5 Molecular Responses to Heat

Why Molecules Matter in Heat Stress

Heat stress affects the body not only at the surface but also deep within. At the cellular level, elevated heat can destabilize proteins, damage DNA, impair membranes, and initiate inflammatory responses. To mitigate damage and restore balance, cells activate protective pathways that are especially relevant during reproductive stages like menstruation and pregnancy, where hormonal changes increase thermal sensitivity (Chersich et al., 2020; Dervis et al., 2021).

Heat Shock Proteins (HSPs): Cellular Defense Systems

Heat shock proteins (HSPs) are among the most important molecular defenses activated in response to elevated temperatures. They serve as molecular chaperones, ensuring that proteins maintain their proper structure and function.

Under normal conditions, HSPs account for about 5–10% of total cellular protein. During heat stress, their expression increases sharply, particularly through activation of heat shock factor 1 (HSF1), a transcription factor that binds heat shock elements on DNA to initiate HSP gene transcription (Sawka et al., 2011).

Key HSP Families:

• HSP70: Rapidly induced by heat. It supports protein refolding, prevents aggregation, and regulates inflammation and apoptosis.

• HSP72: A stress-inducible form of HSP70. It is often used as a biomarker of acute thermal stress in reproductive and environmental physiology studies.

• HSP90: Supports folding and stabilization of signaling proteins, including hormone and growth factor receptors.

• Small HSPs (e.g., HSP27): Help stabilize the cytoskeleton and prevent apoptosis under heat and oxidative stress.

HSPs also interact with steroid hormone receptors and immune signals, making them especially relevant during ovulation, implantation, and pregnancy.

Oxidative Stress and Reactive Oxygen Species (ROS)

Heat exposure disrupts mitochondrial efficiency and increases metabolic rate, leading to excess production of reactive oxygen species (ROS). These unstable oxygen-derived molecules can cause:

• DNA damage through strand breaks and base modification

• Lipid peroxidation of membranes, compromising cell integrity

• Protein oxidation that impairs enzymatic function and signaling

To counteract this, cells activate endogenous antioxidant systems:

• Superoxide dismutase (SOD): Converts superoxide radicals into hydrogen peroxide.

• Catalase (CAT): Breaks down hydrogen peroxide into water and oxygen.

• Glutathione peroxidase (GPx): Neutralizes lipid peroxides using reduced glutathione.

When ROS production exceeds the buffering capacity of these systems, oxidative stress can lead to inflammation, apoptosis, and tissue injury. In reproductive contexts, this may contribute to placental dysfunction and complications such as preeclampsia or preterm birth (Hromadnikova et al., 2015).

Gasotransmitters: Gaseous Stress Signaling

Gasotransmitters are small, endogenously produced gases that modulate cellular responses to stress. The three most studied in heat physiology and reproduction are:

• Nitric Oxide (NO): Promotes vasodilation and increases blood flow to the skin. During heat stress, elevated NO supports thermoregulation and tissue oxygenation.

• Carbon Monoxide (CO): Produced in small quantities via heme oxygenase-1 activity. CO may regulate inflammation and oxidative balance.

• Hydrogen Sulfide (H₂S): Emerging evidence links H₂S to mitochondrial protection and antioxidant effects, although its role in pregnancy is not yet well defined.

These gasotransmitters interact with endocrine, vascular, and immune systems, and may play roles in maintaining placental blood flow under thermal stress.

Prostanoids: Lipid-Derived Inflammatory Mediators

Prostanoids are bioactive lipids derived from arachidonic acid via the cyclooxygenase (COX) pathway. They play central roles in inflammation, vascular tone, and reproductive processes.

Relevant Prostanoids:

• Prostaglandin E2 (PGE₂): Facilitates cervical ripening and helps initiate labor.

• Prostaglandin F2α (PGF₂α): Increases uterine contractility and is upregulated under thermal stress, potentially linking heat exposure to early labor onset (Wolfenson et al., 1993).

Heat-induced prostanoid production may explain associations between high ambient temperature and increased risk of preterm birth (Dadvand et al., 2011).

Stress Granules: Emergency Translational Control

When cells are exposed to acute heat stress, they conserve resources by halting non-essential protein synthesis and forming stress granules. These structures consist of untranslated mRNAs and associated proteins.

Roles of Stress Granules:

• Temporarily suppress protein synthesis

• Protect mRNA from degradation

• Facilitate survival during transient stress

Recent studies suggest that persistent stress granule formation in the uterus or placenta may impair implantation or contribute to early pregnancy loss, though this remains an area of active investigation (Smarr et al., 2016; Hromadnikova et al., 2015).

Summary

• Heat stress triggers coordinated molecular defenses that involve HSPs, antioxidant enzymes, gasotransmitters, and prostanoids.

• These systems are critical for maintaining cellular stability under environmental or metabolic heat load.

• In reproductive health, thermal stress responses are further shaped by fluctuating hormone levels and tissue-specific demands.

• Disruption of these pathways may underlie heat-related risks such as implantation failure, fetal growth restriction, or preterm birth.

References

Chersich, M. F., Pham, M. D., Areal, A., Haghighi, M. M., Manyuchi, A., Swift, C. P., … & Hajat, S. (2020). Associations between high temperatures in pregnancy and risk of preterm birth, low birth weight, and stillbirths: Systematic review and meta-analysis. BMJ, 371, m3811. https://doi.org/10.1136/bmj.m3811

Dadvand, P., Basagaña, X., Sartini, C., Figueras, F., Ballester, F., Medina-Ramón, M., … & Nieuwenhuijsen, M. J. (2011). Climate extremes and the length of gestation. Environmental Health Perspectives, 119(10), 1449–1453. https://doi.org/10.1289/ehp.1003241

Dervis, S., Casasola, W., & Jay, O. (2021). Heat loss responses at rest and during exercise in pregnancy: A scoping review. Journal of Thermal Biology, 99, 103011. https://doi.org/10.1016/j.jtherbio.2021.103011

Hromadnikova, I., Kotlabova, K., Ivankova, K., & Krofta, L. (2015). Assessment of placental and maternal stress responses in patients with pregnancy-related complications via monitoring of heat shock protein mRNA levels. Molecular Biology Reports, 42(3), 625–637. https://doi.org/10.1007/s11033-014-3808-z

Sawka, M. N., Leon, L. R., Montain, S. J., & Sonna, L. A. (2011). Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress. Comprehensive Physiology, 1(4), 1883–1928. https://doi.org/10.1002/cphy.c100082

Smarr, B. L., Zucker, I., & Kriegsfeld, L. J. (2016). Detection of successful and unsuccessful pregnancies in mice within hours of pairing through frequency analysis of high temporal resolution core body temperature data. PLOS ONE, 11(7), e0160127.

Wolfenson, D., Flamenbaum, I., & Berman, A. (1993). Secretion of PGF2α and oxytocin during hyperthermia in cyclic and pregnant heifers. Theriogenology, 39(5), 1129–1141. https://doi.org/10.1016/0093-691X(93)90012-T