A limited number of studies have suggested that some of these compounds may have ecological roles as allelochemicals, specifically including compounds that may inhibit competing species. These allelochemicals may also play a role in defense against potential predators and grazers, particularly aquatic invertebrates and their larvae [89].

In the endless fight between predator and prey, the latter does not play the role of passive victim. Beyond direct defense, characterized by a series of mechanisms to avoid being killed, prey have also developed indirect long-term defenses, a sort of preventive war against predators: in fact, by producing antiproliferative compounds many organisms are able to regulate the population dynamics of their marine predators, in particular, interfering with some crucial processes of their reproductive cycle, such as: maturation, fertilisation, and early embryo development.

Cyanobacteria are Gram-negative bacteria capable of producing a wide range of potent toxins as secondary metabolites, i. e. the cyanotoxins, whose action is still rather unknown [90,91]. On the contrary, other bacteria produce widely known marine neurotoxins; tetrodotoxin (TTX) is one of these; it is a voltage-gated sodium current blocker and a major toxic component contained in pufferfish of the Family Tetraodontidae. Animals containing TTX are not limited to certain species of puffer. A wide variety of marine and terrestrial animals are now known to have TTX, including, but not limited to, pufferfish, salamanders, frogs, horseshoe crabs, xanthid crabs, blue-ringed octopus, and starfish [92]. In the pufferfish, TTX is concentrated in the ovary and liver, but other organs including skin, intestine, and muscle contain TTX in some species of puffer. The reason for such a wide distribution is that TTX is not produced by the puffer fish, but is produced by certain species of bacteria including Vibrio sp. and comes to be in the animals through the food chain [93–96]. As demonstrated in the ascidian Ciona intestinalis, inhibition of sodium currents at the time of fertilisation current generation gave rise to a high percentage of anomalous embryos, in which the spatial orientation at the 8/16-cell stage is lost [14].

The difficulty in identifying the real producer is clear also for another drug, maitotoxin (MTX), which is an extremely potent toxin obtained from the marine dinoflagellate Gambierdiscus toxicus and involved in ciguatera poisoning. MTX was previously detected in the viscera of maito (a small herbivorous fish, Ctenochaetus striatus, called “maito” in Tahiti), but further studies [97,98] found a good correlation between dinoflagellates in the gut contents and the toxicity of the viscera. The dinoflagellate turned out to represent both a new genus and new species, and it was named Gambierdiscus toxicus [99]. This toxin is a powerful activator of changes in the intracellular calcium concentration and it induces a potassium release from the oocytes simultaneously with a sodium entry into unfertilised eggs, although experimental evidence suggests that MTX has no ionophoretic activity per se [100–103]. MTX inhibits sea urchin egg fertilisation in a dose-dependent manner but, maybe, ion transport perturbations are probably not the direct cause of fertilisation inhibition which could be related to a modification of the plasma membrane of the female gametes by this hydrophilic toxin [101]. A different effect has been found in mouse, where the results suggest that putative channels activated by MTX may be involved in the calcium influx required for mouse sperm acrosome reaction [103].

Many marine drugs represent a useful tool for studying cellular processes: one of the most famous is okadaic acid (OA): the latter acts as a potent inhibitor of protein phosphatases [104] and has turned out to be a valuable tool for the study of phosphorylation based processes of cellular signaling [105]. The protein serine/threonine phosphatases are a unique family of enzymes that catalyze the specific dephosphorylation of phosphoserine or phosphothreonine residues in many cell types. The potent activity of OA is remarkably conserved across phyla: this toxin inhibits phosphatase activity in mammals, yeast, and higher plants [106]. OA was initially isolated and characterized from the sponges Halichondria okadai and H. melanodocia [107]. However, it was later shown to be produced by dinoflagellates of the genera Prorocentrum and Dinophysis [104,108–110] and is now considered to be of dietary origin rather than a “true” sponge metabolite in terms of its biosynthetic origin. The function of OA in sponges is not well understood. Studies by Wiens et al. [111] have provided evidence for at least two putative roles of OA within the sponge Suberites domuncula. At low concentrations, OA triggers a MAP kinase p38-regulated defense system against bacteria. At elevated concentrations, OA acts as an apoptogen and promotes expression of the proapoptotic caspase gene with a simultaneous down-regulation of the expression of the anti-apoptotic Bcl-2 homolog gene. In subsequent studies of S. domuncula, Schroder et al. [112] suggested that OA may serve as a defense molecule by inducing apoptosis in symbiotic or parasitic annelids. [113]. As protein phosphatase specific inhibitor, OA has previously been used to stimulate chromatin condensation and premature germinal vesicle breakdown in invertebrate and vertebrate oocytes [114–123].

Like TTX, brevetoxins are also voltage-gated sodium channel inhibitors, but these marine toxins are produced by the dinoflagellate Karenia brevis. Kimm-Brinson and Ramsdell [124] suggested that the larvae of medaka fish (Oryzias latipes), but not the eggs, are susceptible to Karenia brevis. In contrast, an earlier study with the sea urchin (Lytechinus variegatus) reported that lysates of K. brevis administered to eggs did induce developmental abnormalities [125]. This study found that sperm motility, egg fertilisation, and development through the blastula stage were unaffected; however, mortality and developmental abnormalities occurred in about 50% in embryos at gastrula stage and 80% in embryos at pluteus stage. The reason for the difference between the study with the red drum eggs and the sea urchin eggs may result from the use of K. brevis cells and lysates. The persistence of red tides from the late autumn until early spring has suggested that the spawning of some marine species may be subject to the adverse effect of red tide toxins. Steidinger et al. [126] also emphasized the need for attention to the effects of red tide outbreaks on migratory species, as many species seek estuaries for breeding and nursery grounds. Based on studies with other classes of fat-soluble contaminants, somatic stores of toxin in fish are transferred during oogenesis and lead to larval toxicity [127].

K. brevis red tides have been associated with mortality events of many aquatic animals including finfish, sea turtles, and sea birds during their adult stages [126,128–135]. These animals have been known to bioaccumulate substantial body burdens of contaminants at times, and in certain cases transfer toxicity to offspring during oogenesis. Given the similarity of developmental processes found between higher and lower vertebrates, teratogenic effects of brevetoxins have the potential to occur among different phylogenetic classes [124].

The last 2 decades have seen much controversy concerning the negative impacts that consumption of diatoms may have upon copepods. Despite some contrasting data [136], diatom-derived aldehydes have been shown to interfere with reproductive mechanism in copepods [137–139] and polychaetes and echinoderms [140,141]. In the ascidian Ciona intestinalis, 2-trans-4-trans-decadienal (DD) and 2-trans-4-cis-7-cis-decatrienal (DT) inhibit the fertilisation current (Figure 1) which is generated in oocyte upon interaction with the spermatozoon. In particular, DD may have a dual effect on reproductive processes, influencing primary fertilisation events such as gating of fertilisation channels and secondary processes such as actin reorganization which is responsible for the segregation of cell lineages. In the same study, DD altered actin filaments and mitocondrial migration after contraction, leading to a disturbance in cleavage formation (Figure 2A). However, DD also induced larval teratogeny at low concentrations (Figure 2B), possibly due to actin perturbation [142].

Domoic acid (DA) is produced by red alga Chondria armata and planktonic diatoms of the genus Pseudo-nitzschia, [143]. Over the last decade, reproductive failure in California sea lions has been increasingly associated with harmful algal blooms, most notably DA produced by Pseudo-nitzschia spp. [144–146]. The food web plays the primary role in the transmission of DA from Pseudo-nitzschia blooms to the California sea lion [144,147]. Common vectors are pelagic planktivorous fish, which accumulate DA-containing diatoms in their gut exceeding toxin concentrations of one part per thousand, exceptionally high levels for a natural toxin [147,148]. Additionally, Pseudo-nitzschia, which form long chains of cells, will sink to the ocean floor where the DA effectively infiltrates the benthic food web and provides an additional source of vectoring [149]. At the level of the receptor in the brain, DA binds to kainate subtypes of ionotropic glutamate receptors to induce excitotoxicity by release of glutamate and activation of N-methyl-d-aspartate ionotropic glutamate receptors [150]. DA crosses the placenta, readily enters the neonatal brain and is retained in the amniotic fluid [151]. The early fetal brain is electrically silent, but expresses levels of ionotropic glutamate receptors that guide the migration of neurons to the appropriate brain regions and facilitate in the formation correct synapses. DA, which is normally cleared rapidly by renal filtration in adult animals, is more toxic to animals in utero because of a longer residence time in the fetal-maternal unit and greater access to the fetal brain [143].

The effect of DA in invertebrates is also known. As a result of the DA exposure, larval growth of king scallop, Pecten maximus, measured in terms of shell length and the appearance of the eye-spot, and larval survival were significantly compromised. The negative effect of DA exposure suggests that this toxin could possibly influence natural recruitment in P. maximus, and it may be necessary to protect hatchery-cultured scallop larvae from DA during toxic Pseudo-nitzschia blooms [152].

Embryo development is blocked by several drugs isolated from algae: caulerpenyne does not affect the microfilament-dependent processes of fertilisation and cytokinesis and allows the beginning of mitosis, but prevents normal DNA replication and results in metaphase-like arrest of sea urchin embryos [153]; stypoldione uncouples cytokinesis from mitosis at the lowest effective concentrations and, although it can disrupt microtubules at relatively higher concentrations, it inhibits cell division at the lowest effective concentrations by a selective action on cytokinesis through a mechanism that does not appear to involve disassembly of microtubules [154].

Sometimes it happens that the same compound may have several contrasting applications: for example, a sulfono glycolipid (S-ACT-1) isolated from Gelidiella acerosa, a Sri Lankan marine red alga, has a potent human sperm motility stimulating activity in vitro and has the potential to be developed into a sperm stimulant [155], but crude extracts from the same species showed elevated post-implantation loss. Since post-coital contraceptive activity of another red alga, Gracilaria corticata, was due to enhanced pre-implantation loss, marine red algae could represent a useful source to be harvested for potential post-coital contraceptive drugs [156].

Williamson et al. [157] compared the effects of chemical cues from host algae on different life history stages of the sea urchin Holopneustes purpurascens. In sublittoral habitats, H. purpurascens occurred primarily on two algal hosts: red alga (Delisea pulchra) and kelp (Ecklonia radiata). Sea urchin larvae rapidly metamorphosed in the presence of D. pulchra, but metamorphosis was delayed or absent in the presence of E. radiata. D. pulchra produces a polar chemical inducer of metamorphosis not found in E. radiata. In contrast to larval metamorphosis, feeding and performance of juvenile and adult sea urchins were considerably worse on D. pulchra than on E. radiata.

To our knowledge, there are just few marine drugs that affect gamete maturation by interacting with the cytoskeleton [158–160]: among them, jasplakinolide, a marine compound from sponges, was found to arrest oocytes in vitro maturation acting as a microfilament inhibitor, this also affects fertilisation in mice [161,162]; theonellapeptolide Ie, from Petrosa species, induced malformed maturation through disturbance of cortical F-actin distribution [158]; also strongylophorines, isolated from Strongylophora strongylata, inhibited the maturation of starfish oocytes by affecting actin [160].

Other marine toxins, the latrunculins, produced by certain sponges, including genus Latrunculia, inhibit the microfilament-mediated processes during fertilisation, cleavage and early development in sea urchins and mice [163], even more potent than the cytochalasins [164].

However, not all the compounds from the sponge have the same target: for example, (−)-10-epi-axisonitrile-3, a spirocyclic sesquiterpene isocyanide obtained from the marine sponge Geodia exigua, immobilized sperm of sea urchin and starfish and in turn block fertilisation, by inhibiting the phosphocreatine shuttle participating in the high-energy phosphate metabolism [165]; theonellapeptolide IId, isolated from Theonella swinhoei, prevented fertilisation of sea urchin while has no effect on early embryonic development of fertilised eggs [166]; also jaspisin, isolated from the extract of a marine sponge, Jaspis species, has different properties: it is a selective inhibitor of exoplasmic membrane fusion in echinoderms, blocking fusion between the sperm acrosomal process and the egg plasma membrane, and also embryo hatching [167–169]. Similarly to jaspisin, but differently from 10-epi-Axisonitrile-3, there are other inhibitors of echinoderm fertilisation isolated from sponge, callyspongins A and B [170] and halenaquinol sulfate [171,172], that are able to inhibit sperm-egg fusion without affecting sperm motility [165]. Calyculin-A, originally derived from the marine sponge Discodermia calyx, is similar to okadaic acid in its potent inhibition of protein phosphatases and thus in its impact on reproduction [173,174].

Bacteria, algae and sponges are not the only source of marine products: Agius et al. [175] demonstrated that under illumination bonellin, a compound isolated from Bonellia viridis [176], causes depression of oxygen uptake by spermatozoa and developmental arrest of echinoid and Bonellia eggs. The effect on the eggs may primarily be due to the crosslinking of membrane proteins and to the formation of peroxydase that results in the cytolysis of the unfertilised eggs and in the inhibition of cleavage [177]. Bonellin is able to arrest the motility of swimming larvae of C. intestinalis, but, since the fibrillar structures appear to be unaltered, also this impact seems a consequence of membrane modifications [178].

Recently, spermicidal activity has been found in sea cucumber Bohadschia vitiensis whole-body extracts followed by isolation and characterization of bioactive molecule, bivittoside D, able to induce human sperm membrane permeabilization [179].

Even some early chordates are supposed to be a promising source for marine drugs affecting reproduction processes: methoxyconidiol, extracted from the ascidian Aplidium aff. densum [180], inhibits the cleavage of sea urchin Sphaerechinus granularis and Paracentrotus lividus fertilised eggs: infact, it disrupts M-phase progression and completely blocks cytokinesis without having any effect on DNA replication, most likely by affecting microtubule dynamics [181]. In Table 1, we provide a summary of the significant data described above.

As described above, reproduction is a complex process characterized by many crucial steps. It is clear that every marine compound able to affect in some way one of these events could affect reproduction either in natural setting and in vitro. A good example to better understand the huge potential of marine organisms as drug source is given by marine sponges. The latter have been considered to be a gold mine during the past 50 years, with respect to the diversity of their secondary metabolites [182]. A huge amount of marine products has been described [183–187] and sponges, in particular, are the source of more than 5,300 different products. Every year hundreds of new compounds are being discovered [184–186], leading to identification of novel therapeutic agents showing a broad spectrum of pharmacological activity; therefore, more marine natural products will probably become potential leads for clinical development as novel therapeutic agents for the treatment of multiple disease categories [188–190].

Marine compounds showed different effects on many molecules that are in different ways involved in reproduction, for example, they inhibit protein kinase C [113,191–193], calcium [194–196], sodium [197–201] and potassium channels [202–206]. Similarly, other targets are IP₃ receptors, endoplasmic reticulum calcium pumps [207], microtubules [208–216]; microfilaments [217–221]; and plasma membrane [222,223].

Even though this is not proved yet, we may hypothesize their plausible impact on reproduction on the basis of their molecular targets, either in vivo and in vitro. Over the last few decades significant efforts have been made, by both pharmaceutical companies and academic institutions, to isolate and identify new marine-derived natural products. Because of the diversity in ocean life many new potentially interesting compounds are continuously being discovered.

Despite the risks associated with marine toxins, such as food poisoning or harmful algal blooms, these biogenic compounds have proven their advantage and potential in several fields, particularly as new therapeutic agents for a variety of diseases: in fact, marine ecosystem is an enormously rich source of natural products with promising therapeutic usefulness in oncology, providing anticancer agents with novel mechanisms of action [224–227].

This review reports current understanding of the impacts of compounds from marine organisms on the main reproductive processes and some of their specific mechanisms underlying gametogenesis, fertilisation and very early embryo development. Although most of the data provide evidence that such compounds adversely affect reproductive success, marine drugs may represent a wide source with potential application in improving reproductive fitness.