Cellular calcium and redox regulation: the mediator of vertebrate environmental sex determination?

Abstract

Many reptiles and some fish determine offspring sex by environmental cues such as incubation temperature. The mechanism by which environmental signals are captured and transduced into specific sexual phenotypes has remained unexplained for over 50 years. Indeed, environmental sex determination (ESD) has been viewed as an intractable problem because sex determination is influenced by a myriad of genes that may be subject to environmental influence. Recent demonstrations of ancient, conserved epigenetic processes in the regulatory response to environmental cues suggest that the mechanisms of ESD have a previously unsuspected level of commonality, but the proximal sensor of temperature that ultimately gives rise to one sexual phenotype or the other remains unidentified. Here, we propose that in ESD species, environmental cues are sensed by the cell through highly conserved ancestral elements of calcium and redox (CaRe) status, then transduced to activate ubiquitous signal transduction pathways, or influence epigenetic processes, ultimately to drive the differential expression of sex genes. The early evolutionary origins of CaRe regulation, and its essential role in eukaryotic cell function, gives CaRe a propensity to be independently recruited for diverse roles as a 'cellular sensor' of environmental conditions. Our synthesis provides the first cohesive mechanistic model connecting environmental signals and sex determination pathways in vertebrates, providing direction and a framework for developing targeted experimentation.

Novel genetic sex markers reveal high frequency of sex reversal in wild populations of the agile frog (Rana dalmatina) associated with anthropogenic land use

“…Alternatively, but not mutually exclusively, sex reversals may result not only from random variation but also from stressful stimuli, as experiments with fishes showed that various forms of physiological stress can induce sex reversal, and "stress hormones" (activated by the hypothalamus–pituitary–interrenal glands axis) mediate this process (Castañeda Cortés et al., 2019; Fernandino et al., 2013). Furthermore, findings in reptiles suggest that environmental effects on sex determination may be mediated by cellular pathways of the calcium and redox regulation system, which is sensitive to various stressors including heat, hypoxia, glucose deprivation, and osmotic or oxidative stress (Castelli et al., 2020). Therefore, we tentatively speculate that a few of our laboratory‐raised animals experienced relatively high levels of physiological stress despite the generally favourable laboratory conditions, and this led to sex reversal.…”

“…Finally, we examined whether sex reversal was associated with fitness costs by comparing fitness‐related traits between sex‐reversed and normal individuals. We expected poorer performance among sex‐reversed animals in such traits, as physiological stressors may play a causal role in sex reversals (Castañeda Cortés, Arias Padilla, Langlois, Somoza, & Fernandino, 2019; Castelli, Whiteley, Georges, & Holleley, 2020; Fernandino, Hattori, Moreno Acosta, Strüssmann, & Somoza, 2013; Navara, 2018).…”

Effects of global warming on sex ratios in fishes

“…In reptiles with TSD, a calcium and redox (CaRe)‐mediated signal has recently been proposed as a “cellular sensor” that links environment factors ( e.g . temperature) to epigenetic processes (Castelli et al ., 2020), which is an interesting avenue of investigation for fishes.…”

Evolution of Sex Determination in Amniotes: Did Stress and Sequential Hermaphroditism Produce Environmental Determination?

“…Concerning KDM6B , there is another interesting aspect: its linkage to stress. [ 71,77 ] Various epigenetic mechanisms are controlled or at least altered by stress, probably through the activity of certain epigenetic modifiers. [ 78 ] It has been shown that under stress conditions the expression of KDM6B tends to increase.…”

“…[ 91 ] Reactive oxygen species (ROS) serve as important signaling molecules and linked changes in the redox state of the cell have several effects, among others an alteration of gene expression. [ 91,92 ] Castelli and colleagues [ 77 ] describe the possible role of ROS and Ca 2+ in sex determination. The mechanism of ESD could be an interplay of many factors on different levels.…”