult group displayed a more pronounced effect on non-reproductive organs such as liver and adrenal. The authors suggest that 28-day in vivo toxicity studies with pre-pubertal animals is optimal for detection of reproductive system outcomes for agents with estrogenic activities, whereas non-reproductive organ function is optimally assessed in adult animals.Non-alcoholic fatty liver disease (NAFLD) is the most widespread liver disease in humans and it's prevalence is attributed in part to EDC exposure. In NAFLD, hepatocytes accumulate fat, with the presence of steatosis in >5% of hepatocytes being the criteria for diagnosis. Current toxicological assessment of steatosis via OECD protocols uses rodent models of EDC exposure with endpoints of in vivo liver histochemistry and liver function tests. In this topic, Kubickova and Jacobs propose that the development of alternative in vitro hepatocyte assays for chemical screening would be more time and cost effective as well as provide mechanistic insights.Previous research observations allowed the authors to identify a list of suitable chemicals and controls for implementing and optimizing human steatosis in vitro testing methods in hepatocytes. A number of the selected chemicals are established EDCs, and several have known effects on PPARa and g activities. The authors conclude that in vitro steatosis assays can be validated with these chemicals, and thus, endorse this convenient assay for screening of chemicals for human hepatotoxicity to inform regulatory measures going forward.In conclusion, given the difficulty in assessing endpoints of exposure, it is beneficial to have new research into the molecular and structural effect of EDC exposures during various stages of life.The development of more sensitive EDC screening methods and toxicological assessments offers a valuable opportunity on prevention and/or intervention for the numerous global health problems related to EDC exposure, in particular obesity.