Challenges and opportunities at the intersection of toxicology and gasocrinology

PREPRINT DRAFT Gasocrinology is an emerging discipline dedicated to the study of gasocrine system in organisms and its environment. Since gases are a major environmental factor and many gas-synthesizing and gas-receptor proteins are metalloproteins, gasocrinology intersects with toxicology. This is due to the dose-dependent effects of gaseous and metallic pollutants and the resulting disorders or disturbances. I present the fragmented yet robust foundations of gasocrinology by drawing parallels to endocrinology and endocrine-disrupting chemicals like Bisphenol A. I also emphasize the urgent need for policies that address gasocrine-disrupting factors in our rapidly changing environment and discuss the significant challenges and opportunities at the intersection of toxicology and gasocrinology. The brief timeline of bisphenol A research and related policies Experimental research in toxicology has been instrumental in understanding the role and mechanisms of environmental and industrial pollutants. It has also been necessary for developing effective policies that regulate the use and disposal of toxic metals and chemicals. The challenges faced with tackling the bisphenol A (BPA) toxic issue was not a straightforward bench-to-policy route.1 The commercial use of BPA increased dramatically in the 1950s, but research on its endocrine-disrupting toxic effects had little impact until the early 2000s. In the European Union, the European Food Safety Authority's first risk assessment report on BPA in 2006 initiated a multi-phase process to prohibit BPA. This process targeted infant feeding bottles in 2011, plastic bottles in 2018, and thermal paper receipts in 2020. The complete ban on BPA for food contact materials was effected only in 2024. Without well-controlled experimental research on the toxicity of BPA, nonylphenol, nonylphenol ethoxylates, and other mutagenic agents, countries or groups of countries will not be able to develop policies regarding these chemicals. The challenges to toxicology and endocrinology In the case of the toxic effects of BPA, it must be noted that numerous organisms already had well-established endocrine systems that had evolved over millions of years. However, careful experimental research on the effects of BPA and other endocrine-disruptors on the endocrine systems of animal models, as well as clinical research on humans, was required. Additionally, appropriate and well-accepted terms such as pollutant, hormone, endocrine signaling, endocrine system, and endocrinology were necessary.2 Thus, prior to the scientific consensus on policies against BPA, foundational studies on estrogen signaling and the endocrine system had already been accomplished, and the field of endocrinology was well-established in numerous countries. This was also essential for the cross-national ratification and acceptance of such policies. However, in the early years of toxicology and molecular endocrinology research, some pioneering researchers faced challenges convincing their peers and the public. Pioneering toxicologists faced public backlash and skepticism regarding their techniques, and researchers studying major receptors for endocrine signaling molecules had difficulty convincing others of non-traditional receptor mechanisms.3 Nevertheless, both toxicology and endocrinology have emerged as disciplines and fields that now provide a strong foundation for education, policies and even in legal trials. Gasocrine signaling and gasoreceptors This article introduces an emerging discipline: gasocrinology. Gasocrinology is the study of gasocrine system in organisms and its environment, and the resulting disorders or disturbances. First, however, I will explain the foundational terms: "gasoreceptor", "gasocrine", and "gasocrine signaling". By 2026, it will be widely accepted that gases such as nitric oxide (NO) are not only pollutants or toxic gases, but also gaseous signaling molecules that can be sensed via hemoprotein-based receptors and post-translational modifications (e.g., NO-based S-nitrosylation). Similarly, ethylene is also a well-known gaseous signaling molecule that can be sensed by endoplasmic reticulum-localized copper-binding histidine kinase-based receptors in plants. Mosquitoes have specialized carbon dioxide (CO₂) chemoreceptors in their antennae.4 To denote all receptors for gaseous molecules, I proposed the term "gasoreceptor".5 Gasoreceptors are largely metalloproteins, but they can also be metal-independent and localized in various regions of a cell. Unlike the term "endocrine signaling," which denotes all hormone-based signaling, "gasotransmitter signaling" only refers to signaling due to gases such as nitric oxide, carbon monoxide, and hydrogen sulfide, not ethylene, carbon dioxide, or oxygen. Ethylene in plants, plant-fungus interactions, carbon dioxide in mammals, and host-mosquito interactions, as well as oxygen in plants and photosynthetic organism-human interactions, were not considered gasotransmitter signaling. With the exception of ethylene, carbon dioxide and oxygen were considered host interactions or a broader term, "environmental signaling". The term "gasocrine" denotes any process that can synthesize or separate gases. Since the environment is one of the major factors that determine development and disease, the term "gasocrine" was coined to encompass physiological, environmental, and industrial gas-producing events. Examples of gasocrine processes at a physiological level include the synthesis of nitric oxide, carbon monoxide, ethylene, and oxygen by nitric oxide synthase, heme oxygenase, and photosystem complex II, respectively. Examples of gasocrine processes at an environmental level include the UV-, lightning-, rice field-, and heat-based creation or release of ozone, nitric oxide, methane, and water vapor, respectively. Industrial gasocrine processes include the release of gases such as ammonia, carbon dioxide, and other volatile organic compounds. The term "gasocrine signaling" was coined to bring together researchers studying diverse gaseous molecules that trigger gasoreceptor-based signaling events. Therefore, gasocrine signaling encompasses not only signaling mediated by gases from physiological processes, but also from environmental and industrial sources, as exemplified by the examples of nitric oxide, ethylene, and carbon dioxide. Just as the term "endocrine signaling" provided toxicologists with a framework for addressing the issue of BPA, "gasocrine signaling" can provide a framework for addressing various factors that can interfere with gasocrine signaling in humans and other organisms as well as entire ecosystems amidst a rapidly changing environment. Foundations of gasocrinology As with the early years of toxicology and endocrinology research, despite our extensive knowledge of the role of gaseous and volatile signaling molecules, gasocrine signaling research is still in its infancy. Nevertheless, the foundation of gasocrinology is well-established. This is due to the extensive, rigorous, and reproducible research on nitric oxide and ethylene as signaling molecules. There is a strong scientific consensus on the identity of the receptors and the major signaling pathways for both nitric oxide and ethylene. In mice, nitric oxide is sensed via hemoprotein-based gasoreceptors, such as soluble guanylate cyclase and nuclear receptor subfamily 1 group D member 2 (NR1D2 or REV-ERBβ), as well as via S-nitrosylation events. In Arabidopsis thaliana, ethylene is sensed via copper ion-based gasoreceptor kinases. Based on these two robust and reproducible examples of gasocrine signaling alone, the foundation of the emerging discipline of gasocrinology exists but in a fragmented state. In addition to fundamental research, pharmaceutical drugs and agricultural practices based on the nitric oxide pathway and ethylene, respectively, have contributed greatly to the pharmaceutical and agricultural markets. In disease diagnostics, gases such as nitric oxide and hydrogen are measured in humans with lung inflammation or lactose intolerance, respectively. Methane is even considered a negative control in breath tests for lactose intolerance. While gases such as ethylene is widely used to ripen bananas locally in various countries that import them. Thus, based on these diagnostic and food industry practices, it could be said that the foundations of not only the discipline but also the field of gasocrinology exist, despite its fragmented state. This development raises the question of how toxicology, as a well-established field, can benefit and complement the emerging field of gasocrinology, and vice versa. The challenge lies in our limited knowledge of the identity, structure, and role of all gasoreceptors, gas-sensing proteins, and related signaling pathways. From a regulatory and environmental perspective, I foresee three major intersections between toxicology and gasocrinology. If toxicology is about determining accurate chemical doses or ranges, then we urgently need to identify appropriate ranges for: First, all gases, gas-releasing, and gas-scavenging processes and compounds due to technological innovations, industrial practices, and environmental factors. Second, for all gasocrine-disrupting molecules, elements and factors that can interfere with gas synthesis or sensing and lead to a lack of homeostasis in gasocrine signaling in an organism and entire ecosystems. Based on past experiences, we know that some medical, technological, and industrial innovations can be promising in the short term. However, issues due to biological and environmental persistence can create long-term challenges due to their toxic potential. A bottleneck to toxicology-gasocrinology collaborative efforts: A lack of consensus of human oxygen gasoreceptors To reach a scientific consensus on the toxic effect of the endocrine-disrupting chemical BPA, knowledge of estrogen recepto