Existing potentials in Insect Growth Regulators (IGR) for crop pest control

The aim of this review is to explore the potentials existing in insecticides that are considered Insect Growth Regulators (IGR) for the control of insects considered crop pests, with an observation of the main mechanisms of neuroendocrine modifications, development and viability of the species used as study models. The data search on digital platforms, as well as the screening of materials about crop pests, resulted in 74 IGR references and their potentials. The analysis of the information found demonstrated a greater use in works of compounds belonging to chitin synthesis inhibitors class; and orders such as Hemiptera, Lepidoptera, Coleoptera, Orthoptera, Thysanoptera and Diptera were represented in the studies. The main types of activities reunited were morphological and anatomical modifications, reproductive modifications, alterations in developmental stage, alterations in developmental period, ovicidal activity, larvicidal/ninficidal activity and fagoinhibition. The congregated knowledge about the main pests used as study models, the main IGRs compounds and their biological potentials allow an evaluation of their use as an informative source for crop pest control methods.


Introduction
The agricultural sector demonstrates a great contribution in the scope of productivity, being able to be expressed in values relative to ¾ of worldwide economy (FAO, 2013). An insect, when is considered an agricultural pest, has an abundance in its density that cause financial losses in important crops. Sharma et al. (2017) emphasize the damage caused by agricultural pests on a global scale, with an estimated loss of 18-20% in annual production and $ 470 billion.
The use of chemical substances for insect population control, which has as one of its purposes the improvement of economic investment, can often result in environmental toxicity problems (Moreira, et al., 1996). The scientific progress in the last decades have made possible the exploration of alternative methods regarding the regulation of insect development, based on compounds with mechanisms of greater selectivity and less toxicity to non-target organisms; which could overcome problems caused by the use of organochlorine and organophosphate insecticides, characterized as insecticides of the first generations (Faria, 2009).
Insect growth regulators (IGRs) have a role in regulating essential physiological processes in insects; they are not necessarily toxic and may alter specific pathways of hormonal control that are related to molting, metamorphosis and reproduction (Tunaz & Uygun, 2004). Since its potential discovery, credited to the "paper factor" related by Sláma & Williams (1965), IGRs have been commercialized at an industrial level and widely used in pest control. In spite of several of these compounds have been explored in studies, there are few materials that gather information about these substances in a concise way and that show their evaluated potentials, mainly about the study of insect control in agriculture.
Therefore, the aim of this article is to carry out a review of IGRs use in the control of insects considered crop pests, based on the analysis of mechanisms concerning changes in hormonal and developmental pathways, as well as the exploration of the main potentials of existing biological activities, and the quantification and qualification of analyzed data.

Methodology
For the data search, which was made from 2018 to 2020, the platforms Periódicos Capes, National Center for Biotechnology Information (NCBI) and Scientific Electronic Library Online (SciELO) were used. A combination of terms from the main classes of IGRs, mechanisms of action and potentials against agricultural pests was used, such as "ecdysteroid agonists against agricultural pests", where there was an exchange of only the first and second terms according to the IGR class.
Rhodnius prolixus (Hemiptera: Reduviidae)]. Subsequently, a second screening was carried out to reduce the number of sources of IGRs use in agricultural pests, excluding works that took into account insects considered stored product pests [e.g.
The study gathered a total of 107 references and, among them, 74 are specifically about the potential of IGRs in insects considered crop pests. The information includes studies ranging from classic works dating from 1934 to studies of 2019.

Hormonal control modifications by IGRs activities
Insects have physiological processes that are directly related to endocrine centers and integrated and correlated hormonal responses. In neuroendocrine control, represented in Figure 1, the neurosecretory cells (NSC) present in the insect brain consist of neurons that are specialized in hormone production; and that project their axons into a series of endocrine glands and neurohemal organs (Harstenstein, 2006). While the endocrine glands are structures adapted to produce and release hormones in the circulatory system, neurohemal organs are based on the storage of hormone until the neuroendocrine pathways signals mediate its products release (Gullan & Cranston, 2014).
The prothoracicotropic hormone (PTTH) is produced by NCS and stored in the neurohemal organ corpora cardiaca (CC) and, later, it will be released to promote the stimulation of the prothoracic glands and the consequent production of ecdysone (Ec). This Ec is in its inactive form, being converted to a 20-hydroxyecdysone (20HE) in the epidermal cells by 20hydroxylase (Song, et al., 2017), which will circulate in the hemolymph and start a new cycle of division of the epidermal cells to form a new cuticle (Klowden, 2013). The endocrine gland corpora allata (CA) is responsible for the production and release of juvenile hormone (JH), primarily described by Wigglesworth (1934), consisting of a sesquiterpene with the function of inhibiting genes that promote the development of adult characteristics, participating in processes of molting and metamorphosis (Klowden, 2013;Gullan & Cranston, 2014) and, later, in reproductive mechanisms. According to Klowden (2013), the presence of Ec results, in a process of molting, the same type of cuticle; while the absence of JH and the presence of Ec stimulate the reprogramming of epidermal cells to produce specific proteins for the next stage and the completion of metamorphosis process. Research, Society andDevelopment, v. 10, n. 1, e35910111726, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i1.11726  Substances that are characterized as IGRs can interfere with the neuroendocrine balance existing in insects, acting as agonists or antagonists of the hormones involved in the main physiological processes of development. Among the IGRs, there are juvenoids, anti-juvenoids, ecdysteroid agonists and antagonists, chitin synthesis inhibitors and PTTH synthesis inhibitors.
Juvenoids, also known as JH mimics or JH agonists, can prolong nymph/larva/pupa development period by increasing JH levels (Gallo, et al., 2002). Examples of JH analogues are substances such as methoprene and pyriproxyfen, and their capacity for prolonging the larval period is proven (Miranda, et al., 2002).
Anti-juvenoids, also known as JH antagonists or precocenes, were primarily recognized by Bowers et al. (1976) in studies with Oncopeltus fasciatus (Dallas, 1852) (Hemiptera: Lygaeidae), observing effects of nymphs with early development in adults, and sterile adults. They are able to interfere in the synthesis of JH through injuries to CA, maintaining high levels of PTTH and stimulating the reprogramming of epidermal cells for an early metamorphosis process (Gallo et al., 2002).
Hypotheses suggest that there is a competition between anti-juvenoids and JH in the carrier proteins binding, reducing the activity of JH (Staal, 1986;Tunaz & Uygun, 2004). Reports in the literature express the role of precocenes in CA degeneration (Ergen, 2001;Gotoh, et al., 2008); and allatostatins in inhibiting JH synthesis in CA (Woodhead et al., 1989).
Chitin synthesis inhibitors (CSI) comprise a group of substances called benzoylphenylureas, with an inhibitory mechanism in chitin synthetase (Gallo, et al., 2002). According to Tunaz and Uygun (2004), this inhibition can occur in three ways: by inhibiting chitin synthase; by inhibiting proteases that activate chitin synthase; and by inhibiting UDP-Nacetylglucosamine membrane transport. Among the various types of substances known for CSI activity, there are diflubenzuron, triflumuron and lufenuron.
Compounds that act as IGRs have a wide range of action in insect control, representing potential regulators for the development of disease vectors, urban pests and storage products pests. IGRs activities in crop pests can demonstrate several types of biological potentials that will be elucidated below and are also organized and visualized in the Table 1

Data quantification and qualification
The present review demonstrates 45 compounds characterized as IGRs, being cited around 119 times over the 74 references used to compose the study of potentials. Among the existing classes of regulators, CSI proved to be the most explored by the works, accounting for 45.38% of substances with explored potentials. They are compounds that have been widely commercialized for some decades and that show their activities of interference in chitin formation, as well as in insects reproduction and development (Merzendorfer, 2012). Thereafter are JH analogs (16.81%), JH antagonists (12.60%), ecdysteroid agonists (11.76%), azadirachtin and derivatives as PTTH inhibitor representatives (6.72%) and ecdysteroid antagonists (6.72%). Among the most cited substances, diflubenzuron was observed, being represented in nine works; methoxyfenozide, being explored in eight studies; lufenuron and azadiractin, being cited in seven studies each; and novaluron, hexaflumuron, precocene I and pyriproxifen, present in six studies each.
The information obtained about the crop pests used as models in the different studies allows an observation about the main orders and species mentioned. Hemiptera was the largest order explored in the works, with 45.76% of representativeness, followed by Lepidoptera with 33.90%; while Coleoptera obtained 11.86% of expression in the studies, Orthoptera 3.39%, Diptera also 3.39% and Thysanoptera 1.69% of presence. The orders present in this review coincide with those reported by Culliney (2014), which characterizes them as being the most important orders for agricultural pests. Among the species, Spodoptera littoralis (Boisduval, 1833) (Lepidoptera: Noctuidae) was the most used in the studies, being mentioned in nine articles, which can characterize its importance as a source of study for control methods while it demonstrates to be one of the lepidopterans with the greatest economic impact in plantations of cotton, tomatoes, tobacco and maize (CABI, 2019).
Orthoptera demonstrated great relevance in the studies, being represented by insects inserted in economic and historical contexts due to their polyphagy and migration capabilities. Schistocerca gregaria (Foskal, 1775) (Orthoptera: Acrididae) and Locusta migratoria (Linnaeus, 1758) (Orthoptera: Acrididae) appeared in seven and five studies, respectively.
The mechanisms of action exerted by IGRs on crop pests revealed a diversity of biological potentials.
Larvicidal/ninficidal potentials were demonstrated in 27.89% of the results, and morphological/anatomical modifications 23.81%, these being the two major activities found. Reproductive modifications accounted for 18.37% of the results, while fagoinhibitive activities showed 12.24% of the results. Alterations in the development period appeared with 8.84% of representativeness; ovicidal potential were observed in 6.12% of the results; and 2.72% of the data analyzed correspond to alterations in stages of development.

Ovicidal potential
There are methods based on the applicability of IGRs in eggs, in order to assess the effects on their viability and hatching capacity. Juvenoids are types of substances that can express these activities. Ascher and Eliyahu (1988) (Boina, et al., 2009).
Precocenes may also demonstrate ovicidal potential through their mechanisms of JH antagonism, and by acting at different stages of egg development. Pener et al. (1986) evidenced the reduction of JH levels in precocene III treatments in 10-day-old eggs of L. migratoria. Kafi-Farashah et al. (2018), in analyzes of precocene I activity in Eurygaster integriceps (Puton, 1881) (Hemiptera: Scutelleridae), the Sunn pest, showed greater effects of mortality and susceptibility in older eggs.

Larvicidal/ninficidal potential
The use of IGRs to control larvae, nymphs or pupae represents an important strategy to avoid an emergency in reproductively viable adults, affecting the density of insect crops characterized as agricultural pests. Many of these substances can develop toxicity activities when applied to insects at an early stage, affecting their hormone levels and development.   (Eisa, et al., 1991;Perez-Farinos, et al., 1998;Khajepour, et al., 2012;Li, et al., 2014).
JH mimics demonstrate larvicidal/ninficidal activity in the insect orders Lepidoptera and Hemiptera. In lepidopterans, the substances methoprene, pyriproxyfen and fenoxycarb were tested in S. littoralis and Spodoptera frugiperda (J.E. Smith, 1797) (Lepidoptera: Noctuidae), the fall armyworm, with a result of greater toxicity to fenoxycarb in S. littoralis larvae (El-Sheik, et al., 2016). The effectiveness of fenoxycarb was also seen in treatments with P. xylostella, showing high toxicity in third instar larvae (Mahmoudvand & Moharramipour, 2015). In Hemiptera, the activities of a serie of compounds derived from  (Suchy, et al., 1968). Eisa et al. (1991) used C. floridensis as a study model to analyze its development against JH analogues such as fenoxycarb, Pro-done, R-20458 and dofenapine, aiming at preventing the development of nymphs treated with fenoxycarb and dofenapine. Pyriproxyfen expressed lethality in D. citri nymphs, which was not observed in treatments with adults (Boina, et al., 2009).

Potential in reproductive modifications
Substances of IGR activity can exert modifications in mechanisms of insect reproduction, altering not only the reproductive system of males and females but also the fertility, oviposition and eggs hatching.
Ecdysteroid agonists showed responses in lepidopteran agricultural pests. Adel and Sehnal (2000), when analyzing the effects of methoxyfenozide in S.littoralis, reported that the insects that managed to escape the lethality developed in adults with reduced fertility, and a sterility linked to an accumulation of the compound in the body and penetration into the developing gonads. Effects on the reproductive system were also evidenced by Seth et al. (2004), when a treatment with tebufenozide in Spodoptera litura (Fabricius, 1775) (Lepidoptera: Noctuidae), also known as tobacco cutworm, resulted in decrease of reproductive potential of males through the reduction of testicular volume and sperm release. Other mechanisms may be associated by reduction in fertilization, which was speculated by Sun et al. (2003) who, in studies of methoxyfenozide and tebufenozide application in C. pomonella, pointed out the possibility of inhibition in vitelogenic synthesis agonists presented in the fatty body, a translocation of substances in the hemolymph or an absorption by ovary. Exceptions can occur and demonstrate that not all the action exerted by ecdysteroid agonists in fertilization of crop pests is negatively regulated; there are reports that methoxyfenozide has increased not only the fertility in S. littoralis, but also egg laying (Ishaaya, et al., 1995). Oviposition alteration and eggs hatching activities can also demonstrate differences in mode of action. While Seth et al. Among antagonistic activities, the ecdysteroid antagonist cucurbitacin B caused fertility suppression in parental generation of A. gossypii and generated effects that influenced his F1 generation (Yousaf, et al., 2018). JH antagonists can stimulate fertility and eggs maturation, and these data are possible to be visualized in treatments of precocene I in Myzus persicae (Sulzer, 1776) (Hemiptera: Aphididae), known as green peach aphid (Ayyanath, et al., 2015); and in precocene II treatments in S. gregaria (Eid, et al., 1988). On the other hand, Amiri et al. (2010) demonstrated the effects of reduction in laying and hatching eggs of E. integriceps insects submitted to precocene I.
JH analogs expressed the ability to alter the fertility of agricultural pests. While the dofenapine treatment in C.
Transovarian activities related to a low number of nymphs were also seen after the treatment of S. pyrioides adults with azadirachtin (Joseph, 2019). The same substance demonstrated in a treatment with Chaetosiphon fragaefolli (Crockerell, 1901) (Hemiptera: Aphididae), the strawberry aphid, 28% of reduction in fertility (Bernardi, et al., 2012).
Compounds that inhibit chitin synthesis have mechanisms for altering the reproductive system of treated insects. The evaluation of flucycloxuron on the development of Dysdercus koenigii (Fabricius, 1775) (Hemiptera: Pyrrhocoridae), another of the bugs commonly known as cotton stainers, showed effects of reduced fertility, disintegration of follicular epithelium, reduced number of oocytes and an vitelogenesis inhibition (Khan & Qamar, 2011;. Tests with lufenuron presented a sperm reduction in males of Anthonomus grandis Boheman (1843) (Coleoptera: Curculionidae), the boll weevil, as well as ovarian changes in females (Costa, et al., 2017). The same compound was tested in S. gregaria, showing analyzes of ovarian and testicular disruption (Ghazawy, 2012). Tail et al. (2008) observed, in diflubenzuron treatment of S. gregaria, a reduction in eggs number per ootheca and, with the observed results, formulated a hypothesis about the treatment have reduced the ecdysteroids levels in hemolymph, reflecting in ovarian synthesis reduction due to alterations in follicular chambers.
Several CSI demonstrate other types of activity. Novaluron showed effects of reduction in egg viability in L.

Morphological and anatomical modifications generated by IGRs treatments
Insecticides can often have sublethal effects that compromise the morphological and anatomical structures of insects.
Many of the effects reported by IGR for abnormalities of treated insects are related to ecdysis failures and wing deformities, which can constitute mechanisms to block its locomotion, viability and longevity. According to Bransby-Williams (1971), malformations in developmental process can influence the dispersion and reproduction of insects.
Anti-juvenoids demonstrate an influence on wing development process and, according to Hardie et al. (1996), can affect morphogenic pathways of induction or inhibition. Aphids showed sensitivity to JH antagonists regarding alar development, and an inhibition in M. persicae was evaluated by treatment with precocene III (Hales & Mittler, 1981); an induction of a winged offspring for the treatment of precocene I and III in Acyrthosiphon pisum (Harris, 1776) (Hemiptera: Aphididae), known as pea aphid, and Aphis fabae Scopoli (1763) (Hemiptera: Aphididae), known as the black bean aphid (Hardie, 1986); and an induction and inhibition by 2,2-dimethyl chromene and 2,2-dimethyl chroman precocene derivatives treatment in A. pisum (Hardie, et al., 1996). Deformational aspects in wings were observed in Orthoptera, through precocene I treatment in L. migratoria (Pedersen, 1978). Precocene I demonstrates other types of deforming effects in treatments with crop pests, such as the appearance of a poorly developed ventral thoracic portion in L. migratoria (Pedersen, 1978); and the presence of E. integriceps insects with deformities in scutellum, wings, and presenting disproportionately small and narrow abdomen and stomach (Amiri, et al., 2010;Kafi-Farashah, et al., 2018). Precocene II treatment in S. littoralis caused the elongation of treated larvae, and deformations in pupae and adults (Khafagi & Hegazi, 1999). Other alteration activities proposed by precocenes are modifications in the sensory system due to a reduction in the number of sensillae and disturbances in antennae development (Triseleva, 2003), and changes in pigmentation of treated insects (Pedersen, 1978;Eid, et al., 1988).
Different types of deformations could be seen in treatments of JH analogues in insects belonging to Lepidoptera, Hemiptera and Orthoptera. Singh and Kumar (2011), in pyriproxyfen treatments on Papilio demoleus (Linnaeus, 1758) (Lepidoptera: Papilionidae), the lime swallowtail, observed effects that comprised an incomplete detachment of exuvia in ecdysis process, culminating in mortality, and the appearance of an old head capsule linked to the new in some larvae; as well as showing rectal prolapse in larvae, different degrees of melanization in pupae, and deformations in the wings, antennae and legs of adults. Studies of S. litura against pyriproxyfen and diofenolan demonstrated the presence of "larva-pupa mosaics", that is, insects that had altered their development and that acquired both larva and pupa characteristics; in addition to pupae with mouthparts and appendages out of the chrysalis and adults with alterations in wings, legs and genitalia (Singh & Kumar, 2015). migratoria (Cotton & Anstee, 1991) and D. citri (Boina, et al., 2009) in tests with methoprene and pyriproxyfen, respectively.

El
The compound methyl farnesoate dihydrochloride developed modifications in Dysdercus fasciatus (Signoret, 1861) (Hemiptera: Pyrrhocoridae), another cotton stainer, as wings that would be longer than normal, and some insects that had antennae with an extra segment (Critchley & Campion, 1971).
Azadirachtin presented, according to Bernardi et al. (2012), a color change in treated nymphs and mobility reduction, while Mordue and Nisbet (2000) pointed out abnormalities in molting processes of S. gregaria and P. brassicae. In S.
Other effects of methoxyfenozide were reported by Zarate et al. (2009) in S. frugiperda, where larvae treatment reduced not only the size of pupae and females, but also culminated in malformations of wings in adults.
Ecdysteroid antagonists demonstrate few evaluations of morphological changes in studies; however, the work of Bélai & Fekete (2003) serves as a source for this type of potential. In the study of D. cingulatus against azolic compounds, molting failures and insects attached to the old cuticle were reported, in addition to wing deformations that did not cover the entire abdomen. It has been speculated about the performance of 20-HE in wing morphogenesis control, influencing the alar deformations.

Alterations in developmental period
Certain IGRs have mechanisms that modify the insect developmental time, either by delaying the nymph/larva stages or by their prolongation, which constitutes control methods that prevent the appearance of adult insects.
Changes in developmental period are also observed in precocene treatments, showing results of delays in molting and metamorphosis (Chenevert, et al., 1980;Eid, et al., 1988), as well as in treatments with juvenoids and ecdysteroid agonists.
Delays in ecdysis, larval prolongation and decreased pupation time were evidenced in pyriproxyfen applications in P.

Alterations in developmental stage
The ability of juvenoids to keep high the endogenous JH levels can guarantee an appearance of supernumerary nymphs, presenting characteristics of an adult insect, but which are not reproductively mature. In their studies, Singh and Kumar (2015) observed the appearance of adultoids on pyriproxyfen and diafenolan treatments in S. litura, corroborating the characterization of this type of potential in substances similar to JH. The methyl farnesoate dihydrochloride compound was able to stimulate the presence of supernumerary insects of D. cardinalis and D. fasciatus (Bransby-Williams, 1971;Critchley & Campion, 1971). However, the mechanisms that culminate the appearance of supernumerary nymphs have not yet been fully elucidated, and there may even be other compounds capable of inducing these transformations, taking as an example the presence of E. figulilella supernumerary nymphs in treatments with the CSI hexaflumuron and lufenuron (Khajepour, et al., 2012).

Fagoinhibition
Azadirachtin can be considered as one of the main substances studied in terms of the potential for altering insect feeding, integrating inhibitory and physiological processes. According to Mordue and Nisbet (2000), in low concentrations, azadirachtin is capable of expressing changes in chemoreceptors present in mouthparts, triggering a fagoinhibition that will culminate in starve of treated insects. Other compounds can exhibit the same type of activity, being distributed in almost all known classes of IGRs. Adel and Sehnal (2000), in studies with S. littoralis, proved the effects of feeding prevention and death not only in treatments with azadirachtin, but also with the ecdysteroid agonist methoxyfenozide. Methoxyfenozide also demonstrates feeding interruption and weight reduction of S. nonagrioides, in addition to modifications in the digestive tract that restricted food intake (Eizaguirre, et al., 2007). Ascher et al. (1987) analyzed the activity of ecdysteroid antagonists such as withanolide E and 2,3-dihydrowithanolide E in S. littoralis and Epilachna varivestis (Mulsant, 1850) (Coleoptera: Coccinellidae), a pest known as the Mexican bean beetle, and linked the results obtained to a fago-repellency originating a reduction in the consumption of treated leaves or the toxicity exerted by the compounds. Tallamy et al. (1997) performed an analysis of cucurbitacin B activity on various agricultural pests, and came up with a hypothesis about the potential of fagoinhibition for mandibular species and a possible stimulating potential for sucking insects, being used Popillia japonica Newman, 1841 (Coleoptera: Scarabaeidae), known as the Japanese beetle; Cerotoma trifurcata (Foster) (Coleoptera: Chrysomelidae), the bean leaf beetle; Trichoplusia ni (Hubner, 1803) (Lepidoptera: Noctuidae), known as the cabbage looper; Gargaphia solani (Heidemann 1914) (Hemiptera: Tingidae), the eggplant lace bug; Corythucha ciliata (Say, 1832) (Hemiptera: Tingidae), the sycamore lace bug; Peregrinus maidis (Ashmead, 1890) (Hemiptera: Delphacidae), the corn delphacid, Ostrinia nubilalis (Hubner, 1796) (Lepidoptera: Pyralidae), the European corn borer; S. exigua and A. pisum as models of study.

Conclusion
The review demonstrated the different types of potentials existing in IGRs regarding the control of insects considered crop pests. Hormonal deregulation mechanisms were presented, that culminate in the alteration of processes such as development, molting, metamorphosis and reproduction, which would allow a reduction in the density of insects and, consequently, in their economic losses. The knowledge gathered on the main pests used as study models and the main IGR compounds used permit an assessment of their use as a source of information for agricultural pest control methods. Further studies will be conducted to obtain a greater understanding of IGRs and their specific mechanisms of action in the development of insects considered pests.