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Vitellogenesis

Vitellogenesis is the biological process by which yolk precursors, primarily the glycolipophosphoprotein vitellogenin, are synthesized extraovarially and sequestered into developing oocytes to provide nutrients for embryonic development in oviparous animals.^[1] This phase of oogenesis involves the massive accumulation of proteins, lipids, and other macromolecules in the oocyte cytoplasm, enabling egg maturation and supporting post-fertilization growth until hatching or birth.^[1] Essential for reproduction in diverse taxa including vertebrates, insects, and some invertebrates, vitellogenesis is tightly regulated by hormones and nutritional cues to ensure synchronized egg production.^[2] In vertebrates such as fish, amphibians, reptiles, and birds, vitellogenesis typically occurs in the liver, where estrogens stimulate the transcription and synthesis of vitellogenin, a large precursor protein (often 200–600 kDa) that is secreted into the bloodstream.^[1] The vitellogenin is then transported to the ovaries and endocytosed by growing oocytes via specific receptors, such as the vitellogenin receptor (VgR), a member of the low-density lipoprotein receptor (LDLR) superfamily.^[1] Inside the oocyte, vitellogenin is cleaved into yolk platelets, including phosvitin (phosphoprotein for mineral storage) and lipovitellin (lipid carrier), which form the primary nutrient reserves.^[1] Gonadotropins from the pituitary initiate the process by promoting ovarian estrogen production, while progesterone may inhibit it to coordinate with final oocyte maturation.^[1] In insects, vitellogenesis is analogous but adapted to their physiology, with vitellogenin synthesized mainly in the fat body (a multifunctional organ akin to the liver) under the control of juvenile hormone (JH) and 20-hydroxyecdysone (20E).^[2] JH, produced by the corpora allata, induces vitellogenin gene expression and promotes follicular epithelium patency, allowing hemolymph-borne vitellogenin (typically 150–200 kDa subunits) to access oocytes for receptor-mediated uptake via VgR.^[2] Unlike vertebrates, insect vitellogenin synthesis can also occur in ovarian follicle cells or nurse cells in certain species, and nutritional signals like insulin and the target of rapamycin (TOR) pathway integrate with hormonal regulation to modulate the process based on resource availability.^[2] This hormonal interplay varies by insect order; for instance, JH dominates in hemimetabolous insects like locusts, while 20E plays a larger role in holometabolous groups such as flies and moths.^[3] Beyond vertebrates and insects, vitellogenesis exhibits evolutionary conservation in nutrient trafficking mechanisms, as seen in basal metazoans like sea anemones, where yolk accumulation supports non-feeding larvae.^[4] Disruptions in vitellogenesis, such as endocrine disruption from environmental estrogens, can impair reproduction across species, highlighting its sensitivity to xenobiotics.^[1] Overall, this process underscores the adaptive strategies for provisioning eggs in egg-laying organisms, with vitellogenin serving dual roles in nutrition and, in some cases, immunity.^[2]

Overview

Definition and Process

Vitellogenesis is the process by which yolk precursors are synthesized, transported, and accumulated within developing oocytes to supply essential nutrients for embryonic development in oviparous animals. This nutrient-provisioning mechanism is a distinct sub-process within the broader framework of oogenesis, the overall formation and maturation of female gametes, focusing specifically on the provisioning of yolk proteins, lipids, and other macromolecules rather than nuclear or cytoplasmic maturation events.^[5] The accumulated yolk serves as the primary energy and biosynthetic reserve for the embryo until it achieves nutritional independence, ensuring reproductive success in species that lay eggs.^[6] While typically extraovarian, with yolk precursors synthesized in maternal tissues away from the ovary, vitellogenesis can be intraovarian in some invertebrates such as nematodes.^[7] In many oviparous vertebrates, such as fish, the process is often divided into three stages: primary, secondary, and tertiary vitellogenesis. In the primary phase, oocyte growth is initiated with the formation of cortical alveoli and early uptake of minor yolk components, marking the transition from previtellogenic growth to active nutrient accumulation.^[8] The secondary phase involves the bulk uptake of yolk proteins, primarily vitellogenin, through receptor-mediated endocytosis at the oocyte surface, leading to the coalescence of internalized vesicles into yolk granules within the ooplasm.^[9] These granules form via clathrin-coated pits that facilitate the sequestration and processing of yolk precursors into storage forms. Finally, the tertiary phase encompasses final oocyte maturation, where yolk deposition completes and the oocyte prepares for ovulation, often triggered by hormonal cues.^[10] Vitellogenesis represents an ancient and evolutionarily conserved process across metazoans, originating early in animal phylogeny to enable nutrient trafficking from maternal tissues to oocytes via maternal transport mechanisms.^[11] This conservation underscores its fundamental role in reproductive strategy, with yolk accumulation mechanisms traceable to basal metazoan lineages such as cnidarians, highlighting adaptations that have persisted for over 600 million years to support embryonic viability in diverse taxa.^[12]

Biological Importance

Vitellogenesis plays a pivotal role in reproduction among oviparous species by enabling the accumulation of essential nutrients in the egg yolk, which supports embryonic development independent of maternal resources after fertilization. The primary yolk precursor, vitellogenin, a large lipoglycophosphoprotein synthesized extraovarially in maternal tissues, such as the liver in vertebrates or the fat body in insects, delivers proteins, lipids (including phospholipids and polyunsaturated fatty acids), vitamins, minerals, phosphorus, and calcium to the oocyte via receptor-mediated endocytosis.^[13]^[1]^[14] These components are cleaved into yolk proteins such as lipovitellin and phosvitin, providing amino acids and energy reserves that sustain the embryo through early cleavage stages until the mid-blastula transition, when zygotic transcription initiates and external nutrient uptake becomes feasible. This process ensures offspring viability in nutrient-scarce environments post-oviposition.^[13]^[1]^[14] Evolutionarily, vitellogenesis confers significant advantages by enhancing fecundity and survival rates in oviparous animals, allowing for the storage of substantial nutrient reserves to support prolonged embryonic development without parental care. In birds, the yolk formed during vitellogenesis serves as the nearly exclusive source of lipids, proteins, vitamins, and minerals, fueling the extended incubation period typical of avian reproduction and contributing to high offspring survival in diverse ecological niches. Similarly, in fish, vitellogenesis provides critical yolk nutrients for egg and larval stages, enabling adaptation to variable aquatic environments where embryonic development can span weeks. This nutrient provisioning mechanism, conserved across vertebrates and invertebrates, underscores vitellogenin's ancient origins as a key innovation in metazoan reproductive strategy.^[15]^[16]^[17] The efficiency of vitellogenesis also exerts ecological influence on population dynamics in oviparous species, as yolk deposition directly affects egg size and quality, which in turn correlate with larval survival and recruitment rates. Larger eggs resulting from robust vitellogenic processes often yield stronger hatchlings with higher resistance to environmental stressors, thereby stabilizing populations in species-dependent on external spawning sites, such as many fish and amphibians. Disruptions to vitellogenesis, whether from nutritional deficits or pollutants, can reduce fecundity and skew age structures, amplifying vulnerability in fluctuating habitats.^[18]^[19] In mammals, the vestigial remnants of vitellogenesis highlight its ancestral importance, with the three vitellogenin-encoding genes progressively inactivated and lost during evolution—VIT3 around 170 million years ago, VIT1 around 140–50 million years ago, and VIT2 around 60–90 million years ago—coinciding with the rise of placentation and lactation as alternative nutrient transfer systems. This shift eliminated reliance on yolk provisions, as placental mammals instead utilize direct maternal-embryonic exchange and post-hatching milk for sustenance, marking a key divergence from oviparous lineages.^[20]

Molecular Mechanisms

Vitellogenin Synthesis and Structure

Vitellogenin (Vtg) is a large lipophosphoglycoprotein that serves as the primary precursor to yolk proteins in oviparous animals, synthesized predominantly in the liver of vertebrates and the fat body of invertebrates.^[21]^[2] In vertebrates, such as birds and amphibians, Vtg production occurs in hepatocytes under estrogen stimulation, while in insects like mosquitoes, the fat body acts as the analogous site, releasing Vtg into the hemolymph for transport to developing oocytes.^[21]^[22] The molecule typically has molecular weights ranging from 180 to over 600 kDa, depending on the species and whether considering the full precursor or subunits, reflecting its complex composition rich in lipids, phosphates, and carbohydrates.^[23]^[24]^[25] The synthesis of Vtg is tightly regulated at the transcriptional level, primarily through estrogen-dependent activation in vertebrates. In species like chickens and Xenopus, the Vtg gene promoter contains estrogen response elements (EREs), palindromic DNA sequences that bind estrogen receptors to initiate transcription upon hormone binding.^[26]^[27] This mechanism was first elucidated in the 1970s, when studies demonstrated Vtg as an estrogen-inducible protein in frog and avian livers, marking a key discovery in hormone-regulated gene expression.^[28]^[29] Multiple Vtg isoforms exist, particularly in fish, where genes such as VtgAa and VtgAb encode distinct variants that contribute differently to yolk formation, reflecting evolutionary diversification of the Vtg gene family.^[15]^[30] Sequence conservation across species underscores the fundamental role of Vtg in reproduction, with homologous domains preserved from amphibians to teleosts.^[15] Recent cryo-electron microscopy (cryo-EM) structures, such as that of native honey bee vitellogenin resolved in 2024, have revealed its multi-domain assembly, including a conserved N-terminal domain and lipid-binding regions, highlighting taxa-specific variations in pleiotropy.^[31] Structurally, Vtg is a multi-domain protein comprising a heavy chain (lipovitellin, ~110–150 kDa), a highly phosphorylated phosvitin domain (~20–30 kDa), a polyserine linker, and a C-terminal light chain (beta-component, ~30–40 kDa).^[15]^[32] The lipovitellin domain forms a beta-sheet shell that binds lipids, facilitating nutrient storage, while phosvitin, one of the most phosphorylated proteins known (up to 10% phosphate by weight), sequesters minerals like iron and calcium.^[33]^[15] Post-translational modifications, including N-linked glycosylation and serine/threonine phosphorylation, occur during biosynthesis in the endoplasmic reticulum and Golgi, enhancing Vtg's solubility, stability, and transport efficiency.^[34]^[25] These modifications are essential for Vtg's function as a nutrient reservoir, with glycosylation aiding protein folding and phosphorylation enabling metal ion binding.^[34]^[35]

Yolk Deposition and Processing

Vitellogenin (Vtg), synthesized in extraovarian tissues such as the liver in vertebrates or fat body in insects, circulates in the bloodstream or hemolymph before being transported to developing oocytes.^[36] In insects, Vtg passes through patency channels in the follicular epithelium to reach the oocyte surface for uptake, while in vertebrates like birds and fish, it is taken up via receptor-mediated endocytosis. This transport ensures high concentrations of Vtg are available for rapid yolk accumulation during vitellogenesis.^[36]^[37] Upon arrival, Vtg binds specifically to vitellogenin receptors (VtgR) on the oocyte membrane, which belong to the low-density lipoprotein receptor (LDLR) superfamily.^[38] These receptors, such as the yolkless (yl) protein in Drosophila melanogaster or homologs in fish like rainbow trout, recognize a receptor-binding domain on Vtg, initiating uptake.^[38]^[36] Binding triggers receptor-mediated endocytosis through clathrin-coated pit formation at the oocyte cortex.^[39] The Vtg-VtgR complex invaginates into coated vesicles, which fuse with early endosomes; acidification of the endosomal lumen (via ATP-dependent proton pumps) dissociates Vtg from VtgR, allowing the receptor to recycle to the plasma membrane while Vtg is directed to multivesicular bodies and yolk granules.^[39] This process assembles yolk granules, where Vtg accumulates as crystalline vitellin in insects or unstructured precursors in vertebrates.^[36] Inside the oocyte, internalized Vtg undergoes proteolytic processing to form functional yolk proteins.^[40] Primarily mediated by lysosomal aspartic proteases such as cathepsin D in fish and birds, Vtg is cleaved at specific sites into major components: lipovitellin (a lipid-rich dimer providing phospholipids and neutral lipids), phosvitin (a phosphoserine-rich peptide for mineral storage), and smaller β-component and C-terminal fragments that remain cytosolic.^[40] In some species like killifish, cathepsin B contributes under acidic conditions (pH 5–6) within yolk granules, ensuring controlled degradation and nutrient packaging. This pH-dependent cleavage protects yolk integrity until embryogenesis, with lipovitellin and phosvitin crystallizing or aggregating into storage forms.^[40] The efficiency of Vtg sequestration directly influences oocyte growth and final size, as higher uptake rates correlate with larger yolk reserves essential for embryonic development.^[41] A basic kinetic model describes the uptake rate as proportional to circulating Vtg concentration, receptor density on the oocyte surface, and an endocytic rate constant:

\text{Rate} = [\text{Vtg}] \times \text{Receptor density} \times k_e

where k_e represents the endocytic constant.^[41] This model highlights how variations in these factors, observed in species like rainbow trout, modulate vitellogenic oocyte expansion without saturation at physiological concentrations.^[41]

Regulation

Hormonal Control

In vertebrates, vitellogenesis is primarily induced by estrogen, particularly 17β-estradiol (E₂), which acts as the key endocrine signal to trigger the transcription of vitellogenin (Vtg) genes in the liver.^[42] E₂ binds to nuclear estrogen receptors (ERα and ERβ), inducing a conformational change that promotes receptor dimerization and translocation to the nucleus.^[43] The dimerized ER complex then binds to specific estrogen response elements (EREs) in the promoter regions of Vtg genes, recruiting co-activators such as SRC-1 and CBP/p300 to facilitate chromatin remodeling and initiate transcription.^[43] This pathway ensures synchronized Vtg synthesis during the reproductive cycle, with ERα often mediating stronger transcriptional activation in hepatic cells.^[42] Feedback mechanisms involving progesterone help regulate the timing and duration of vitellogenesis, often counteracting estrogen effects to prevent overproduction of Vtg.^[44] In fish, for instance, progesterone inhibits estrogen-induced Vtg synthesis at the post-transcriptional level, ensuring vitellogenesis aligns with oocyte maturation stages.^[44] Seminal studies in the 1960s on amphibians, such as Xenopus laevis, demonstrated that estrogen administration to males induces hepatic Vtg production and its selective uptake by ovaries, confirming E₂'s essential role.^[45] In fish species like tilapia, vitellogenesis is arrested without estrogen surges, as E₂ is required to elevate circulating Vtg levels for yolk deposition.^[46] In invertebrates, particularly insects, vitellogenesis is regulated by parallels to vertebrate systems through ecdysteroids (e.g., 20-hydroxyecdysone, 20E) and juvenile hormone (JH), which activate the fat body for Vtg synthesis.^[47] JH, acting via the methoprene-tolerant (Met) receptor, promotes fat body competency by inducing polyploidy and upregulating genes like Kr-h1, preparing cells for Vtg production.^[47] Meanwhile, 20E binds to the ecdysone receptor (EcR)/ultraspiracle (USP) complex, directly stimulating Vtg gene expression and oocyte maturation, as seen in species like Aedes aegypti and Locusta migratoria.^[47] These hormones coordinate to synchronize vitellogenesis with environmental cues, mirroring estrogen's inductive role in vertebrates.^[47]

Environmental and Genetic Factors

Environmental factors such as photoperiod and temperature play crucial roles in timing vitellogenesis, particularly in species with seasonal reproductive cycles. In temperate fish like the Atlantic salmon (Salmo salar), increasing day length in spring triggers the onset of vitellogenesis by synchronizing gonadal maturation with optimal environmental conditions, while shorter photoperiods in autumn induce regression.^[48] Similarly, temperature modulates the rate of vitellogenic progression; for instance, in the killifish (Fundulus heteroclitus), warmer temperatures increase the vitellogenin response to estrogens, accelerating aspects of yolk accumulation, whereas cooler conditions delay it to align with spawning seasons.^[49] These cues ensure reproductive success by preventing mistimed egg production in suboptimal habitats.^[50] Nutritional status also influences vitellogenin (Vtg) production through insulin signaling pathways, linking energy availability to reproductive investment. In insects such as the German cockroach (Blattella germanica), nutrient-rich diets activate insulin receptors in the fat body, promoting juvenile hormone synthesis and subsequent Vtg gene expression for oocyte provisioning.^[51] Deficient nutrition, conversely, suppresses these pathways, reducing Vtg levels and oocyte quality.^[51] Genetic factors, including mutations and epigenetic modifications, directly impact vitellogenesis efficiency and fertility. Knockout models of Vtg genes, such as vtg1 and vtg3 in zebrafish, result in severely impaired yolk deposition and embryonic lethality, demonstrating Vtg's essential role in oocyte maturation.^[52] Similarly, mutations in the vitellogenin receptor (e.g., in the diamondback moth Plutella xylostella) disrupt Vtg uptake into oocytes, leading to reproductive deficiency, reduced fertility, and underdeveloped gonads.^[53] Epigenetic regulation via DNA methylation fine-tunes Vtg expression; in zebrafish (Danio rerio), hypomethylation of the vtg1 promoter enhances transcription in response to estrogenic cues, while hypermethylation silences it during non-reproductive phases.^[54] In birds like the European starling (Sturnus vulgaris), epigenetic mechanisms may play a potential role in enabling seasonal reproductive transitions of liver yolk-precursor production.^[55] Gene-environment interactions highlight how pollutants disrupt vitellogenesis through xenoestrogens, mimicking or antagonizing natural signals. Environmental xenoestrogens, such as bisphenol A from industrial effluents, induce aberrant Vtg synthesis in male fish like the fathead minnow (Pimephales promelas), altering hepatic gene expression and causing reproductive impairment via estrogen receptor activation.^[56] This interplay is evident in field studies where sewage treatment plant effluents elevate plasma Vtg in wild roach (Rutilus rutilus), linking pollution to skewed sex ratios and reduced fecundity through epigenetic and transcriptional modifications.^[57] Such disruptions exemplify how anthropogenic chemicals interfere with genetic programs tuned to natural cues. Studies from the 2000s revealed links between clock genes like Per and Cry and vitellogenic cycles via circadian regulation of reproductive timing. Similarly, Cry modulates photoperiodic responses in insects, integrating light signals to gate vitellogenic progression and prevent off-cycle reproduction.^[58] These findings illustrate how core clock components couple environmental rhythms to genetic control of oogenesis.

Comparative Aspects

In Vertebrates

In vertebrates, vitellogenesis exhibits class-specific adaptations that support diverse reproductive strategies, particularly in oviparous species where yolk accumulation is essential for embryonic nutrition. In teleost fish, which represent the majority of oviparous vertebrates, the process is characterized by the expression of multiple vitellogenin (Vtg) genes, often including paralogues such as VtgAa, VtgAb, VtgC, and VtgE in acanthomorph species, allowing for the production of diverse yolk protein variants tailored to embryonic needs.^[59] These genes enable the synthesis of yolk precursors in the liver under estrogen stimulation, with uptake by oocytes via receptor-mediated endocytosis, resulting in yolk granules that constitute the primary nutrient reserve.^[15] In teleosts, vitellogenesis typically follows seasonal cycles synchronized with environmental cues like temperature and photoperiod in temperate species, whereas continuous or multiple spawning cycles occur in tropical fishes, facilitating year-round reproduction.^[60] For pelagic eggs common in many marine teleosts, high yolk content—often accounting for 80-90% of the mature oocyte volume—provides buoyancy and energy for free-floating larvae, in contrast to the reduced or absent vitellogenesis in viviparous vertebrates where maternal nutrient transfer occurs via placental-like structures.^[46]^[61] Amphibians and reptiles, as oviparous or ovoviviparous ectotherms, rely on estrogen-driven hepatic synthesis of vitellogenin to build substantial yolk reserves adapted for terrestrial or semi-terrestrial development. In these groups, estradiol from developing follicles induces liver transcription of Vtg genes, leading to the secretion of large, multidomain Vtg polypeptides (typically 150-600 kDa) that are cleaved into phosvitin, lipovitellin, and other yolk components upon oocyte sequestration.^[62] This results in lecithotrophic eggs with large yolk masses—often exceeding 50% of egg weight—to sustain embryogenesis without external feeding, a critical adaptation for species laying eggs on land where desiccation and limited resources pose challenges.^[63] For example, in some reptiles like certain turtles, vitellogenesis supports the formation of calcareous-shelled eggs with dense yolk for prolonged incubation periods.^[64] In birds, vitellogenesis is a highly synchronized, rapid process aligned with clutch formation, enabling efficient production of multiple eggs in a short breeding window. Hepatic synthesis of vitellogenin and very low-density lipoprotein (VLDL) peaks dramatically under estrogen influence, with yolk deposition occurring at rates up to 50-100 mg per hour in species like chickens, filling hierarchical follicles over 7-10 days before ovulation.^[65] This rapid accumulation supports the energy demands of precocial or altricial chicks, with yolk providing lipids, proteins, and vitamins for post-hatching growth. Additionally, while the core yolk forms pre-ovulation in the ovary, oviductal contributions include the deposition of the vitelline membrane proteins and initial chalaziferous layers around the yolk upon its entry into the infundibulum, stabilizing the yolk structure during albumen addition and shell formation.^[66]

In Invertebrates

In invertebrates, vitellogenesis exhibits remarkable diversity across phyla, reflecting adaptations to varied reproductive strategies and lacking the centralized liver-like synthesis seen in vertebrates. Yolk precursors are often produced extrasomatically and transported to oocytes, with hormonal and environmental cues playing pivotal roles in regulation. Unlike vertebrate systems dominated by estrogen, invertebrate vitellogenesis frequently involves ecdysteroids, juvenile hormones, and local synthesis mechanisms.^[2] In insects, vitellogenin (Vg), the primary yolk precursor, is predominantly synthesized in the fat body, a multifunctional organ analogous to the vertebrate liver and adipose tissue. The synthesized Vg is secreted into the hemolymph for transport to the ovaries, where it is selectively endocytosed by developing oocytes via receptor-mediated mechanisms. This process is tightly regulated by two key hormones: juvenile hormone (JH), which initiates Vg gene transcription through the Methoprene-tolerant (Met) receptor pathway in species like the red flour beetle Tribolium castaneum, and 20-hydroxyecdysone (20E), an ecdysteroid that synergizes with JH to promote ovarian maturation in holometabolous insects such as mosquitoes (Aedes aegypti). For instance, JH application restores Vg expression in JH-deficient mutants, underscoring its essential role.^[2]^[2]^[2] Crustaceans employ a dual strategy for yolk formation, combining heterosynthetic vitellogenesis—where Vg is produced in the hepatopancreas and transported via hemolymph to oocytes—and autosynthetic processes, in which yolk components are synthesized directly within ovarian cells like oocytes and follicle cells. This bimodal approach supports the production of large, nutrient-rich eggs typical of many decapod species. Environmental salinity significantly influences these dynamics; in the orange mud crab Scylla olivacea, intermediate salinity of 20 ppt optimizes ovarian maturation, yielding the highest proportion of stage IV ovaries (80% after 60 days) and largest oocyte diameters compared to 10 or 30 ppt, though 17β-estradiol levels remain unaffected across treatments. Elevated salinity (e.g., 12–18 ppt) can accelerate ovarian development even without mating, highlighting osmoregulation's role in reproductive physiology.^[67]^[67]^[68] Mollusks and echinoderms feature simplified vitellogenin homologs adapted to their reproductive modes, often with contributions from nurse cells or accessory structures. In mollusks like the Sydney rock oyster Saccostrea glomerata, a Vtg homolog (sgVtg) is expressed in the ovary and upregulated by estrogenic compounds such as 17β-estradiol, which activates transcription via estrogen-responsive elements in the promoter, facilitating yolk deposition as a potential biomarker for endocrine disruption.^[69]^[69] Some species utilize follicular contributions for yolk provisioning, where yolk proteins are synthesized locally rather than solely via hemolymph transport. In echinoderms, vitellogenesis varies by class; sea stars (Patiriella regularis) rely on Vtg homologs (PrVtg1 and PrVtg2) synthesized in follicle cells and pyloric caeca, which are cleaved into yolk polypeptides upon oocyte uptake, while echinoids and holothuroids predominantly use a transferrin-like major yolk protein (MYP). Nurse cells in asteroids, such as those in Asterias rubens, contribute to vitellogenesis by supplying nutrients through the haemal system, potentially via direct cytoplasmic transfer or fluid-mediated transport.^[70] A notable example of evolutionary divergence occurs in Drosophila melanogaster, where egg provisioning relies on yolk proteins (Yp1, Yp2, Yp3) rather than a true vitellogenin, enabling nutrient accumulation without the large precursor complexes of other insects or vertebrates. These Yps are synthesized in both the fat body and ovarian follicle cells, with uptake into oocytes occurring via the yolkless receptor, and their genes have evolved independently, reflecting adaptations to meristic egg production and distinct from vertebrate Vtg pathways. This system supports rapid oogenesis, with Yps providing essential lipids and amino acids for embryogenesis.^[71]^[71]^[72]

Applications and Research

As a Biomarker

Vitellogenin (Vtg) induction in male or juvenile fish serves as a sensitive biomarker for exposure to xenoestrogens, which are environmental endocrine disruptors such as those derived from pesticides, plastics, and sewage effluents.^[73] In these non-reproductive individuals, where Vtg is normally undetectable, elevated plasma levels indicate estrogenic contamination, allowing detection of low-level pollutants that mimic natural estrogens and disrupt reproductive physiology.^[74] This biomarker is particularly valuable in ecotoxicology because it provides an early warning of ecosystem-wide impacts before overt population declines occur.^[46] The measurement of Vtg typically involves enzyme-linked immunosorbent assay (ELISA) to quantify plasma concentrations, offering high specificity and sensitivity for species like rainbow trout and fathead minnow.^[75] These assays have been standardized in OECD Test Guidelines, such as TG 230 (21-day Fish Assay) and TG 229 (Fish Short Term Reproduction Assay), with validation efforts beginning in the late 1990s to support regulatory screening of endocrine disruptors.^[76] For instance, ELISA kits calibrated against species-specific standards enable detection limits as low as 1-10 ng/mL, facilitating reproducible assessments in field and laboratory settings.^[77] In practice, Vtg monitoring is applied to assess water quality in aquatic systems affected by industrial and municipal effluents. Studies on UK rivers, such as the Thames and Aire, have used caged male trout to detect estrogenic activity downstream of sewage treatment works, revealing Vtg induction correlating with effluent discharge volumes.^[78] Similarly, research in Catalonian rivers exposed to combined sewage and industrial inputs demonstrated dose-dependent Vtg elevation in wild carp, linking it to nonylphenol and alkylphenol ethoxylates from textile and paper industries.^[79] These applications have informed environmental management, including effluent treatment upgrades to reduce xenoestrogen loads.^[80] The utility of Vtg as a biomarker was established in the early 1990s through UK field studies, where researchers first linked elevated Vtg in male rainbow trout to estrogenic compounds in sewage effluents, marking a pivotal advancement in identifying anthropogenic pollution sources.^[73] Recent advances include the use of vitellogenin in fish skin mucus as a non-invasive, sensitive biomarker for xenoestrogen exposure, enabling rapid field assessments without plasma sampling.^[81]

Pathological Implications

Disruptions to vitellogenesis are implicated in reproductive disorders involving impaired oocyte maturation in oviparous species. For example, in medaka fish models of endocrine disorders resembling polycystic ovary syndrome (PCOS), altered gonadotropin signaling leads to abnormal yolk protein deposition and reduced fertility.^[82] Endocrine-disrupting chemicals (EDCs) pose significant pathological risks by inducing abnormal vitellogenin (Vtg) expression and yolk formation in wildlife. Exposure to EDCs, such as those in polluted aquatic environments, triggers ectopic Vtg synthesis in male fish, leading to abnormal yolk accumulation and gonadal abnormalities that compromise reproductive health. In female wildlife, EDCs disrupt normal vitellogenesis, causing incomplete yolk deposition and reduced egg viability, with effects observed across species like amphibians and reptiles.^[74] Toxicological agents further exacerbate vitellogenic impairments. Heavy metals like cadmium and aluminum inhibit Vtg synthesis and mRNA expression in the liver, while also blocking Vtg uptake by oocytes, thereby arresting yolk deposition and reducing fecundity in exposed organisms.^[83] Chemotherapy treatments, including alkylating agents and taxanes, induce ovarian toxicity by promoting follicular atresia and disrupting steroid biosynthesis essential for vitellogenesis, often leading to diminished oocyte quality and infertility in affected species.^[84] In aquaculture, vitellogenic arrest due to poor nutrition represents a major pathological concern, resulting in ovarian atresia and economic losses. Studies on species like Atlantic salmon and eel have shown that inadequate dietary lipids and proteins halt vitellogenic oocyte development, reducing spawning success and farm productivity in affected populations. Therapeutically, modulating Vtg pathways offers promise for fertility interventions; for instance, gonadotropin-releasing hormone analogues (GnRHa) administered during vitellogenesis enhance yolk accumulation and reproductive performance in fish models, suggesting potential applications in treating infertility across oviparous species.^[85]

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Synthesis of vitellogenin in cultures of male and female frog liver ...
Sustained synthesis of vitellogenin requires continuous exposure to estradiol. A nonestrogenic steroid, dexamethasone, does not induce vitellogenin synthesis ...Missing: paper | Show results with:paper
[25]
Induction of vitellogenin synthesis by estrogen in avian liver - PubMed
We have investigated the estrogen-mediated induction of vitellogenin synthesis in rooster liver. We compared the concentrations of vitellogenin messenger ...Missing: history 1970s
[26]
Genome-Wide Identification of Vitellogenin Gene Family and ...
Jan 16, 2024 · Most fish possess a tripartite Vtg system (VtgAa, VtgAb, and VtgC) in which all three forms of Vtg make a different contribution to the yolk.
[27]
Vitellogenin-Derived Yolk Proteins of White Perch, Morone americana
In chickens and Xenopus, vitellogenin gives rise to two major yolk proteins, lipovitellin and phosvitin [1, 4, 5]. Additional proteins derived from vitellogenin ...
[28]
VTG1 - Vitellogenin-1 - Gallus gallus (Chicken) | UniProtKB | UniProt
May 1, 1997 · Phosvitin, an egg yolk storage protein, is one of the most highly phosphorylated (10%) proteins in nature. Cathepsin D is responsible for ...
[29]
Biosynthesis of the Vitellogenins - Journal of Biological Chemistry
The stages of vitellogenin biosynthesis may be ordered as follows: polypeptide synthesis + glycosylation + phos- phorylation -+ secretion. The presence of only ...
[30]
Deconstructing honeybee vitellogenin: novel 40 kDa fragment ...
Feb 15, 2011 · We show that both protein units are N glycosylated and phosphorylated. Focusing on the novel 40 kDa fragment, we present a homology model based ...
[31]
https://www.nature.com/articles/s41467-024-58575-y
[32]
https://academic.oup.com/biolreprod/article/67/2/655/2683765
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Regulation of the Vitellogenin Receptor during Drosophila ...
Oct 13, 2017 · The transition to the vitellogenic stages is marked by the accumulation of yolk via clathrin-coated vesicles. After this transition, yolk ...
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https://www.jbc.org/article/S0021-9258%2818%2934858-0/pdf
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https://journals.biologists.com/jeb/article/214/4/582/10690/Deconstructing-honeybee-vitellogenin-novel-40-kDa
[36]
Multihormonal Control of Vitellogenesis in Lower Vertebrates
Aug 6, 2025 · ... Estrogens are the major endocrine hormones that stimulate Vtg biosynthesis in the liver 810 of non-mammalian oviparous vertebrates, therefore ...
[37]
Estrogen receptor signaling mechanisms - PMC - NIH
Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling ...
[38]
Modulation of Vitellogenin II Gene by Estradiol and Progesterone in ...
Interestingly, progesterone, and progestins counteracts estrogen-induced vitellogenesis in fish, reptiles, and birds (Callard et al., 1990; Gupta and Kanungo, ...
[39]
Studies on amphibian yolk: VIII. The estrogen-induced hepatic ...
The estrogen-induced hepatic synthesis of a serum lipophosphoprotein and its selective uptake by the ovary and transformation into yolk platelet proteins in ...
[40]
Vitellogenesis and choriogenesis in fishes | Fisheries Science
Jan 23, 2016 · In general, Vtg in oviparous vertebrates is a lipoglycophosphoprotein and serves as a major precursor of egg yolk proteins stored as essential ...Vitellogenesis And... · Vitellogenesis In Fish · Multiplicity Of Fish...<|separator|>
[41]
Regulatory Mechanisms of Vitellogenesis in Insects - Frontiers
Vitellogenesis is prerequisite to insect egg production and embryonic development after oviposition. During insect vitellogenesis, the yolk protein ...
[42]
The Role of Manipulating Photoperiod and Temperature in Oocyte ...
Dec 7, 2020 · Photoperiod controls gametogenesis via imposing seasonality on life cycle, while temperature is more related to the metabolism of the ...
[43]
Impact of photoperiod and temperature on melatonin, growth ...
Photoperiod and temperature, as environmental factors, can affect gonadal development and physiological reproductive functions in fish [[1], [2], [3]], ...
[44]
Fish reproduction in a warming world: vulnerable points in hormone ...
Feb 5, 2024 · Gametogenesis in fishes is influenced by environmental conditions, including photoperiod, lunar cycle, tides, water flow rate and temperature, ...
[45]
Insulin receptor-mediated nutritional signalling regulates juvenile ...
InR-mediated nutritional signalling is necessary for correct growth and moulting and activates JH and vitellogenin production.
[46]
Insulin signaling mediates previtellogenic development and ...
Jul 5, 2019 · Insulin signaling mediates previtellogenic development and enhances juvenile hormone-mediated vitellogenesis in a lepidopteran insect, Maruca ...
[47]
Genome editing reveals reproductive and developmental ... - bioRxiv
Oct 29, 2018 · For both vtg1-KO and vtg3-KO, the introduced mutation altered the ... mutations in the targeted vtg genes. For this purpose, embryos ...
[48]
CRISPR/Cas9-Mediated Vitellogenin Receptor Knockout Leads to ...
Interestingly, the DGXR motif in the AoVg amino acid sequence was mutated to that of DGKS. The mutation of the conserved motif also occurred in Plutella ...
[49]
Changes in CpG Methylation of the Vitellogenin 1 Promoter in Adult ...
Interestingly, DNA methylation changes were observed at 4 days. Decreases in the overall methylation of the vtg1 promoter in exposed males resulted in ...Missing: modifications | Show results with:modifications
[50]
A potential role for epigenetic mechanisms enabling appropriate ...
Oct 21, 2025 · We hypothesized that changes in DNA methylation in the promoter for VTG2 in the liver may be one mechanism ensuring appropriately timed seasonal ...
[51]
Vitellogenesis as a biomarker for estrogenic contamination of ... - NIH
We have found that effluent from sewage treatment works contains a chemical, or mixture of chemicals, that induces vitellogenin synthesis in male fish.
[52]
Long-term exposure of xenoestrogens with environmental relevant ...
Long-term exposure of xenoestrogens with environmental relevant concentrations disrupted spermatogenesis of zebrafish through altering sex hormone balance.
[53]
Photoperiod regulates growth of male accessory glands through ...
These data indicate that circadian factors Clock, Cycle and Cry2 are responsible for photoperiod measurement, whereas Met and its partner protein Taiman ...
[54]
Integration of photoperiodic and temperature cues by the circadian ...
Aug 16, 2023 · For instance, CRY was replaced by a light-insensitive CRY (mammalian CRY ... In this case, per would not be a fundamental gene for photoperiodism ...
[55]
[PDF] Multiple vitellogenins and product yolk proteins in - HAL
May 27, 2020 · The presence of multiple forms of Vtg is widespread in higher (acanthomorph) teleosts, which generally possess two complete Vtg paralogues ...
[56]
2. REPRODUCTIVE CYCLES AND ENVIRONMENTAL CUES
A majority of teleost fishes are seasonal breeders, while a few breed continuously. Among the seasonal breeders, there is wide variation in the time of the year ...
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Mother-to-embryo vitellogenin transport in a viviparous teleost ... - NIH
S1A). Expression of the vtg genes in the liver was not decreased in pregnant females, despite the cessation of vitellogenesis (Fig. 1C).
[58]
Roles of Estrogens in the Healthy and Diseased Oviparous ...
Estrogens and thyroid hormones direct the initiation and progression of vitellogenesis and metamorphosis in frogs raising the question of a potential interplay ...
[59]
Yolkless Egg and the Evolution of Eutherian Viviparity
VTG, the principal constituent of yolk in vertebrates, is made in the liver in response to ovarian estrogens. VTG is a very large (150–600 kDa), complex ...
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Vitellogenin precursors in the liver of the lizard Podarcis sicula
Aug 5, 2025 · In reptiles, as in the other oviparous vertebrates, vitellogenin (VTG) synthesis is stimulated in the liver by ovarian estrogens.Missing: driven | Show results with:driven
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Vitellogenesis and Yolk Proteins, Birds | Request PDF - ResearchGate
Egg formation in well-studied poultry includes rapid yolk deposition (RYD), which completes the formation of the ovum, then ovulation and uptake of the ovum by ...
[62]
Domestic goose egg yolk vitelline membrane structure and ... - NIH
May 28, 2025 · The vitelline membrane (VM) of an avian egg is a multilayered protein structure that surrounds the yolk and plays important roles in bird reproduction.
[63]
Role of Oxytocin/Vasopressin-Like Peptide and Its Receptor in ...
Mar 26, 2020 · In oviparous animals, the vitellogenesis, divided into autosynthesis and heterosynthesis according to the yolk origins, is an important process ...
[64]
Does water salinity affect the level of 17β-estradiol and ovarian ...
This study determined the effect of water salinity on the level of 17β-estradiol and the ovarian physiology (histological changes) of Scylla olivacea in ...
[65]
Mechanistic insights into induction of vitellogenin gene expression ...
Marine molluscs, such as oysters, respond to estrogenic compounds with the induction of the egg yolk protein precursor, vitellogenin (Vtg), availing a biomarker ...
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A comparative study of vitellogenesis in Echinodermata - PubMed
The provision of yolk precursor proteins to the oviparous egg is crucial for normal embryo development. In Echinodermata, a transferrin-like yolk component ...Missing: nurse | Show results with:nurse
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Yolk Synthesis in Ovarian Follicles ofDrosophila - PubMed
When labelled follicles were cut at the nurse cell/oocyte border the three yolk proteins (YP1, YP2, YP3) were found only in posterior fragments containing ...Missing: no true
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Yp1 - Vitellogenin-1 - Drosophila melanogaster (Fruit fly) | UniProtKB
Vitellogenin is the major yolk protein of eggs where it is used as a food source during embryogenesis. Along with Yp2 and Yp3, and their receptor yl ...Missing: vitellogenesis nurse no true
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Estrogenic Effects of Effluents from Sewage Treatment Works
Sep 23, 2006 · Thus, the presence of vitellogenin in the plasma is indicative of estrogenic stimulation of the liver. an initial study, at a sewage-treatment ...
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Assessment of Feminization of Male Fish in English Rivers by the ...
The induction of a female specific protein, vitellogenin, in male fish exposed to sewage effluents demonstrated that fish had been exposed to estrogenic ...
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Test No. 230: 21-day Fish Assay - OECD
This Test Guideline describes an in vivo screening assay for certain endocrine active substances where sexually mature male and spawning female fish are held ...
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[PDF] Test No. 229: Fish Short Term Reproduction Assay (EN) - OECD
Oct 2, 2012 · Each ELISA plate used for VTG assays should include the following quality control samples: at least 6 calibration standards covering the range ...
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[PDF] TECO®Multi Species Vitellogenin ELISA | DiaPharma
Therefore VTG determination is one of the core endpoints in screening and testing for endocrine disrupting chemicals standardized in the OECD Guidelines for the ...
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Estrogenic activity in five United Kingdom rivers detected by ...
Oct 26, 2009 · It was recently demonstrated that most, if not all, effluents of sewage-treatment works (STWs) in the United Kingdom are estrogenic to fish.
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Integration of chemical analysis and biological effects on feral carp
The objectives were to determine the levels of EDCs in two Catalonian rivers receiving effluents from several STPs, to study the effects of STP effluents on the ...Endocrine Disruptors In... · Experimental · Results And Discussion<|control11|><|separator|>
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The extent of oestrogenic contamination in the UK estuarine and ...
In the first instance, this was detected by measuring the biomarker vitellogenin (VTG) in the blood plasma of male fish. VTG is the protein precursor of ...